Culture

A genetically edited form of a herpes simplex virus -- rewired to keep it from taking refuge in the nervous system and eluding an immune response -- has outperformed a leading vaccine candidate in a new study from the University of Cincinnati, Northwestern University and the University of Nebraska-Lincoln.

Published Nov. 6 in the journal Nature Vaccines, the study found that vaccinating guinea pigs with the modified live virus significantly increased the production of virus-combating antibodies. When challenged with a virulent strain of herpes simplex virus, the vaccinated animals displayed fewer genital lesions, less viral replication and less of the viral shedding that most readily spreads infection to others.

The modified virus is actually a form of herpes simplex virus type 1, best known for causing cold sores around the lip. The fact that it demonstrated cross-protection against HSV type 2 -- the sexually transmitted type usually responsible for genital herpes -- suggests that an HSV-2-specific edition of the vaccine could prove even more effective, the researchers said.

The World Health Organization estimates that more than 500 million people have HSV-2, which persists for a lifetime and often flares up in response to stress. In addition to causing blisters, HSV-2 increases the risk for HIV infection and may contribute to Alzheimer's disease or other forms of dementia.

Despite the prevalence of the viruses, more than four decades of research have yet to yield an approved vaccine for HSV-1 or HSV-2. Part of the difficulty: The alphaherpesviruses, which include HSV, have evolved an especially sophisticated way of evading the immune responses aimed at destroying them.

After infecting mucosal tissues of the mouth or genitourinary tract, HSV works its way to the tips of sensory nerves that transmit signals responsible for the sensations of pain, touch and the like. With the help of a specialized molecular switch, the virus then breaks into the nerve cell, hitching a ride on the molecular equivalent of a trolley car that transports it along a nerve fiber and into the nucleus of a sensory neuron. Whereas the mucosal infection is soon cleared by the immune response, the infected neurons become a sanctuary from the body's immune system, with HSV leaving only when stirred by rises in steroids or other stress-elevated hormones in the host.

Nebraska's Gary Pickard and Patricia Sollars, alongside Northwestern's Gregory Smith and Tufts University's Ekaterina Heldwein, have spent years studying how to prevent HSV from reaching the safety of the nervous system. Heldwein advanced those efforts when she characterized the architecture of a certain alphaherpesvirus protein, pUL37, that the team suspected was integral to the virus moving along nerve fibers. Computer analyses based on that architecture suggested that three regions of the protein might prove important to the process.

Smith then carefully plucked out and replaced five codons, the fundamental coding information in the DNA, from the viral genome of each region. The researchers hoped that those mutations might help impede the virus from invading the nervous system.

Their hopes were rewarded when Pickard and Sollars injected mice with a virus modified in region 2, or R2, of the protein. Rather than advancing deeper into the nervous system, the virus was stuck at the nerve terminal. But the team also knew that modifying HSV could have unintended consequences.

"You can keep the virus from getting into the nervous system," said Pickard, professor of veterinary medicine and biomedical sciences at Nebraska. "That's not that hard to do by making broadly debilitating mutations. But when you knock down the virus so much that it doesn't replicate well, you are not rewarded with a robust immune response that can protect you from future exposures."

So the researchers were heartened when further studies showed that the R2-mutated virus performed well as a vaccine in mice. Moreover, it circumvented certain stubborn issues that have cropped up with other vaccine approaches. Some approaches have involved challenging the immune system with only a subset of HSV components, or antigens, priming the body to recognize them but potentially miss others. Some have modified the virus so that it can replicate just once, preventing long-term persistence in the nervous system but also reducing spread in mucosal tissues and, by extension, a stout immune response.

"So it's the same story over and over again: Either your subunit vaccine doesn't present enough antigens, or you make the live virus essentially so sick that it doesn't work really well to generate an immune response," Pickard said. "That's why we're so optimistic about our R2 platform, because it avoids all those problems."

David Bernstein, a researcher at Cincinnati Children's Hospital Medical Center who evaluates herpesvirus vaccine candidates through a program supported by the National Institutes of Health, took note of the team's success and reached out to Northwestern's Smith in 2018. Armed with an R2-modified form of HSV-1, Bernstein decided to test its effectiveness against HSV-2 infection in guinea pigs. As promising as their prior results had been, Pickard conceded that he wasn't sure an HSV-1 vaccine would be up to the task of generating immunity against HSV-2.

But just one of the dozen R2-inoculated guinea pigs developed acute lesions after being injected with HSV-2, compared with five of 12 animals receiving another promising vaccine candidate that recently failed a human clinical trial. Whereas that latter vaccine candidate had no discernible effect on the number of days that guinea pigs shed the virus, the team's R2 vaccine cut the shedding period from 29 days to about 13. And unlike the guinea pigs receiving no vaccine or the other candidate, those receiving the R2 vaccine showed no sign of HSV-2 in the cluster of brain cells that normally house it. Neutralizing antibodies, meanwhile, registered about three times higher in the R2-inoculated guinea pigs than in those inoculated with the other vaccine candidate.

"The fact that the viral shedding was knocked down so much with the R2 vaccine is really important, because it's the viral shedding -- even if it doesn't cause lesions -- that can then pass on the virus," Pickard said. "If you have genital herpes, you can pass that on to your significant other, not knowing that you're doing it. It's very problematic. So the fact that the shedding was knocked down so much is a really good sign."

With an HSV-1 version of the R2 vaccine showing such promising cross-protection against its sexually transmitted counterpart, the researchers' to-do list now includes making and testing an HSV-2 vaccine against the HSV-2 virus.

"If you're making antibodies against the proteins of that particular virus, it stands to reason (that) it would work better than if you're making an antibody against something that's slightly different," he said. "So that's our expectation."

'IT'S GOING TO HAVE A BIG IMPACT'

Around the time that Bernstein and his NIH program were expressing interest in the R2 vaccine design, Pickard and Smith were launching a startup, Thyreos LLC, aimed at further developing and eventually licensing their R2 vaccine design.

