Culture

(SYDNEY, Monday 17th May 2021) The early immune response in a person who has been vaccinated for COVID-19 can predict the level of protection they will have to the virus over time, according to analysis from Australian mathematicians, clinicians, and scientists, and published today in Nature Medicine.

The researchers from UNSW's Kirby Institute, the Peter Doherty Institute for Infection and Immunity, and the University of Sydney have identified an 'immune correlate' of vaccine protection. This has the potential to dramatically cut development times for new vaccines, by measuring neutralising antibody levels as a 'proxy' for immune protection from COVID-19.

"Neutralising antibodies are tiny Y-shaped proteins produced by our body in response to infection or vaccination. They bind to the virus, reducing its ability to infect," says Dr Deborah Cromer from the Kirby Institute.

"While we have known for some time that neutralising antibodies are likely to be a critical part of our immune response to COVID-19, we haven't known how much antibody you need for immunity. Our work is the strongest evidence to date to show that specific antibody levels translate to high levels of protection from disease."

The researchers analysed data from seven COVID-19 vaccines to examine the how the response measured soon after vaccination correlated with protection. They then used statistical analysis to define the specific relationship between immune response and protection. Their analysis was remarkably accurate and was able to predict the efficacy of a new vaccine.

Dr Cromer said that this finding has the potential to change the way we conduct COVID-19 vaccine trials in the future.

"Antibody immune levels are much easier to measure than directly measuring vaccine efficacy over time. So, by measuring antibody levels across the range of new vaccine candidates during early phases of clinical trials, we can better determine whether a vaccine should be used to prevent COVID-19."

Vaccine boosters likely to be required within a year

Another crucial application of this analysis is its ability to predict immunity over time. The researchers predict that immunity to COVID-19 from vaccination will wane significantly within a year, with the level of neutralising antibodies in the blood dropping over the first few months following infection or vaccination.

"Vaccination works very well to prevent both symptoms and severe disease in the short to medium term, but efficacy is predicted to decline over the first few months for most of these vaccines," says Dr David Khoury, also from the Kirby Institute.

"However, it is very important to understand the difference between immunity against infection and protection from developing severe disease. Our study found that a 6-fold lower level of antibodies is required to protect against severe disease. So even though our analysis predicts that we will start losing immunity to mild infection in the first year after vaccination, protection from severe infection should be longer lived," says Dr Khoury.

"But ultimately, for optimal protection against moderate disease and transmission of COVID-19, these findings suggest we may be looking at annual vaccine boosters, just like what we have with the flu vaccine."

Applying the model in the real word

A major global challenge is the evolution of the virus and the emergence of new variants. There is a growing concern, based on laboratory studies, that antibodies developed against the dominant strains are less effective at neutralising these new variants.

"An added advantage of our work is that allows us to predict how protective an immune response will be against different variants," says Professor Jamie Triccas from the University of Sydney's Marie Bashir Institute and Faculty of Medicine and Health.

"This analysis shows a very good correlation between the immune response - which is very easy to test for - and the efficacy of a vaccine in preventing infection, which is incredibly hard to test for. This means we can predict how protective an immune response will be against different variants, without having to determine efficacy against each variant in large and costly clinical trials.

"This work can facilitate decision making by providing the necessary data much earlier on in the vaccine development pipeline and in a far more efficient way."

A limitation of this study is that it analyses the relationship between early immune responses to infection and vaccination and protection from infection (the data that is currently available), and uses this relationship to project how immunity will change in the future and in the response to different viral variants. Future studies should aim to confirm these predictions as data becomes available.

COLUMBUS, Ohio - New research provides the best evidence to date into the timing of how our early Milky Way came together, including the merger with a key satellite galaxy.

Using relatively new methods in astronomy, the researchers were able to identify the most precise ages currently possible for a sample of about a hundred red giant stars in the galaxy.

With this and other data, the researchers were able to show what was happening when the Milky Way merged with an orbiting satellite galaxy, known as Gaia-Enceladus, about 10 billion years ago.

Their results were published today (May 17, 2021) in the journal Nature Astronomy.

"Our evidence suggests that when the merger occurred, the Milky Way had already formed a large population of its own stars," said Fiorenzo Vincenzo, co-author of the study and a fellow in The Ohio State University's Center for Cosmology and Astroparticle Physics.

Many of those "homemade" stars ended up in the thick disc in the middle of the galaxy, while most that were captured from Gaia-Enceladus are in the outer halo of the galaxy.

"The merging event with Gaia-Enceladus is thought to be one of the most important in the Milky Way's history, shaping how we observe it today," said Josefina Montalban, with the School of Physics and Astronomy at the University of Birmingham in the U.K., who led the project.

By calculating the age of the stars, the researchers were able to determine, for the first time, that the stars captured from Gaia-Enceladus have similar or slightly younger ages compared to the majority of stars that were born inside the Milky Way.

A violent merger between two galaxies can't help but shake things up, Vincenzo said. Results showed that the merger changed the orbits of the stars already in the galaxy, making them more eccentric.

Vincenzo compared the stars' movements to a dance, where the stars from the former Gaia-Enceladus move differently than those born within the Milky Way. The stars even "dress" differently, Vincenzo said, with stars from outside showing different chemical compositions from those born inside the Milky Way.

The researchers used several different approaches and data sources to conduct their study.

