Culture

Researchers at Vanderbilt University Medical Center (VUMC) and their colleagues have determined a key factor as to why COVID-19 appears to infect and sicken adults and older people preferentially while seeming to spare younger children.

Children have lower levels of an enzyme/co-receptor that SARS-CoV-2, the RNA virus that causes COVID-19, needs to invade airway epithelial cells in the lung.

The findings, published today in the
Journal of Clinical Investigation, support efforts to block the enzyme to potentially treat or prevent COVID-19 in older people.

"Our study provides a biologic rationale for why particularly infants and very young children seem to be less likely to either get infected or to have severe disease symptoms," said Jennifer Sucre, MD, assistant professor of Pediatrics (Neonatology), who led the research with Jonathan Kropski, MD, assistant professor of Medicine.

Sucre and Kropski are co-corresponding authors of the paper. Bryce Schuler, MD, PhD, a resident in Pediatrics and Genetics at VUMC and postdoctoral fellow in the Vanderbilt Stimulating Access to Research in Residency program, is the paper's first author.

There is still much to learn about SARS-CoV-2. But this much is known: After a viral particle is inhaled into the lungs, protein "spikes" that stick out like nail studs in a soccer ball attach to ACE2, a receptor on the surfaces of certain lung cells.

A cellular enzyme called TMPRSS2 chops up the spike protein, enabling the virus to fuse into the cell membrane and "break into" the cell. Once inside, the virus hijacks the cell's genetic machinery to make copies of its RNA.

Sucre and Kropski, who have collaborated since 2016 on studies of lung diseases in premature infants and adults, wondered if TMPRSS2 had something to do with the greater severity of COVID-19 symptoms observed in older people compared to children.

"Our research has always focused on understanding lung development and how infant lungs differ from adult lungs in their vulnerability to injury," Sucre said. "In this study we actually took the opposite approach, and were able to see how the developing lung by its differences is protected from SARS-CoV-2 infection."

The researchers were well equipped to begin such a study. As members of the international Human Cell Atlas (HCA) Lung Biological Network, they and their colleagues had built a dataset on lung development in the mouse using a technique called single-cell RNA-sequencing.

The technique can detect the expression of genes in individual cells of tissues such as the lung. In this way the researchers were able to track the expression of genes known to be involved in the body's response to COVID-19 over time.

They found that while the gene for ACE2 was expressed at low levels in the mouse lung, "TMPRSS2 stood out as having a really striking trajectory of increased expression during development," Schuler said.

With the help of VUMC pathologists, the researchers obtained and analyzed human lung specimens collected from donors of different ages, and confirmed a similar trajectory in TMPRSS2 expression to what they'd found in mice.

"What we found is that expression of (TMPRSS2) goes up significantly with aging, and we see that at the level of the gene and at the level of the protein," Sucre said. "We see a lot more TMPRSS2 in older individuals, in both humans and mice."

The researchers also used fluorescent probes to analyze autopsy specimens from three patients who died of COVID-19, and found the virus in three types of cells that express TMPRSS2.

TMPRSS2 is well known for its role in the development of prostate cancer. Drugs that block the enzyme and which have been approved for the treatment of advanced prostate cancer currently are being tested clinically as potential treatments for COVID-19.

The new findings reported today support further investigation.

"We do think TMPRSS2 could be an attractive target both in treatment and potentially as a prophylaxis for (preventing infection in) people at high risk of COVID exposure," Sucre said.

Given that phages are able to destroy bacteria, they are of particular interest to science. Basic researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin are especially interested in the tube used by phages to implant their DNA into bacteria. In collaboration with colleagues from Forschungszentrum Jülich and Jena University Hospital, they have now revealed the 3D structure of this crucial phage component in atomic resolution. The key to success was combining two methods - solid-state NMR and cryo-electron microscopy. The study has just been published in the journal Nature Communications.

With growing antibiotic resistance, phages have increasingly become the focus of research. Phages are naturally occurring viruses with a very useful property: they implant their DNA into bacteria and proliferate there until the bacterial cell is ultimately destroyed. This is why they are also referred to as bacteriophages (bacteria eaters).