Fittingly for a couple of researchers based in Nebraska and Illinois, the duo is working on vaccines for livestock -- cattle and hogs, specifically -- that contend with alphaherpesviruses of their own. In cattle, the bovine herpesvirus can cause respiratory disease, curb appetite and even contribute to aborted calves, all of which add up to billions of dollars in lost revenue annually. Though a modified live-virus vaccine for cattle does exist, it also gets into the bovine nervous system. And that, Pickard said, can spell trouble in cattle just as easily as in people.

"What happens, then, is that when those cows are loaded on a truck and shipped to a feedlot, it's a stressful environment," he said. "The virus hiding in the immune system reactivates. They start shedding the virus from excretions in their nose, and they can then pass that virus on to other animals in that feedlot, and the cattle can get respiratory disease.

"So the fact that our R2-modified viruses don't enter the nervous system is not just an academic thing. Actually, it has a real, practical application for the cattle industry."

As they prepare to embark on a new series of studies that they hope will show the R2 design's superiority to the current industrywide vaccine, Pickard and Smith are also kicking off an initial round of seed funding for the enterprise.

Given that the team initially developed its R2 design in the alphaherpesvirus that infects pigs -- the so-called pseudorabies virus -- Pickard also expressed confidence in the design's promise for protecting hogs. In the late 1990s and early 2000s, the United States waged a successful campaign to eradicate pseudorabies from the country, in large part through vaccination. As with cattle, though, the vaccine can enter the nervous system of hogs and has proven less successful in countries that are less vigilant about outbreaks.

"Again, we are pretty confident that our pseudorabies virus R2 vaccine is going to be more effective than what's been out there," Pickard said. "In terms of protecting pigs, it's going to have a big impact at some point.

"These pathogens can survive trans-Pacific transport in feed ingredients or feed products. When you talk to people who are concerned about biosecurity, they say that whatever is going on elsewhere in the world in terms of these viruses, eventually, they may show up here. It's just a matter of time."

A small team of astronomers have found a new way to 'see' the elusive dark matter haloes that surround galaxies, with a new technique 10 times more precise than the previous-best method. The work is published in Monthly Notices of the Royal Astronomical Society.

Scientists currently estimate that up to 85% of the mass in the universe is effectively invisible. This 'dark matter' cannot be observed directly, because it does not interact with light in the same way as the ordinary matter that makes up stars, planets, and life on Earth.

So how do we measure what cannot be seen? The key is to measure the effect of gravity that the dark matter produces.

Pol Gurri, the PhD student at Swinburne University of Technology who led the new research, explains: "It's like looking at a flag to try to know how much wind there is. You cannot see the wind, but the flag's motion tells you how strongly the wind is blowing."

The new research focuses on an effect called weak gravitational lensing, which is a feature of Einstein's general theory of relativity. "The dark matter will very slightly distort the image of anything behind it," says Associate Professor Edward Taylor, who was also involved in the research. "The effect is a bit like reading a newspaper through the base of a wine glass."

Weak gravitational lensing is already one of the most successful ways to map the dark matter content of the Universe. Now, the Swinburne team has used the ANU 2.3m Telescope in Australia to map how gravitationally lensed galaxies are rotating. "Because we know how stars and gas are supposed to move inside galaxies, we know roughly what that galaxy should look like," says Gurri. "By measuring how distorted the real galaxy images are, then we can figure out how much dark matter it would take to explain what we see."

The new research shows how this velocity information enables a much more precise measurement of the lensing effect than is possible using shape alone. "With our new way of seeing the dark matter," Gurri says, "we hope to get a clearer picture of where the dark matter is, and what role it plays in how galaxies form."

Future space missions such as NASA's Nancy Grace Roman Space Telescope and the European Space Agency's Euclid Space Telescope are designed, in part, to make these kinds of measurements based on the shapes of hundreds of millions of galaxies. "We have shown that we can make a real contribution to these global efforts with a relatively small telescope built in the 1980s, just by thinking about the problem in a different way," adds Taylor.

ATLANTA -- New research shows that corticosteroid injections for knee OA treatment do not hasten a patient's progression to a total knee replacement when compared with hyaluronic acid injections. Details of this study was presented at ACR Convergence, the American College of Rheumatology's annual meeting (ABSTRACT #1652).

Osteoarthritis (OA) is a common joint disease that most often affects middle age to older people. It is commonly referred to as "wear and tear" of the joints, but it is now known that OA is a disease of the entire joint, involving the cartilage, joint lining, ligaments, and bone. OA is characterized by breakdown of the cartilage, bony changes of the joints, deterioration of tendons and ligaments, and various degrees of inflammation of the joint lining, or synovium.

The researchers wanted to know if corticosteroid injections for knee OA sped up the progression of the disease, leading to a need for total knee replacement surgery sooner. Recent research suggests that steroid injections have a threefold-higher risk of progression for people with knee OA. However, many patients in this and other studies of corticosteroid therapy have more advanced knee arthritis, which is a risk factor for disease progression in and of itself. To clarify the potential risks of steroid injections for knee OA progression, this new study compared steroid injections to hyaluronic acid injections, which is not associated with cartilage loss.

"The treatment options we have for knee OA are limited. Weight loss can reduce pain from knee OA and delay progression of disease, but this is very difficult for most patients to achieve," says the study's co-author, Justin J. Bucci, MD, assistant professor of medicine at Boston University School of Medicine. "Pain medications cannot be used safely by many patients with OA because of co-existing heart or kidney disease. Steroid injections are considered a safe and effective intervention for relieving pain from knee OA. Recent studies have raised the possibility that steroid injections are associated with progression of OA. Clinicians and patients need to know if steroid injections are making knee OA worse so they can make informed decisions about their treatment."

The researchers used two large cohort studies of people with knee OA who received either corticosteroid or hyaluronic acid injections. They reviewed the rates of radiographic progression, or joint damage seen on X-rays, and total knee replacement surgery. Patients in the first cohort had medical visits every 12 months, and those in the second cohort had visits every 30 months. Their exams included knee X-rays and questions about their steroid or hyaluronic acid injections over the previous six months. Knee OA progression was measured using two standard scores Kellen and Lawrence grades (KL) and medial joint space narrowing, both of which are radiographic measures

When they analyzed X-ray progression, the researchers excluded anyone with a baseline KL 4 score and anyone who had received either corticosteroid or hyaluronic acid injections in the past. They compared X-rays from each patient's medical visits before their first injection to those taken after their last injection. They assigned KL and joint space narrowing scores to each X-ray at medical visits where total knee replacement surgery was prescribed.