One way the researchers were able to get such precise ages of the stars was through the use of asteroseismology, a relatively new field that probes the internal structure of stars.

Asteroseismologists study oscillations in stars, which are sound waves that ripple through their interiors, said Mathieu Vrard, a postdoctoral research associate in Ohio State's Department of Astronomy.

"That allows us to get very precise ages for the stars, which are important in determining the chronology of when events happened in the early Milky Way," Vrard said.

The study also used a spectroscopic survey, called APOGEE, which provides the chemical composition of stars - another aid in determining their ages.

"We have shown the great potential of asteroseismology, in combination with spectroscopy, to age-date individual stars," Montalban said.

This study is just the first step, according to the researchers.

"We now intend to apply this approach to larger samples of stars, and to include even more subtle features of the frequency spectra," Vincenzo said.

"This will eventually lead to a much sharper view of the Milky Way's assembly history and evolution, creating a timeline of how our galaxy developed."

Researchers at the Francis Crick Institute have found out how microscopic structures called lipid droplets may help to prevent a high-fat diet causing kidney damage. The work in fruit flies, published in PLoS Biology opens up a new research avenue for developing better treatments for chronic kidney disease.

Eating foods high in fats can cause inflammation and metabolic stress in the kidneys, leading to chronic disease, which in severe cases requires dialysis or a transplant. And with obesity on the rise globally, it's a growing problem - around 10% of people in the UK are living with chronic kidney disease.

Scientists at the Crick have been studying a common characteristic of the disease, the appearance of lipid droplets inside kidney cells, to solve a long-standing mystery of whether this protects or harms kidney function.

Working with electron microscopy experts at the Crick, the team used the sophisticated genetic methods available in the fruit fly (Drosophila) to show that lipid droplets protect the renal system against damage from excess dietary fats.

When fed a high-fat diet, lipid droplets accumulate inside nephrocytes, the flies' equivalent of human kidney cells called podocytes. Here, the droplets act as a 'safe haven' for storing excess fats away from the rest of the cell. An enzyme called ATGL sits on the surface of lipid droplets and helps to dispose of the stored fats in a safe way. ATGL does this by feeding the fats in a digestible form to nearby mitochondria, where they can be broken down into less toxic molecules.

Lipid droplets are essential for the protective process as when the scientists used genetic methods to prevent their formation, the fats left free inside the nephrocytes caused substantial damage and impaired kidney function.

Alex Gould, head of the Physiology and Metabolism Laboratory at the Crick and lead researcher of the study says: "It has been known for many years that lipid droplets pop up in a wide range of diseases, all the way from diabetes to brain cancer. What's been far less clear is whether they are making things better or worse."

"It's exciting to find that lipid droplets are an essential part of the kidney's fight back against fat overload. These fascinating structures are turning out to be so much more than tiny balls of fat, and we now want to find out whether their protective role in the kidney also applies to other disease contexts."

The scientists also found that boosting the expression of the ATGL enzyme in fruit flies was able to repair most of the damage caused by a high-fat diet, restoring normal function to the kidney cells.

Fruit flies are a useful model for understanding the biology of kidney disease in humans because there are important similarities in the renal systems of both species, including the presence of the ATGL enzyme.

Ola Lubojemska, who carried out much of this work in the Physiology and Metabolism Laboratory at the Crick, explains: "These findings are at an early stage but open up a new direction for clinical research into chronic kidney disease. It may, for example, be possible to develop a drug that boosts the ATGL enzyme in renal patients. This would allow excess dietary fats to be more efficiently detoxified by kidney cells, thus improving kidney function."

The University of Kent's School of Physical Sciences, in collaboration with the Science and Technology Facilities Council (STFC) and the Universities of Cardiff, Durham and Leeds, have developed an algorithm to train computers to analyse signals from subatomic particles embedded in advanced electronic materials.

The particles, called muons, are produced in large particle accelerators and are implanted inside samples of materials in order to investigate their magnetic properties. Muons are uniquely useful as they couple magnetically to individual atoms inside the material and then emit a signal detectable by researchers to obtain information on that magnetism.

This ability to examine magnetism on the atomic scale makes muon-based measurements one of the most powerful probes of magnetism in electronic materials, including "quantum materials" such as superconductors and other exotic forms of matter.

As it is not possible to deduce what is going on in the material by simple examination of the signal, researchers normally compare their data to generic models. In contrast, the present team adapted a data-science technique called Principal Component Analysis (PCA), frequently employed in Face Recognition.

The PCA technique involves a computer being fed many related but distinct images and then running an algorithm identifying a small number "archetypal" images that can be combined to reproduce, with great accuracy, any of the original images. An algorithm trained in this way can then go on to perform tasks such as recognising whether a new image matches a previously-seen one.

Researchers adapted the PCA technique to analyse the signals sent out by muons embedded in complex materials, training the algorithm for a variety of quantum materials using experimental data obtained at the ISIS Neutron and Muon source of the STFC Rutherford Appleton Laboratory.

The results showed the new technique is equally as proficient as the standard method at detecting phase transitions and in some cases could detect transitions beyond the capabilities of standard analyses.

Dr Jorge Quintanilla, Senior Lecturer in Condensed Matter Theory at Kent and leader of the Physics of Quantum Materials research group said: 'Our research results are exceptional, as this was achieved by an algorithm that knew nothing about the physics of the materials being investigated. This suggests that the new approach might have very broad application and, as such, we have made our algorithms available for use by the worldwide research community.'