This approach has already been shown to fight multidrug-resistant bacteria. Last year, the case of a girl from England hit the headlines, when she was cured from a serious antibiotic-resistant infection using engineered phages.

However, the widespread use of phage therapy is still a long way off. Many of the underlying principles that are key to advancing this therapy are not yet understood. For example, little was previously known about the appearance of the exact architecture of the tube used by phages to implant their DNA into bacteria. Now scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, together with colleagues from Forschungszentrum Jülich and Jena University Hospital, have managed to reveal the 3D structure of this crucial phage component in atomic resolution.

Designed for transporting DNA

"The structure and flexibility of the DNA tube attached to the icosahedron-shaped capsid is somewhat reminiscent of a spinal column," stated FMP's Professor Adam Lange, describing one of the new findings. "It seems to be perfectly designed for transporting DNA."

The researchers were able to gain fascinating insights into the structure and function of this sophisticated DNA transport pathway - in this case, from a variant of phage SPP1 - by innovatively combining solid-state NMR with cryo-electron microscopy (cryo-EM). Lange's research group further developed nuclear magnetic resonance spectroscopy (NMR) especially for this task under an ERC Grant; cryo-EM expert Professor Gunnar Schröder from Forschungszentrum Jülich performed the electron-microscopic investigations. In addition, new modeling algorithms were required for the computer-based combination of the two data sets for structure determination. These algorithms were developed by Professor Michael Habeck from Jena University Hospital. "The key to success was combining the two methods, representing a methodological milestone," commented Professor Lange.

While solid-state NMR is ideal for visualizing flexible structures and tiny details, cryo-EM provides insight into the overall architecture. The resulting image shows that six gp17.1 proteins organize into stacked rings, forming a hollow tube. The rings are connected by flexible linkers, making the tube very bendable. "We are now able to understand how negatively charged DNA is repelled from the likewise negatively charged interior wall of the flexible tube, passing through it smoothly," explained FMP's Maximilian Zinke, lead author of the study now published in Nature Communications. "The bacteria are ultimately destroyed via this pathway."

Milestone for integrated structural biology

According to group leader Adam Lange, besides representing a quantum leap forward in phage research, the work will also advance "integrated structural biology", the term for the combination of these two complementary methods.

Thanks to the recent installation of a new high-resolution Titan Krios electron microscope, the infrastructure required to achieve this is now available on Campus Berlin-Buch. Moreover, a 1.2 gigahertz device will soon be added to the existing NMR spectrometers. "Equipped with cryo-EM and the most sensitive NMR spectrometer in the world, we will be very present in integrative structural biology in the future," enthused Adam Lange. "This offers bright prospects for the campus and for the research location of Berlin."

Embargoed until 12:10 p.m. CT/1:10 p.m. ET, Friday, Nov. 13, 2020

DALLAS, Nov. 13, 2020 -- A single, daily pill combining blood pressure and cholesterol medications, along with the addition of a daily dose of aspirin, reduced cardiovascular disease events in people at risk for heart disease, according to late-breaking research presented today in a late-breaking clinical trial presentation at the American Heart Association's Scientific Sessions 2020. The virtual conference, held Friday, November 13 - Tuesday, November 17, 2020, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide. The manuscript of this study is simultaneously published today in The New England Journal of Medicine.

The medicine tested in this study is a fixed-dose combination therapy (or a "polypill") combining blood pressure and cholesterol lowering medications. Researchers assessed the polypill's effects on cardiovascular disease events - such as heart attack, stroke and cardiovascular death - when given alone or with aspirin, in patients considered at intermediate risk of cardiovascular disease. They also examined the effects of aspirin alone.

The International Polycap Study (TIPS)-3 is a large, randomized, placebo-controlled trial conducted in nine countries. The study included 5,700 people considered at intermediate risk of developing heart disease. The average age of the participants was 64 years, and 47% were male.

Participants were randomly assigned to different interventions: 1) 75 mg daily of aspirin; 2) a polypill combining blood pressure and cholesterol medication daily; 3) polypill and 75 mg aspirin daily; or 4) vitamin D 5,000 IU daily. Each intervention included a control group who received a matching placebo. The medications in the polypill were atenolol 100mg, ramipril 10mg, hydrochlorothiazide 25 mg, and simvastatin 40 mg.