In all, the researchers analyzed 792 knees, including 647 treated with corticosteroid injections and 145 with hyaluronic acid injections. They found that the rate of total knee replacement surgery was greater among patients with a single exam where they reported hyaluronic acid injection compared to those with a single exam where they reported corticosteroid injection. They did not find a difference in those patients reporting injections at multiple exams. Further analysis showed similar rates of X-ray progression for both injection treatments at either single or multiple medical exams.

Corticosteroid injections are not associated with higher risk of two key signs of worsening knee osteoarthritis, either radiographic progression or progression to a total knee replacement, compared to hyaluronic acid injections, the study's findings show.

"We did not find any association between steroid injections and worsening knee OA in our study. Patients and clinicians should see this study and feel reassured that these injections are not causing progression of OA or earlier total knee replacement," says Dr. Bucci. His group's future research will focus on magnetic resonance imaging (MRI) of knees undergoing steroid injection treatment for OA. "MRI provides a more detailed look at structures within the knee compared to X-rays and these images were obtained as part of the cohorts we studied. This information will add to the findings from our current study, and give patients and clinicians a better understanding of what happens to knees treated with steroid injections."

ATLANTA -- New research presented at ACR Convergence, the American College Rheumatology's annual meeting, reveals that romosozumab, an osteoporosis drug, produces substantial gains in bone mineral density in the hip and lumbar spine within one year, and that transitioning patients to a potent antiresorptive drug can lead to even more bone density gains (ABSTRACT #1973).

Osteoporosis results from a loss of bone mass, measured as bone mineral density (BMD), and from a change in bone structure. Many factors will raise your risk of developing osteoporosis and breaking a bone. Bone is living tissue that is in a constant state of regeneration. The body removes old bone (called bone resorption) and replaces it with new bone (bone formation).

Earlier studies have shown that another bone building medication, teriparatide, which stimulates both bone formation and bone breakdown, boosts BMD in both the spine and hip when used first, followed by an antiresorptive drug. However, when antiresorptive drugs are given first, particularly bisphosphonates, such as alendronate, and denosumab, the effect of teriparatide is different, and a patient's BMD may decline in their hips.

To find out more about how romosozumab may be given in sequence with different antiresorptive drugs, researchers launched this new study that reviewed results from four recent, large-scale trials.

"Romosozumab exerts a unique mechanism of action on bone tissue. It increases bone formation and decreases bone resorption. When it's given as initial therapy for one year, followed by an antiresorptive medication such as alendronate or densosumab, the treatment sequence significantly increases BMD and reduces fracture risk compared to both placebo and alendronate treatment," says the study's co-author, Felicia Cosman, MD, professor of medicine at Columbia University College of Physician and Surgeons in New York City. "This study was designed to determine if, despite the different mechanism of action for romosozumab versus teriparatide, the effect on BMD would be different when romosozumab was given as the second treatment, after an antiresorptive medication, compared to using romosozumab first."

The researchers found that osteoporosis patients had noticeably different results when romosozumab was administered first, rather than after, an antiresorptive treatment. In the two studies where romosozumab was given first, over the year of romosozumab treatment, patients' total hip BMD increased 6% in one study and 6.2% in the other. In contrast, when they took alendronate first, the total hip BMD increased only 2.9% with romosozumab treatment. When denosumab was given first, the total hip BMD increased only 0.9% with romosozumab administration.

Over two years, when romosozumab was followed by alendronate, the 2-year total hip BMD gain was 7.1% and when romosozumab was followed by denosumab, the 2-year total hip BMD gain was 8.5%. In contrast, with the inverse sequence, when denosumab was given first, followed by romosozumab, the 2-year total hip BMD gain was less than half - only 3.8%.

What about the effect of different treatment sequences on bone density in the lumbar spine? The researchers found similar results here. Over one year, when romosozumab was given first, patients' spine BMD increased 13.7% in one study and 13.1% in the other. When romosozumab was given after alendronate, lumbar spine BMD gain was 9.8%. When romosozumab was given after denosumab, the spine BMD gain was only 5.3%.

Similarly, over two years, when romosozumab was followed by alendronate, two-year spine BMD gain was 15.2%, and when romosozumab was followed by denosumab, two-year spine BMD gain was 16.6%. When denosumab was followed by romosozumab, two-year spine BMD gain was lower, at 11.5%.

Because women who have had recent or multiple fractures in adulthood are at very high risk for more, this data could help both osteoporosis patients and their doctors make more effective preventive treatment choices, says Dr. Cosman.

"These women need medication that can build BMD fast to improve bone strength and reduce the risk of fractures. The standard approach that most health care providers use is to start treatment with antiresorptive medicine. However, bone building agents like romosozumab, abaloparatide and teriparatide reduce fracture risk faster than antiresorptive medicines. There are about two million fractures every year from osteoporosis," she says. "Patients need to know that the best option for them might be to receive a bone building medication first, rather than an antiresorptive treatment."

ATLANTA -- New research shows that children with Kawasaki Disease remain at an increased risk for cardiovascular events more than 10 years after hospitalization for their condition, highlighting the need for long-term heart disease surveillance and risk reduction strategies for these young patients. Details of the study was presented at ACR Convergence, the American College of Rheumatology's annual meeting (ABSTRACT #0937).

Kawasaki disease (KD) is a childhood illness that causes blood vessels to become inflamed (vasculitis) and swell. KD is most common in children younger than five years old; however, older children can be affected too. Its exact cause is unknown. Without prompt medical evaluation and treatment, serious damage to the blood vessels of the heart may develop. KD is associated with coronary artery aneurysms.

Researchers in Ontario, Canada noticed that the incidence of KD has significantly increased in their province over the past two decades. However, the risk of long-term cardiovascular events after childhood KD diagnosis remains unknown. They launched this study to determine the risk and timing of long-term cardiovascular events and death among KD survivors.