In its response to pathogens and vaccines, our immune system relies on dendritic cells. These white blood cells patrol the body's tissues, collect components of pathogens and vaccines and transport them via lymphatic vessels to the nearest lymph node. There, they present the collected material to other immune cells in order to trigger an immune response.

How exactly dendritic cells get from the tissue into lymphatic vessels and from there to the lymph node is the focus of research conducted by Cornelia Halin, Professor of Pharmaceutical Immunology at ETH Zurich. For a long time, scientists assumed that dendritic cells choose the path of least resistance and migrate from the tissue into the smallest branches of the lymphatic vessels, the lymphatic capillaries. This is because, unlike other lymphatic vessels, capillaries are surrounded only by a thin, barely closed layer of cells, allowing dendritic cells to slip through the spaces between neighbouring cells relatively easily.

However, this route is slow. While cells in blood vessels and in most other lymphatic vessels are carried along by a flow of fluid, virtually no flow is present in lymphatic capillaries. Consequently, cells in these capillary vessels need to actively move themselves forward, which only happens at an extremely low speed.

Faster despite obstacles

With her team, ETH Professor Halin has now discovered that dendritic cells can take a shortcut. In studies performed on mouse tissues and employing microscopy, the scientists were able to show that dendritic cells can also migrate directly into those lymphatic vessels into which the capillaries merge: the collecting lymphatics. These vessels are surrounded by a well-sealed layer of cells and a thicker membrane of connective tissue. Consequently, migration across these barriers is more difficult for dendritic cells, and entry takes longer than into capillaries. All in all, however, dendritic cells taking this path arrive in the lymph nodes much faster, since immediately after entry they are carried along by the lymph flow present in the collecting vessels and can bypass the slow active migration step in the capillaries.

Thinner barrier in case of inflammation

At present, it is not yet completely understood under which circumstances dendritic cells choose the known path via the capillaries and under which they take the newly discovered shortcut. As ETH Professor Halin and her colleagues have shown, the shortcut becomes available when there is an ongoing inflammatory response in the tissue. Specifically, the researchers were able to show that the connective tissue membrane surrounding the collecting lymphatics becomes degraded during inflammation, making it easier for dendritic cells to penetrate into the collectors.

It thus appears that an inflammatory response is the key factor that allows dendritic cells to take this shortcut and arrive more quickly in the lymph nodes. The scientists will now investigate whether all dendritic cells or only specific subtypes can travel via this route. In particular, they plan to explore the importance of the newly discovered pathway for the activation of the immune system and for installing immune responses. They suspect that the ability to sound the alarm in the lymph node more quickly may provide an advantage in fighting certain infections.

For the first time, Penn State researchers have identified a gene that controls flowering in cacao, a discovery that may help accelerate breeding efforts aimed at improving the disease-ridden plant, they suggested.

Characterizing the Flowering Locus T gene in cacao, responsible for the production of florigen -- a protein that triggers flowering in most plants -- is important, according to study co-author Mark Guiltinan, J. Franklin Styer Professor of Horticultural Botany and professor of plant molecular biology. He expects this advancement to enable scientists to develop disease-resistant trees faster, which is critical because 20% to 30% of the world's cacao crop is lost to disease annually.

"Breeding tree crops like cacao is very slow and can take 20 or more years to release a new variety," he said. "Knowledge of the mechanisms of flowering may lead to methods to accelerate cacao breeding and to develop trees that produce fruit sooner than conventional varieties, which takes two to four years. Each year we move closer to these goals as we continue to explore the molecular biology of the cacao tree."

To find the flowering gene in cacao, lead researcher Sarah Prewitt, doctoral candidate in plant science in the College of Agricultural Sciences, first looked at genes known to be responsible for flowering in the Arabidopsis plant, the genome of which has been studied widely for decades. Before finding the cacao flowering gene, she tested an Arabidopsis flowering gene in cacao to see how the plant developed.

Testing her theory, she overexpressed that gene to trigger very early flowering in cacao "plantlets" in the lab and showed that those tiny flowers produced grains of pollen that were viable.

"To find the flowering gene in cacao, we used a bioinformatics approach, taking the sequence of the gene from Arabidopsis and looking for similar genes in the cacao genome," Prewitt said. "I found the cacao gene that promotes flowering because the sequences look very similar."

Geneticists consider the function of the florigen flowering gene to be "highly conserved," Prewitt added. "That means the gene is extremely consistent -- it does what it does in every plant genome that you look in," she said. "The florigen flowering gene certainly has been looked at in a lot of plants, and it's very reliable. It controls the timing of flowering."

In findings published May 15 in BMC Plant Biology, the researchers reported on the role of cacao's single flowering gene, Flowering Locus T, demonstrated by gene-expression analysis. They also documented the results of their introduction of the flowering gene from Arabidopsis into cacao. Overexpressing that gene resulted in "precocious" flowering in cacao tissue culture, they explained, which demonstrated the extremely similar function of florigen genes and the mechanisms that control flowering in both Arabidopsis and cacao.

While intriguing on a scientific level, the discovery of the cacao Flowering Locus T gene could have a potentially significant, real-world impact, Guiltinan noted, by helping to improve the lives of millions of cacao farmers in developing countries sooner than previously thought possible. He pointed out that the breeding of cacao varieties with high yields, disease resistance, resilience to climate change and desirable quality traits is an important component of a broader goal to develop sustainable farming systems for cacao.