"The motivation to perform this study came from a conversation I had with a patient's family as a first-year pediatric resident. Their child had been diagnosed with KD and was almost ready to be discharged from the hospital. They asked me whether their child would be at risk of heart disease later in life," says study co-author Cal Robinson, MD, BSc, Pediatric Nephrology Resident at The Hospital for Sick Children and the University of Toronto. "Not knowing the answer, I dug deeper into the published literature about cardiovascular outcomes after KD and found that a significant knowledge gap existed, particularly in children who did not develop coronary artery aneurysms during their acute illness. It's very important that we better understand the cardiovascular risk after childhood KD. Earlier diagnosis provides opportunities for intervention, which may mitigate the risk of heart disease later in life."

The researchers identified all children up to 18 years of age who survived hospitalization for KD in Ontario between 1995-2018 using health administrative databases. They included only the first eligible hospitalization, excluding children who were previously diagnosed with KD, as well as non-residents of Ontario. They matched each KD case to 100 non-exposed control cases by age, sex and year. They then followed these patients until death or March 2019, or up to 24 years old. They determined the rates of cardiovascular events, major adverse cardiac events (such as heart attack or stroke) and death, comparing children who had KD with those who were not exposed to the disease. They looked specifically at four time periods after hospital discharge: 0-1 year, 1-5 years, 5-10 years and more than 10 years.

They found that, among 4,597 KD survivors, 746 or 16.2% experienced cardiovascular events compared with 5.2% of children without the disease. They also found that 79 or 1.7% experienced major adverse cardiac events compared to 0.7% of children without the disease, and nine died during the median 11-year follow-up period. The most frequent cardiovascular events experienced by KD survivors were ischemic heart disease, arrhythmias, high blood pressure and peripheral vascular disease. KD survivors were at higher risk of heart problems compared to patients who did not have the disease and they experienced cardiovascular events sooner. Their risk was highest in the first year after they were discharged from the hospital. They were also at higher risk of heart surgery like coronary artery bypass grafting. However, their risk of death during follow-up was lower than non-exposed patients.

"Our study results provide a signal that KD survivors have a higher risk of developing heart disease more than ten years after their initial diagnosis. This suggests that KD survivors should be screened at regular intervals for cardiovascular diseases and associated risk factors," says Dr. Robinson. "Cardiovascular risk reduction strategies should be implemented for all KD survivors, including healthy active lifestyle counselling and early intervention when cardiovascular risk factors are identified."

ATLANTA -- A new study shows that patients with rheumatic diseases across Africa, Southeast Asia, the Americas and Europe had trouble filling their prescriptions of antimalarial drugs, including hydroxychloroquine, during the 2020 global coronavirus pandemic, when antimalarials were touted as a possible COVID-19 treatment. Patients who could not access their antimalarial drugs faced worse physical and mental health outcomes as a result. Details of the research was presented at ACR Convergence, the American College of Rheumatology's annual meeting (ABSTRACT #0007).

Systemic lupus erythematosus, also called lupus or SLE, is a chronic (long-term) disease that causes systemic inflammation which can affect multiple organs: the skin, joints, kidneys, the tissue lining the lungs (pleura), heart (pericardium) and brain. Many patients experience fatigue, weight loss and fever. Antimalarial drugs are taken regularly by most people with lupus, as well as many with rheumatoid arthritis (RA) and other rheumatic diseases.

In the early weeks of the global SARS-CoV-2 (COVID-19) pandemic, two antimalarial drugs often used to treat lupus and RA, hydroxychloroquine and chloroquine, were touted to potentially prevent or treat COVID-19 infections. Both drugs were suddenly repurposed as COVID-19 treatments despite a lack of data to support this use, leading to worldwide shortages of both. A team of international researchers launched this study to assess the effects of antimalarials on COVID-19 infection and the impact of drug shortages on people with rheumatic disease.

"The COVID-19 Global Rheumatology Alliance's Patient Experience Survey was launched in April 2020 during the early days of the pandemic, when the scientific and research communities were under extraordinary pressure to identify safe and effective treatments for SARS-CoV-2. Since hydroxychloroquine is an essential treatment for RA and lupus, reported drug shortages of antimalarials became a major concern," says the study's lead author, Emily Sirotich, a doctoral student at McMaster Centre for Transfusion Research in Hamilton, Ontario. and Patient Engagement Lead of the COVID-19 Global Rheumatology Alliance. "The aims of this study were to assess the prevalence and impact of drug shortages during the COVID-19 pandemic, and whether the use of antimalarials in patients with rheumatic disease was associated with a lower risk of COVID-19 infection."

Data for the new study was collected using the COVID-19 Global Rheumatology Alliance Patient Experience Survey. The survey was distributed online through patient support organizations and social media. Both patients with rheumatic diseases and parents of pediatric patients anonymously completed the surveys with information on their rheumatic disease diagnosis, medications they take, COVID-19 status and any disease outcomes. The researchers evaluated the impact of antimalarial drug shortages on patients' disease activity, as well as their mental health and physical health.

Of the 9,393 people who responded to the survey, 3,872 were taking antimalarial drugs and 230 said they were unable to continue taking their medications because of a lack of supply at their pharmacy. Antimalarial shortages were worse for people in Africa and Southeast Asia: 26.7% of respondents in Africa and 21.4% of respondents in Southeast Asia reported inadequate supplies at local pharmacies. Patients in the Americas (6.8%) and Europe (2.1%) also reported being unable to fill their prescriptions at their pharmacy due to lack of supply.

The study found that patients on antimalarials and those who did not take these drugs had similar rates of COVID-19 infection. A total of 28 patients with COVID-19, who were also taking antimalarials, were hospitalized. Of 519 patients diagnosed with COVID-19 in the survey, 68 reported that they were prescribed an antimalarial for their coronavirus infection. Patients who could not fill their antimalarial prescriptions experienced higher levels of disease activity and also experienced worse mental and physical health symptoms, the study found.