"Better cacao varieties can increase the income, and thus the well-being, of cacao farmers who live in some of the most impoverished regions of the world, such as West Africa," he said. "In turn, this will benefit the economies of these countries and the environment and will provide a sustainable source of the main raw ingredient for the chocolate industry."

Paper Title: SARS-CoV-2 infects human adult donor eyes and hESC-derived ocular epithelium

Authors: Timothy Blenkinsop, PhD, Assistant Professor, Cell, Developmental & Regenerative Biology, and Benjamin tenOever, PhD, Professor, Microbiology, Icahn School of Medicine at Mount Sinai, New York, and other coauthors.

Bottom Line: SARS-CoV-2, the causative agent of COVID-19, is thought to transmit and begin infection in the upper respiratory tract. For this reason, the use of face masks has been recommended for the general public. However, it remains unclear whether infection can also be initiated from the eye, thus requiring additional protective measures.

Results: The new study finds that cells in the eye can be directly infected by SARS-CoV-2, the virus that causes COVID-19.

Why the Research Is Interesting: The findings have an immediate impact on preventive measures to help mitigate the spread of COVID-19 and support new guidance for eye protection that can be instituted worldwide.

Who: Adult human eyes in an in vitro stem cell model.

When: Eyes were exposed to SARS-CoV-2 and studied after 24 hours.

What: The study evaluated whether SARS-CoV-2 could infect both tissues and primary cells in the eye.

How: The donor cells were infected with SARS-CoV-2 and then analyzed through RNA sequencing. The sequences were then mapped to the human genome and compared to non-infected control cells from adult tissues. The expression of the exposed cell where then evaluated. Contracting the virus through the eye could also be corroborated using a small animal model in independent work done Ramus Møller in the tenOever lab.

Study Conclusions: SARS-CoV-2 can infect surface cells of the eye. The exposed cells revealed the presence of infection-associated proteins including ACE2, the virus receptor, and TMPRSS2, an enzyme which allows viral entry. IFNβ, a protein that has antiviral and antibacterial properties, was also found to be suppressed from the exposure to the virus. Additionally, the researchers found that ocular surface cells, particularly the limbus, were susceptible to infection, while the central cornea was less vulnerable.

Said Mount Sinai's Dr. Timothy Blenkinsop of the research:
We hope this new data results in additional measures to protect the eyes. We also intend to use these models to test approaches to prevent ocular infections.

Said Mount Sinai's Dr. Benjamin tenOever of the research:

This work was the result of a very productive collaboration from two very different scientific programs. More importantly, the data generated not only adds to our understanding concerning the biology of SARS-CoV-2, but the results also highlight the importance of washing hands, as rubbing one's eyes should now be viewed as an entry point for infection.

Some words sound like what they mean. For example, "slurp" sounds like the noise we make when we drink from a cup, and "teeny" sounds like something that is very small. This resemblance between how a word sounds and what it means is known as iconicity.

In her lab at the University of Miami, Lynn Perry, an associate professor in the College of Arts and Sciences Department of Psychology, previously found that children tend to learn words higher in iconicity earlier in development then they do words lower in iconicity. She also found that adults tend to use more iconic words when they speak to children than when they speak to other adults.

"That got us curious about why," said Stephanie Custode, a doctoral student in psychology, who worked with Perry to answer questions posed by her prior work. "Does iconicity play a causal role in children's language development, helping them learn new words, eventually even those words that have non-iconic, or arbitrary, sound-meaning associations?"

For their new study, published in the journal Cognitive Science, the researchers explored whether parents' who used iconic words as they played with novel objects with children between 1 and 2 helped them learn those objects' names. The objects were novel toys and foods that the researchers made and gave names to, like the word "blicket" to describe a clay toy with a made-up shape. They found that when parents named a novel object, their children were more likely to remember those novel names later if the parent also used highly iconic words in the same sentence. This was true both for parents speaking English and Spanish.

"Consider when a parent teaches their child about 'cats' by talking about how they 'meow,' or about a sweater by talking about how 'fuzzy' it is, or about 'honey' by talking about how sticky it is," Perry said. "The resemblance between the sound of a word like 'sticky' and the texture of the honey helps the child pay attention to that property. If the parent also says 'honey' while describing its stickiness, the child can form a stronger memory of that new word and its meaning, because they're paying attention to its important properties--its sticky texture in this case."

The researchers found it was beneficial for parents to use iconic language specifically when they introduced a novel name. "If a parent talks about stickiness without saying the name 'honey', there's no new name to associate with that sticky texture, and if a parent names the honey but talks about it being yellow, a word that doesn't particularly sound like its meaning, the child might pay less attention to the honey and forget about it. In both cases, the child wouldn't learn the new word 'honey'," said Perry.

From these findings, the researchers concluded that iconicity could be an important cue that parents and other caregivers can use to facilitate word learning.

Next the researchers plan to investigate whether using more iconic words can help children with language delays learn new words. They also are interested in studying how parents talk to children changes over time and whether they decrease their use of iconic language as they recognize that their child is becoming a stronger word learner.

Before undergoing surgery, patients often go through a number of tests: blood work, sometimes a chest X-ray, perhaps tests to measure heart and lung function.

In fact, about half of patients who had one of three common surgical procedures done in Michigan between 2015 and the midway point of 2019 received at least one routine test beforehand.

That's according to new research in JAMA Internal Medicine from a collaboration between the University of Michigan-based Michigan Program on Value Enhancement (MPrOVE) and the Michigan Value Collaborative, a statewide initiative that focuses on improving medical and surgical quality.

Yet plenty of evidence suggests that preoperative testing is often unnecessary for low-risk surgeries.

At best, it's costly and doesn't usually improve outcomes for patients. At worst, it can lead to more invasive testing and delay surgery, which can create complications that could have been avoided if the tests weren't done.

"There aren't that many areas in medicine where the data is pretty definitive that something is low-value," says Lesly Dossett, M.D., the division chief of surgical oncology at Michigan Medicine and the co-director of MPrOVE, "but preoperative testing before low-risk surgeries is certainly one of them."

How testing started -- and why it continues

In the latter half of the 19th century, modern surgery was still in its infancy.

Anesthesia was new, and even minor surgeries were not routine. So researchers used tests to assess their patients' physical health and measure their risk of complications during operations.

"There was probably a time when some of the testing did reduce adverse events," Dossett says. "But now there's been so many advances in surgery -- complication rates are so low that a lot of these tests are not necessarily helpful anymore."

Others agree with her.

Professional organizations ranging from the American College of Surgeons and the Society of General Internal Medicine to the American Society of Anesthesiologists have identified routine preoperative testing as a low-value type of care that should be reduced whenever possible.

In 2012, the American Board of Internal Medicine Foundation even launched an initiative called the Choosing Wisely campaign that promotes conversations between health care providers and patients about unnecessary medical tests and procedures.

But, almost a decade later, preoperative tests continue to be ordered.

Of about 40,000 patients in the U-M study who had surgery to either remove the gall bladder, repair a groin hernia, or remove cancerous breast tissue, close to a third underwent two or more tests beforehand, and about 13% had three or more.

The most common tests were a complete blood count, an electrocardiogram and a basic metabolic panel, all of which aren't inherently necessary before these surgeries.

"It's one thing to say that this is well recognized in the literature," says Hari Nathan, M.D., Ph.D., who happens to be the division chief of hepato-pancreato-biliary surgery at Michigan Medicine as well as the director of the MVC, "but it's a different thing to put it in the hands of the clinicians who are at the bedside in an easy-to-read, easy-to-understand and convenient-to-carry-around format."

Patients who had a complete medical history and physical done during a visit that was separately billed were more likely to have had preoperative testing as were those who were older or had more than one medical condition.

"I could see those two latter factors being in the background, hypothetically giving some pressure to do more testing," says Nicholas Berlin, M.D., M.P.H., a plastic surgery resident at Michigan Medicine and the first author of the study. "That's not to suggest there's an age threshold or a comorbidity that requires preoperative testing every single time. There's not."

A small number of people who fall into these categories may actually benefit from having these tests done, although it's difficult to know exactly how many based on this data, the researchers say. Yet, when they adjusted their model to account for that issue, they still found overuse of testing.

The data also revealed wide variations in testing, not only between the 63 hospitals studied but also within health systems for the same procedures, pointing to the need for more research to drill down further into the origins of the problem.

"We have more work to do on our end to figure out what's driving these differences within and between hospitals," says Berlin, who's also a National Clinician Scholar at the University of Michigan Institute for Healthcare Policy and Innovation. "This is signaling to other projects in the future between MPrOVE and statewide quality collaboratives that use more of an on-the-ground approach."

Value added statewide

This study represents one of the first partnerships between the Michigan Value Collaborative and MPrOVE, a joint venture of IHPI and Michigan Medicine that tries to optimize patient care, improve quality and demonstrate the value of care at Michigan Medicine through research and analytics.

In the past, MPrOVE has worked to reduce preoperative visits and tests such as EKGs before cataract surgery at Michigan Medicine, but its leaders wanted to expand the scope of their research to include other procedures and more hospitals.

The MVC was an ideal partner to do so: Funded by Blue Cross Blue Shield of Michigan, the initiative allows more than 90 hospitals and 40 physician organizations in Michigan to compare their data and identify best practices as well as opportunities for improvement.

"It's something that's squarely in MVC's strike zone and fits very well with MPrOVE's mission," Nathan says, "It just made sense for us to work together on this."

Limiting preoperative testing is one of two signature projects for the MVC, and Nathan has already started meeting with area health systems to tackle the issue.

"Some hospitals routinely send patients through a preoperative clinic, which represents a way to move the needle here in a very targeted way, just by influencing what gets ordered in the setting of that clinic," he says. "At other hospitals, there is no such clinic, and the individual surgeons and/or anesthesiologists are ordering tests, so that might require a different approach in order to get more adherence to guidelines."

"But I love seeing variation because when we see variation, that means there's an opportunity to learn from one another," he adds.

One of the challenges in reducing preoperative testing is that it generates revenue for hospitals, which means there's not a financial incentive to do less of it, Dossett says. But Nathan says that, based on his interactions with local health systems, he believes there's an appetite for change in this area.

"At the end of the day, we all recognize that as a society, we need to find ways to curb health care costs," he says. "That's in everybody's interest. Even if, on your balance sheet, you think it makes sense to do more tests just to make money, as health care providers and as a nation, it does not make sense. It is unsustainable. When we talk to our members, everybody gets that."