"The findings from this study highlight the harmful consequences of repurposing antimalarials, without adequate evidence for benefit, on patients who rely on access to their hydroxychloroquine or chloroquine prescriptions for their rheumatic diseases," says Ms. Sirotich. "It is necessary to maintain scientific rigor even in the context of a pandemic and recognize the potential impacts of drug shortages. It is also important to address regional disparities in access to medications, to ensure all people, particularly those living in developing countries, receive fair and equitable access to their essential medications."

Researchers at the Francis Crick Institute and University College London have found that some antibodies, created by the immune system during infection with common cold coronaviruses, can also target SARS-CoV-2 and may confer a degree of protection against the new viral strain.

In response to infection with a virus, the immune system creates antibodies to help fight it. These antibodies remain in the blood for a period after infection, and in the case of re-infection, they are able to tackle the virus again.

In their paper, published in Science today (Friday 6 November), the scientists found that some people, notably children, have antibodies reactive to SARS-CoV-2 in their blood, despite not ever having being infected with the virus. These antibodies are likely the result of exposure to other coronaviruses, which cause a common cold and which have structural similarities with SARS-CoV-2.

The researchers made this discovery while developing highly sensitive antibody tests for COVID-19. To see how well their assay tests were performing, they compared the blood of patients with COVID-19 to patients who had not had the disease. Surprisingly, they found that some people who had not been exposed to SARS-CoV-2 had antibodies in their blood which would recognise the virus. To confirm their findings, they analysed over 300 blood samples collected before the pandemic, between 2011 and 2018.

Nearly all samples had antibodies that reacted with common cold coronaviruses, which was expected given how everyone has been exposed to these viruses at some point in their lives. However, a small fraction of adult donors, about 1 in 20, also had antibodies that cross-reacted with SARS-CoV-2, and this was not dependent on recent infection with a common cold coronavirus.*

Notably, such cross-reactive antibodies were found much more frequently in blood samples taken from children aged 6 to 16.

Kevin Ng, lead author and post-graduate student in the Retroviral Immunology Laboratory at the Crick says: "Our results show that children are much more likely to have these cross-reactive antibodies than adults. More research is needed to understand why this is, but it could be down to children being more regularly exposed to other coronaviruses.

"These higher levels we observed in children could also help explain why they are less likely to become severely ill with COVID-19. There is no evidence yet, however, that these antibodies prevent SARS-CoV-2 infection or spread."

In the lab, the researchers tested the antibodies they found in blood from uninfected people to confirm they are able to neutralise SARS-CoV-2. They found the cross-reactive antibodies target the S2 subunit of the spike protein on the surface of the virus.

George Kassiotis, senior author and group leader of the Retroviral Immunology Laboratory at the Crick says: "The spike of this coronavirus is made of two parts or subunits, performing different jobs. The S1 subunit allows the virus to latch onto cells and is relatively diverse among coronaviruses, whereas the S2 subunit lets the virus into cells and is more similar among these viruses. Our work shows that the S2 subunit is sufficiently similar between common cold coronaviruses and SARS-CoV-2 for some antibodies to work against both.

"It was previously thought that only antibodies to the S1 could block infection, but there is now good evidence that some antibodies to S2 can be just as effective. This is exciting as understanding the basis for this activity could lead to vaccines that work against a range of coronaviruses, including the common cold strains, as well as SARS-CoV-2 and any future pandemic strains.

"But it is important to stress that there are still many unknowns which require further research. For example, exactly how is immunity to one coronavirus modified by exposure to another? Or why does this activity decline with age? It is not the case that people who have recently had a cold should think they are immune to COVID-19."

A large study is now underway, in partnership with researchers at Imperial College London and University College London, to uncover the role that different antibodies and other immune defences play in protection against COVID-19 and how severely ill people become.

ATLANTA -- New research at ACR Convergence, the American College of Rheumatology's annual meeting, reveals that people of color with rheumatic disease have worse health outcomes from COVID-19 infection, are more likely to be hospitalized to treat their coronavirus infection, and are more likely to require invasive ventilator treatment (ABSTRACT #0006).

COVID-19 is the disease caused by the novel SARS-CoV-2 coronavirus. As part of the response to the global pandemic, the rheumatology community launched the COVID-19 Global Rheumatology Alliance physician registry, an international collection of data on patients with rheumatic diseases who have been diagnosed with COVID-19. These data have been used for a number of studies that clarify how people with rheumatic diseases, many of whom take immunosuppressant drugs to control their conditions, are affected by COVID-19.

People with rheumatic disease, particularly those on immunosuppressants, are may be at higher risk for severe infections. What doctors and their patients do not know is why.. This new study used the data collected in the registry to determine if patients are more likely to experience more severe outcomes from COVID-19, and to learn if COVID-19 health outcomes vary by race and ethnicity for patients in the United States (U.S.).

"At the time we were examining data from the registry, there was growing attention on the disproportionate impact of COVID-19 among racial/ethnic minorities in the U.S.," says study co-author Milena Gianfrancesco, PhD, MPH, Assistant Adjunct Professor at the University of California, San Francisco School of Medicine. "We know that racial/ethnic minority rheumatic disease patients experience higher risk and disease severity in general. We were interested in examining whether the inordinate burden of COVID-19 also affected this susceptible population. Understanding disparities in COVID-19 outcomes can help us identify vulnerable populations and ensure that patients at high risk are adequately tested and treated."

The study included 694 U.S. patients who were defined as white, Black, Latinx or other race/ethnicity from the global rheumatology registry from March 24 to May 22, 2020. The researchers examined COVID-19 outcomes, including whether patients were hospitalized, required ventilation support such as supplementary oxygen and/or invasive ventilation, and if they died or survived their coronavirus infection. They controlled the data for age, sex, smoking status and rheumatic disease diagnoses (including rheumatoid arthritis, lupus, psoriatic arthritis, ankylosing spondylitis and others). They also controlled data for other common health problems that affect people with rheumatic diseases, such as cardiovascular disease, hypertension, lung disease, diabetes, and chronic renal insufficiency or end-stage renal disease. They also looked at arthritis medications that patients used, including immunosuppressants. The study's data also included each patient's level of rheumatic disease activity, or if their inflammatory arthritis was in remission, low, moderate or high.