The experimental heart failure drug omecamtiv mecarbil reduced heart failure hospitalizations by a greater margin among patients with more severely reduced ejection fraction, a measure indicating severe impairment in the heart's pumping ability, compared with those who had moderately reduced ejection fraction, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

Omecamtiv mecarbil works by improving the ability for heart muscle cells to contract and operates through a different biological pathway than any of the current heart failure medications. The research is an extended analysis of data from GALACTIC-HF, a trial involving more than 8,200 participants that found omecamtiv mecarbil significantly improved outcomes in terms of a composite of cardiovascular death or heart failure events among patients with heart failure with reduced ejection fraction. The new analysis focused on how patient outcomes varied based on the level of severity of their reduced ejection fraction.

"This is a drug that will potentially help the very group of patients that are most difficult to care for," said John R. Teerlink, MD, a cardiologist at the University of California, San Francisco and the San Francisco VA Medical Center, and the study's lead author. "While the results from GALACTIC-HF show omecamtiv mecarbil brought improvements overall, these new findings point to a group of patients with more severe heart failure in whom there is even greater benefit."

Heart failure is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body. The trial investigated omecamtiv mecarbil in patients with heart failure with an ejection fraction of less than or equal to 35%. Ejection fraction is a measure of the amount of oxygen-rich blood that the heart pushes out with each heartbeat (50-70% is considered normal).

As previously reported, the GALACTIC-HF trial met its primary endpoint, which was a composite of time to first heart failure event or death due to cardiovascular causes, and the benefit was predominantly driven by reductions in heart failure events, with no significant improvement in the rate of death from cardiovascular causes compared to placebo. An additional benefit, according to Teerlink, is that when compared with other commonly used heart failure medications, omecamtiv mecarbil did not adversely affect blood pressure, heart rate, potassium concentrations or renal function, even when used alongside current heart failure medications. In addition, there was no increase in cardiac ischemic or ventricular arrhythmic events.

"The good news is omecamtiv mecarbil can be added on to a patient's treatment regimen at any time, because it doesn't interact with any of the commonly used heart failure therapies in terms of adverse effects," Teerlink said. "While it doesn't provide a benefit in terms of reducing cardiovascular death, it can provide its benefit in terms of reducing heart failure hospitalizations virtually anywhere in the treatment process."

In the new analysis, researchers found that the relative and absolute benefits from omecamtiv mecarbil significantly improved with progressively lower ejection fraction. Patients in the two lowest quartiles in terms of ejection fraction had a 15-17% reduction in the risk of dying from cardiovascular causes or being hospitalized with heart failure, compared to 8% for the entire patient population. In the lowest quartile, the absolute risk reduction was 7.4 per 100 patient years, meaning that treating fewer than 12 patients with omecamtiv mecarbil would result in preventing one cardiovascular death or heart failure hospitalization.

"That's a very important and clinically meaningful finding, particularly given that patients with low ejection fraction tend to be at the highest risk and the hardest to treat," Teerlink said.

The study did not show a clear benefit of omecamtiv mecarbil among patients with ejection fraction higher than about 30%. The researchers plan to further investigate this finding to determine whether a subset of these patients may benefit from the therapy. Additional studies are underway to examine whether having atrial fibrillation or other conditions in addition to heart failure may affect outcomes from the drug.

One of the enduring mysteries of the COVID-19 pandemic is why most children tend to experience fewer symptoms than adults after infection with the coronavirus. The immune system response that occurs in the rare cases in which children experience life-threatening reactions after infection may offer an important insight, a Yale-led study published in the journal Immunity suggests.

While many children infected with the virus are asymptomatic or go undiagnosed, about one in 1,000 children experience multi-system inflammatory response (MIS-C) four to six weeks after confirmed infection with SARS-CoV-2, the virus that causes COVID-19. The condition is marked by a variety of symptoms, including fever, abdominal pain with vomiting and/or diarrhea, rash, and cardiovascular and neurological problems. If diagnosed early, the condition is readily treatable with immune suppressants such as steroids. If left untreated, however, it can be fatal.

"Why does this happen when there is no virus or anti-viral response still present and in kids? And why is it only occurring in youth?" asked Carrie Lucas, an assistant professor of immunobiology at Yale and corresponding author of the new study.

In an exhaustive analysis, Lucas and her lab tested blood from children with MIS-C, adults with severe COVID symptoms, as well as healthy children and adults. They found that children with MIS-C had immune system signatures distinct from other groups.

Specifically, the children with MIS-C had high levels of alarmins, molecules that make up part of the innate immune system which is mobilized quickly to respond to all infections. Other research findings have suggested that a child's innate immune system response may be stronger than those of adults, one possible explanation for why they generally experience milder symptoms than adults after infection.

"Innate immunity may be more active in children who are infected with virus," Lucas said. "But on the flip side, in rare cases it may get too revved up and contribute to this inflammatory disease."

Children diagnosed with MIS-C were also found to have a marked elevation of certain adaptive immune responses, which are defenses to combat specific pathogens -- such as the virus causing COVID-19 -- and that typically confer immunological memory. But instead of being protective, the responses produced in these affected children appear to attack a variety of host tissues, a hallmark of autoimmune diseases.

Lucas speculates that the initial immune response in these rare cases triggers a cascade that damages healthy tissue, which in turns makes the tissue more susceptible to attack by autoantibodies.