According to the study's findings, people with rheumatic disease who are of racial or ethnic minorities were more likely to experience poor health outcomes from COVID-19 infection, including hospitalization and necessary ventilation support, compared to white patients. Black and Latinx patients had 2.7 and 1.98 higher odds, respectively, of needing hospitalization for COVID-19 compared to whites. Black and Latinx patients had threefold increased odds of needing ventilation support compared to whites. The study found no differences in mortality rates based on race or ethnicity.

"Bringing these results to light will hopefully lead to actionable changes within the rheumatology community and beyond," says Dr. Gianfrancesco. "We need to be sure that patients who are at high risk of severe COVID-19 outcomes have access to testing, treatment and a vaccine when one is eventually available. I would also add that rheumatology providers can be advocates and trusted allies for their patients. They can ensure that patients are aware of disease risks by providing materials in multiple languages."

A short online game in which players are recruited as a "Chief Disinformation Officer", using tactics such as trolling to sabotage elections in a peaceful town, has been shown to reduce susceptibility to political misinformation in its users.

The free-to-play Harmony Square is released to the public today, along with a study on its effectiveness published in the Harvard Misinformation Review.

It has been created by University of Cambridge psychologists with support from the US Department of State's Global Engagement Center and Department of Homeland Security Cybersecurity and Infrastructure Security Agency (CISA).

The gameplay is based on "inoculation theory": that exposing people to a weak "dose" of common techniques used to spread fake news allows them to better identify and disregard misinformation when they encounter it in future.

In this case, by understanding how to incite political division in the game using everything from bots and conspiracies to fake experts, players get a form of "psychological vaccine" against the product of these techniques in the real world.

"Trying to debunk misinformation after it has spread is like shutting the barn door after the horse has bolted. By pre-bunking, we aim to stop the spread of fake news in the first place," said Dr Sander van der Linden, Director of the Cambridge Social Decision-Making lab and senior author of the new study.

Twitter has started using a "pre-bunk" approach: highlighting types of fake news likely to be encountered in feeds during the US election. However, researchers argue that familiarising people with techniques behind misinformation builds a "general inoculation", reducing the need to rebut each individual conspiracy.

In the 10-minute game Harmony Square, a small town neighbourhood "obsessed with democracy" comes under fire as players bait the square's "living statute", spread falsehoods about its candidate for "bear controller", and set up a disreputable online news site to attack the local TV anchor.

"The game itself is quick, easy and tongue-in-cheek, but the experiential learning that underpins it means that people are more likely to spot misinformation, and less likely to share it, next time they log on to Facebook or YouTube," said Dr Jon Roozenbeek, a Cambridge psychologist and lead author of the study.

Over the course of four short levels, users learn about five manipulation techniques: trolling to provoke outrage; exploiting emotional language to create anger and fear; artificially amplifying reach through bots and fake followers; creating and spreading conspiracy theories; polarizing audiences.

In a randomized controlled trial, researchers took 681 people and asked them to rate the reliability of a series of news and social media posts: some real, some misinformation, and even some faked misinformation created for the study, in case participants had already come across real-world examples.

They gave roughly half the sample Harmony Square to play, while the other half played Tetris, and then asked them to rate another series of news posts.

The perceived reliability of misinformation dropped an average of 16% in those who completed Harmony Square compared to their assessment prior to playing. The game also reduced willingness to share fake news with others by 11%. Importantly, the players' own politics - whether they leaned left or right - made no difference.

Having the "control group" who played Tetris allowed the scientists to determine an "effect size" of 0.54 for the study, said Van der Linden.

"The effect size suggests that if the population was split equally like the study sample, 63% of the half that played the game would go on to find misinformation significantly less reliable, compared to just 37% of the half left to navigate online information without the inoculation of Harmony Square," he said.

The project follows other playful attempts by CISA to illustrate how "foreign influencers" use disinformation to target "hot button" issues. A previous demonstration took the example of whether pineapple belongs on pizza.

However, Harmony Square is based on the findings of a number of studies from the Cambridge team showing how similar gamified approaches to digital literacy significantly reduce susceptibility to fake news and online conspiracies.

The team behind the game, which includes the Dutch media agency DROG and designers Gusmanson, have recently worked with the UK Cabinet Office on Go Viral!, an intervention that specifically tackles conspiracies around COVID-19.

Harmony Square is geared towards the politically charged misinformation that has plagued many democracies over the last decade. "The aftermath of this week's election day is likely to see an explosion of dangerous online falsehoods as tensions reach fever pitch," said Van der Linden.

"Fake news and online conspiracies will continue to chip away at the democratic process until we take seriously the need to improve digital media literacy across populations. The effectiveness of interventions such as Harmony Square are a promising start," he said.

The combined environmental threat of plastic pollution and ocean acidification are having significant impacts on species living in our oceans, according to new research.

An international team of scientists found that after three weeks of being submerged in the ocean, the bacterial diversity on plastic bottles was twice as great as on samples collected from the surrounding seawater.

However, in areas of elevated carbon dioxide, a large number of taxonomic groups - including bacteria that play an important role in carbon cycling - were negatively impacted.

Conversely, other species - including those have previously been shown to thrive in areas of high ocean plastics and to potentially cause disease on coral reefs - were enriched by it.

The research also showed that while many groups of bacteria were shared between plastic, free-living and particle-associated samples, almost 350 were found uniquely on plastics.

Writing in the journal Marine Pollution Bulletin, researchers say the study adds to growing evidence that the increasing presence of plastic marine debris is providing a novel habitat for bacteria.

However, their results highlight that environmental conditions and local ecological processes will play an important role in determining its broader impact over the coming decades.

The study was led by the University of Tsukuba (Japan) and the University of Plymouth (UK), in collaboration with Keimyung University (Korea), Kyungpook National University (Korea) and Nanjing University (China).

Scientists submerged a number of plastic bottles in seas off the Japanese Island of Shikine, a region renowned for its CO2 seeps where the escaping gas dissolves into the sea water and creates conditions similar to that expected to occur worldwide in coming years.

They then used a combination of DNA sequencing and statistical techniques to analyse how bacteria colonise the plastic in comparison to the surrounding natural environment, and whether the increased CO2 levels would cause changes in the bacteria's distribution.

Lead author Dr Ben Harvey, Assistant Professor at the University of Tsukuba's Shimoda Marine Research Center and a graduate of the BSc (Hons) Ocean Science programme in Plymouth, said: "Discarded plastic drinking bottles have become a common sight in our oceans and we were expecting to see them being colonised by different types of bacteria. We also predicted that raised CO2 levels would cause significant changes in the bacterial colonies, but it was still surprising to see the extent of that change and how the raised levels affected species differently. To see beneficial species dwindling while harmful species thrive is an obvious present and future cause for concern."

Researchers from Tsukuba, Plymouth and other collaborators have published several studies over the past decade showing the threats posed by ocean acidification in terms of habitat degradation and a loss of biodiversity.

It is also the latest research by the University of Plymouth into plastics, with it being awarded a Queen's Anniversary Prize for Higher and Further Education in 2020 for its ground-breaking research and policy impact on microplastics pollution in the oceans.

Jason Hall-Spencer, Professor of Marine Biology at the University of Plymouth and senior author on the study, added: "Up to 13 million tons of plastics from land end up in the oceans each year and they have been shown to affect all types and sizes of marine species. Combine that with rising CO2 levels and the threat posed to the global ocean is stark. It reinforces the importance of taking steps to meet the standards demanded by international climate treaties so as to reduce the impact of ocean acidification and warming. It is also within our power to change cultures so that litter created on land does not become an environmental hazard in our oceans, both now and for future generations."

Researchers from Illinois State University, North Carolina State University, University of South Carolina, and University of Maryland published a new paper in the Journal of Marketing that examines the impact of moving nutrition labels, typically placed on the back of product packages, to the front.

The study, forthcoming in the Journal of Marketing, is titled "Competitive Effects of Front-of-Package Nutrition Labeling Adoption on Nutritional Quality: Evidence from Facts Up Front Style Labels" and is authored by Joon Ho Lim, Rishika Rishika, Ramkumar Janakiraman, and P.K. Kannan.

Can changing food packaging improve product nutrition quality? While this change may be simple, there's a lot at stake.

Diet-related chronic diseases impose a growing burden on the United States economy by increasing costs of health care and widening diet-related health disparities. Since the 1970s, the American diet has shifted considerably towards foods higher in calories and lower in nutritional quality. According to the Centers for Disease Control and Prevention estimates, more than one-third of American adults are obese. Childhood and adolescent obesity rates have also skyrocketed in the last 30 years with one in five school-aged children considered obese. To combat this disconcerting trend, public policy makers, food manufacturers, and grocery retailers have made efforts over time to design nutrition labels that can educate consumers about the nutritional value of the foods they purchase and help consumers make healthier choices. The World Health Organization (WHO) also considers nutrition labeling to be a key policy option for promoting healthier diets.

The packaged food industry has voluntarily taken steps to inform consumers about the nutritional value of food products so that consumers can make better choices. One such initiative undertaken by is the Front-of-Package (FOP) nutrition label. FOP nutrition labels are voluntarily adopted by food manufacturers and provide nutrient information on the front of food packaging in a clear, simple, and easy-to-read format. The FOP labels present the key information listed on the Nutrition Facts Panel (NFP; displayed on the back or side of food packages) more concisely and often include calorie content and the amounts of key nutrients to limit (e.g., saturated fat, sugar, and sodium per serving). In an innovative study, our research team assessed the effect of the introduction of a FOP nutrition label in a product category on the nutritional quality of food products in the category.

The study reports four sets of findings. First, the adoption of FOP nutrition labeling in a product category results in a significant improvement in the nutritional quality of food products in that category. Second, the effect of FOP is stronger for premium (high-priced) brands and brands with a narrower product line breadth. Third, the FOP adoption effect is stronger for unhealthy categories and categories with a higher competitive intensity. Fourth, manufacturers increase the nutritional quality of products by reducing the calorie content and limiting nutrients such as sugar, sodium, and saturated fat.

Lim explains that "This implies that policy makers, in partnership with food manufacturers and retailers, should encourage adoption of voluntary, standardized, and transparent labeling programs and consider options for broadening the information presented in FOP labels. We believe that policy makers should also invest in educational campaigns that inform consumers about the value of FOP labels and that would further incentivize food manufacturers to offer nutritionally better products."

For food manufacturers, the results suggest that they must devote significant resources to product innovation to stay competitive. Specifically, manufacturers in unhealthy and more competitive categories can be more strategic and invest in innovation so they are ready to provide better products following FOP adoption. Rishika adds that "Food retailers should partner with manufacturers and give them incentives to adopt FOP because this can lead to better-quality products for their consumers and help build a positive brand image. Retailers can also promote products with FOP labels, especially in more competitive and unhealthy product categories, which can spur manufacturers toward more innovation and lead to an increase in the nutritional quality of foods over time." The researchers encourage retailers to invest in measures that help monitor and track sales of products with FOP labels and provide this feedback to their manufacturers regularly to speed up the competitive effect of FOP labels. For consumers, the study finds that the brands that adopted FOP labeling offer nutritionally superior products than those that did not adopt the labeling. This result is particularly helpful for time-starved consumers looking to purchase relatively healthier products.

What The Study Did: Clinicians in the U.S. were interviewed and described their experiences of planning and providing care for patients in settings of limited resources during the COVID-19 pandemic.

Authors: Catherine R. Butler, M.D., M.A., of the University of Washington in Seattle, 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/jamanetworkopen.2020.27315)

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.

What The Study Did: Researchers assessed changes in birth rates by income level among commercially insured women before and after the elimination of cost sharing for contraception under the Patient Protection and Affordable Care Act.

Authors: Vanessa K. Dalton, M.D., of the University of Michigan in Ann Arbor, 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/jamanetworkopen.2020.24398)

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.

Neuroscientists at UCL have used laser beams to "switch on" neurons in mice, providing new insight into the hidden workings of memory and showing how memories underpin the brain's inner GPS system.

The study, published in the journal Cell, explains how researchers harnessed an 'all-optical' approach using twin lasers to simultaneously read and write the activity of 'place cells' (a type of neuron) in mice, as they navigated a virtual reality environment.