In the meantime, the peculiar immune system signatures of MIS-C could help in the diagnosis and early treatment options of children at high risk of the disorder, Lucas said.

Inserm teams led by Laurent Reber (Infinity, Toulouse) and Pierre Bruhns (Humoral Immunity, Institut Pasteur, Paris) and French company NEOVACS have developed a vaccine that could induce long-term protection against allergic asthma, reducing the severity of its symptoms and thus significantly improving patient quality of life. Their research in animals has been published in the journal Nature Communications.

Asthma is a chronic disease affecting around 4 million people in France and 340 million worldwide. Allergic asthma is characterized by inflammation of the bronchial tubes and respiratory discomfort caused by the inhalation of allergens, most often dust mites. This exposure to dust mites and other allergens leads to the production of antibodies called immunoglobulin E (IgE) and type 2 cytokines (such as interleukin-4 (IL-4) and IL-13) in the airways. This leads to a cascade of reactions resulting in hyperresponsiveness of the respiratory tract, overproduction of mucus, and eosinophilia (when there are too many eosinophils, a type of white blood cell, in the airways).

Inhaled corticosteroids are the gold standard for controlling asthma. However, in the case of severe asthma, this treatment is not enough. The use of therapeutic monoclonal antibodies that target IgE or the IL-4 and IL-13 pathways is then required. However, these are costly and require the long-term or even lifelong administration of injections.

To overcome this problem, researchers from Inserm, Institut Pasteur, and the company NEOVACS, have developed a conjugate vaccine, called a kinoid, by coupling the recombinant cytokines IL-4 and IL-13 with a carrier protein called CRM197 (a non-pathogenic mutated form of the diphtheria toxin, used in many conjugate vaccines).

The preclinical results (in animal models) show that this vaccine induces the sustained production of antibodies specifically directed against IL-4 and IL-13. Indeed, six weeks after the first injection of the conjugate vaccine, 90% of the mice presented high levels of antibodies. Over one year after primary immunization, 60% of them still had antibodies capable of neutralizing IL-4 and IL-13 activity.

The researchers also showed an effect on asthma symptoms: the vaccine was able to strongly decrease levels of IgE, eosinophilia, mucus production and airway hyperresponsiveness in a model of dust mite allergic asthma. This study therefore suggests both the prophylactic and therapeutic efficacy of the vaccine in this model of asthma and no adverse effects were observed in the animals.

The research team's findings will now need to be tested in a clinical trial setting.

Patients with heart failure with preserved ejection fraction who took the antifibrotic drug pirfenidone saw a significant reduction in a marker of heart muscle scarring compared with patients who received a placebo, based on findings from an early-phase trial presented at the American College of Cardiology's 70th Annual Scientific Session.

"Observational data suggests that heart muscle scarring, or fibrosis, is an important disease process for heart failure prognosis," said Chris Miller, MD, a cardiologist and National Institute for Health Research Clinician Scientist at the University of Manchester and Manchester University NHS Foundation Trust and the study's lead author. "With cardiac MRI, we were able to select a group of patients in whom fibrosis appears to be important and then reduce that scarring. While further investigation is needed, it suggests that fibrosis is an effective treatment target."

Heart failure means that the heart is no longer able to pump blood around the body properly, causing shortness of breath, swelling and fatigue. In about half of patients with heart failure, the forward pumping function of the heart, or ejection fraction, is normal. This is called heart failure with preserved ejection fraction, or HFpEF. While heart failure can involve multiple factors, scarring of the heart muscle is thought to be an important contributing factor in up to two-thirds of patients with HFpEF. This new trial suggests clinicians could one day use a personalized approach to prevent or reverse scarring in those individuals, thereby slowing the progression of heart failure, Miller said.

Pirfenidone is currently approved for treating adults with idiopathic lung fibrosis, or scarring in the lungs that makes it hard to breathe. While the mechanism of action has not been fully established, the drug is thought to work by inhibiting biological processes involved in scar formation. Preclinical studies suggest pirfenidone can both reduce scar tissue formation and reduce existing scarring in the heart.

Researchers enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated natriuretic peptides (markers of fluid retention). Eligible patients underwent cardiac MRI scanning. Those who had evidence of scarring in the heart muscle, as indicated by an extracellular volume (a measurement of heart muscle scaring) of 27% or greater, were randomly assigned to take pirfenidone or a placebo daily. In total, 94 patients were randomized, with 47 assigned to each treatment group.

At one year, patients underwent a second cardiac MRI to measure change in heart muscle extracellular volume, the primary endpoint. Extracellular volume declined by 1.21% on average in patients who took pirfenidone compared with those receiving placebo, a reduction Miller said was likely to be clinically significant.

"Based on the data we have from previous observational studies, this amount of change in fibrosis could translate into a significant reduction in death and hospitalization for heart failure, but further work is needed to determine this," Miller said.

The study also found evidence that fluid retention, measured using natriuretic peptides, improved in patients who took pirfenidone compared to those receiving placebo.

"The associated reduction in natriuretic peptides provides support for heart scarring having a causal role in heart failure and being an efficacious therapeutic target," Miller said. "Hopefully this work can lead to further development of therapeutics that target heart fibrosis and scarring, and a phase three trial to see if pirfenidone improves patient outcomes."

The most common adverse events were nausea, insomnia and rash.