Remarkably, by stimulating the place cells, scientists were able to reactivate (or retrieve) the memory of a location where the mice obtained a reward, which in turn "mentally teleported" the mice, causing them to act as if they were in the rewarded place.

This new research builds on the groundbreaking work of Professor John O'Keefe (UCL Cell & Developmental Biology), who won the Nobel Prize in 2014 for discovering place cells. These cells are found in a brain region called the hippocampus, and only become active when an animal enters a specific location in the environment.

Place cells are thought to represent a cognitive map of the environment - like an inner GPS - and retain location memory. The new UCL study is the first to show directly that place cell activity underlies the brain's ability to navigate.

The results provide a deeper understanding of how memories are stored, and the UCL scientists believe the findings could eventually help us develop new therapies for conditions such as dementia and Alzheimer's disease, which affect memory.

First author Dr Nick Robinson (UCL Wolfson Institute for Biomedical Research) said: "These results provide direct causal evidence that mice use the information represented by place cell activity to guide their behaviour. In other words, place cells really do tell the mouse where it is, and mice actually 'listen' to their place cells when they make decisions. This provides new insights about how memories are stored in the brain, as well as new tools for manipulating these memories to influence behaviour."

He added: "Disorders of memory - such as in dementia and Alzheimer's - represent a huge cost to society. This work may eventually lead to a better understanding of these diseases, as well as new targets for therapeutic intervention."

Senior author Professor Michael Hausser (UCL Wolfson Institute for Biomedical Research) said: "This study is a game-changer as it shows that we can use optical reading and writing of activity in specific neurons to manipulate memories, allowing us to better understand - and potentially improve - how neural circuit activity helps us to make decisions."

The experimental study explained

Researchers at UCL Wolfson Institute for Biomedical Research leveraged a powerful approach which combines two revolutionary technologies for using light to read and write electrical activity in the brain.

First, they engineered neurons to express genetically encoded calcium sensors, which allow cells to light up when they are active. Second, they expressed light-sensitive 'optogenetic' proteins in the same neurons, allowing them to activate specific cells with beams of laser light, targeted using digital holography (the same technology as used in a laser light show).

By combining these two techniques, the team could both record and manipulate activity in the same neurons in the brain of a mouse navigating in virtual reality.

The UCL scientists used this approach to perform targeted activation of place cells in the hippocampus in mice navigating to a specific location within the virtual world to collect a sugar water reward. They first optically recorded the activity of large numbers of hippocampal place cells, identifying those which were active specifically at the rewarded location and which could therefore form the basis of the memory for that location. They then used holographically targeted laser beams to activate these specific place cells in a different location in the virtual world.

Remarkably, place cell stimulation was sufficient to retrieve the memory of the rewarded location, leading the mouse to seek the reward at the new location. In other words, the stimulation of the neurons with light "mentally teleports" the animal, causing them to act as if they were in the rewarded place. This is the first demonstration of how the activation of place cells enables us to retrieve memories of our environment and helps us to navigate.

ATLANTA -- Results from a large, international survey shows that only a small fraction of children with rheumatic diseases reported contracting COVID-19. Those who did become infected with COVID-19 all had benign outcomes and did not develop significant complications, despite the fact that most children were taking immunosuppressive medications. The research was presented at ACR Convergence, the American College of Rheumatology's annual meeting (ABSTRACT #1685).

The most common pediatric rheumatic disease is juvenile idiopathic arthritis (JIA), which is a group of chronic conditions that cause arthritis (joint swelling and inflammation) affecting children and teenagers. JIA may involve one or many joints, may also affect the eyes, and cause other symptoms, such as fevers or rash.

As the COVID-19 pandemic surged worldwide in early 2020, the risk of COVID-19 and serious complications or death was unknown for children with rheumatic diseases. Many of these patients are treated with immunosuppressive medications that leave them more susceptible to infections.

"At the time, parents and physicians did not know whether to continue a child's immunosuppressive medications to prevent COVID-19 and related complications," says the study's co-author, Jonathan S. Hausmann, MD, Instructor in Medicine at Harvard Medical School and a pediatric rheumatologist at Boston Children's Hospital.

To learn more about the impact of COVID-19 on children with rheumatic diseases, Dr. Hausmann and his fellow researchers analyzed data from the international COVID-19 Global Rheumatology Alliance Patient Experience Survey, a global patient registry. They sent surveys to parents of children with rheumatic diseases through patient support organizations and social media. Parents provided information on their child's rheumatic disease diagnosis, medications, whether or not the child ever developed COVID-19 and any outcomes they experienced if they were infected.

The study collected data from April 3 to May 8, 2020 and includes 427 children under age 18. Most of the children in the study lived in the Americas, and were white, female and between 5 and 14 years old. Most had JIA, and they were taking either conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). Both classes of drugs suppress the immune system and help to control the arthritis, while also making children at increased risk of infection. The survey also included children with other pediatric rheumatic diseases such as lupus, dermatomyositis, and autoinflammatory diseases.

Among the 427 children in the study, only five, or 1.2%, were diagnosed with COVID-19, none of whom required hospitalization or had severe outcomes. Because the study is based on self-reported responses from parents who were engaged in social media or who were willing to fill out a survey, it may not fully represent all children with pediatric rheumatic diseases, and it may be more likely to include a healthier population, the researchers say.

"These findings are important as policymakers and educators contemplate reopening schools with the pandemic still ongoing, and with parents and physicians struggling to make decisions of whether to send their children back to school," says Dr. Hausmann. "Our study suggests that children with rheumatic disease should continue their immunosuppressive drugs during the pandemic, as it does not appear to place them at increased risk of COVID-19 related complications. Our findings support the recent ACR guidelines for managing immunosuppression during the pandemic."

Next, this research group plans to develop a prospective, international registry of people with rheumatic disease of all ages to assess long-term outcomes of the COVID-19 pandemic, explore the willingness to receive and assess the efficacy of a vaccine, assess the impact of the environment on COVID-19, and track the effects of the pandemic on the physical and mental health of participants over time, he adds.