The study was funded by the National Institute for Health Research (UK). The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Neither company had any role in study design or conduct, including data collection, management, analysis and interpretation; preparation, approval of, and the decision to submit the abstract/manuscript.

Patients with heart failure with reduced ejection fraction (HFrEF) did not have better health outcomes if they took sacubitril/valsartan combination therapy compared with valsartan alone, according to new data presented at the American College of Cardiology's 70th Annual Scientific Session.

Heart failure, a leading cause of hospitalization among adults over age 65, is a condition in which the heart becomes too weak to pump blood effectively to the rest of the body, causing fatigue and shortness of breath. For patients with severe heart failure, treatment options are limited to a mechanical heart pump or heart transplant. Doctors have sought ways to slow the progression of severe heart failure to delay the need for these invasive options.

The U.S. Food and Drug Administration has approved sacubitril/valsartan for treatment of heart failure, but the major clinical trial that led to the drug combination's approval, called PARADIGM-HF, had relatively few participants with New York Heart Association (NYHA) Class IV heart failure, the most severe form of the disease. The new trial, called LIFE, was designed to determine whether sacubitril/valsartan is superior to valsartan alone in patients with severe HFrEF.

The trial found no significant improvements with the combination drug when compared with valsartan in terms of the primary endpoint: change in heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The results also showed no difference in terms of clinical outcomes, though results for some secondary and tertiary endpoints favored valsartan, including a finding that patients taking valsartan were significantly less likely to experience hyperkalemia (elevated potassium levels).

"The results of the LIFE trial show that sacubitril/valsartan is not superior to valsartan for lowering NT-proBNP levels in patients with advanced heart failure," said Douglas L. Mann, MD, Lewin Distinguished Professor of Cardiovascular Disease at Washington University School of Medicine and the study's lead author. "This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF. Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan."

For the trial, researchers enrolled 335 patients with advanced heart failure as defined by having reduced pumping capacity with an ejection fraction of less than 35% (a measure of the heart's squeezing ability for which a value of 50-70% is considered normal) as well as other physiological and functional markers of severe heart failure. Participants were randomly assigned to take either sacubitril/valsartan or valsartan alone for 24 weeks.

About one-third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials due to side effects including hypotension (low blood pressure and dizziness) and worsening renal function. These patients took a reduced dose.

"Patients with advanced heart failure are a very difficult group of patients to treat. It has been widely assumed that sacubitril/valsartan would be effective in all patients with heart failure," Mann said. "I think the drug works very effectively in patients with milder heart failure, but the results of the LIFE trial indicate that there is no evidence that sacubitril/valsartan is better than valsartan for more advanced heart failure, and there appears to be less hyperkalemia with valsartan."

The combination of sacubitril/valsartan is thought to work in part by reducing the size of the heart and improving its pumping ability.

"We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies. However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial," Mann said.

The study was limited by its relatively short duration, Mann said. In addition, the sample size fell short of the planned enrollment of 400 patients since the trial was stopped early in response to the COVID-19 pandemic.

The likelihood of people surviving COVID-19 in UK hospitals has been improving over time, a new study has found.

Research published in The Lancet Respiratory Medicine by the ISARIC Coronavirus Clinical Characterisation Consortium found that in-hospital mortality declined from 32% at the start of the first wave (Mar-Apr 2020) to 16% at the end of the first wave (Jun-Jul 2020).

In their study of 63,972 adults admitted to 247 UK hospitals the researchers found reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. This improvement was found to be associated with adoption of steroids as a newly proven treatment and improvements in respiratory support and critical care use, in part reflecting improved clinical knowledge.

Dr Annemarie Docherty, Senior Clinical Lecturer at the University of Edinburgh and a Consultant in Intensive Care Medicine, said: "The risk of death for people admitted to hospital with covid-19 was extremely high at around one in three at the beginning of the first wave, and consistently improved over subsequent months. Part of this improvement can be explained by differences in the people who were admitted to hospital, and how sick they were. Further reduction in the risk of death can be explained by improvements in care of covid-19 patients with treatments such as dexamethasone and better use of advanced respiratory support."

Professor Calum Semple, Professor of Child Health and Outbreak Medicine at the University of Liverpool and Co-Lead of ISARIC4C, said: "This is good news in a week where there is some anxiety about how new variants will impact upon the roadmap out of lock down. We now understand better how changes in patient characteristics and improvement in medical care have led to improved survival in UK hospitals. The discovery of what works and as importantly what does not work was only possible because of prepared research capacity that was put in place by the investigators collaborating at Universities of Liverpool, Edinburgh, Imperial College, and Oxford with NIHR support."

Professor Chris Whitty, Chief Medical Officer and co-lead of the National Institute for Health Research, said: "This National Institute for Health Research (NIHR) supported research provides evidence that frontline clinicians and healthcare professionals learnt and adapted to COVID-19 to improve patient care. Many of those healthcare professionals also facilitated research into treatments, such as dexamethasone, which was vital to the improvement in mortality described in this paper. These improvements are testament to the hard work of many."

The work is the latest result from ISARIC - a global network of clinicians and scientists who have been preparing to prevent disease and death from severe outbreaks since 2012 in readiness for a pandemic such as this. The ISARIC4C study is led by researchers from Liverpool, Edinburgh and Imperial College London and is principally funded by grants from the National Institute for Health Research (NIHR) and UK Medical Research Council.