Over the follow-up period of nearly five years, participants were monitored for the first occurrence of a major cardiovascular event, such as non-fatal heart attack, non-fatal stroke, heart failure, resuscitated cardiac arrest or cardiovascular death.

The analysis of all patient groups found:

the polypill alone reduced cardiovascular disease by 21%;

aspirin alone reduced cardiovascular death, heart attack or stroke by 14%;
and
the polypill plus aspirin reduced cardiovascular disease by 31%.

"Aspirin should be prescribed with a polypill in primary prevention for patients at intermediate risk of heart disease," said Salim Yusuf, M.D., B.S., D. Phil., a co-author of the study and professor of medicine at McMaster University School of Medicine in Toronto, Canada. "Our study results provide important data regarding the role of the polypill in preventing the development of heart disease."

Co-author Prem Pais, M.B.B.S., M.D., a professor in the division of clinical research and training at St. John's Research Institute in Bangalore, India, added, "We were also interested in evaluating if combining blood pressure and cholesterol reduction medications in a single pill would be effective for this population. This is a cost-effective strategy that could help meet global targets of reducing CVD by 30% by 2030."

"Use of a polypill plus aspirin can avert 3 - 5 million cardiovascular deaths globally," said Yusuf. "Future polypills, with newer statins, may reduce LDL cholesterol and blood pressure to a greater extent and could reduce cardiovascular disease risk greater than 50%."

DALLAS, Nov. 13, 2020 -- Patients who were hospitalized with acute heart failure and had iron deficiency were less likely to return to the hospital if given intravenous iron replacement, according to late-breaking research presented today at the American Heart Association's Scientific Sessions 2020. The virtual meeting is Friday, November 13 - Tuesday, November 17, 2020. It is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care. The manuscript of this study is simultaneously published today in The Lancet.

Study participants were stabilized after an episode of acute heart failure and given intravenous ferric carboxymaltose, an iron replacement therapy, at hospital discharge.

"Iron deficiency is common in patients with heart failure, and it is an independent risk factor for hospital admission and death," said Piotr Ponikowski, M.D., Ph.D., head of the department of heart diseases at Wroclaw Medical University in Wroclaw, Poland, and lead author of the study. "We tested the hypothesis that correcting iron deficiency with ferric carboxymaltose in patients admitted for an episode of acute heart failure and who have iron deficiency is effective in reducing the risk of recurrent hospitalization and cardiovascular death."

The AFFIRM-AHF trial enrolled 1,108 patients in 15 countries who were being discharged after a hospitalization for acute heart failure and found to have iron deficiency during their hospital stay. The participants' average age was 71, and 56% were men, with average heart ejection fraction measures of 33%. Ejection fraction measures the amount of blood pumped out by the heart with each contraction. A normal ejection fraction is between 50% and 70%.

After their heart condition was stabilized, patients received either intravenous ferric carboxymaltose or a placebo during the following 24 weeks, dosed according to the level of iron deficiency.

The analysis found significantly fewer hospital readmissions due to heart failure among the patients treated with intravenous ferric carboxymaltose compared to those who received the placebo. After 52 weeks, patients who received iron supplementation were 26% less likely to be re-admitted to the hospital for heart failure. This result was achieved with only one or two injections in 80% of the patients in the ferric carboxymaltose group.

Results for reduced risk of hospitalization were statistically significant; however, when the researchers looked at the combined goal of reducing hospitalizations and death, the results were not statistically different.

"This is the first study demonstrating the benefits of iron supplementation initiated in stabilized patients hospitalized for acute heart failure, and only two doses were needed in the vast majority of patients," Ponikowski said. "Health care professionals should screen patients with heart failure for the presence of iron deficiency, and intravenous iron should be considered for those with iron deficiency and ejection fraction of 50% or lower."

The rheumatoid arthritis drug baricitinib can block viral entry and reduce mortality in patients with moderate to severe COVID-19, according to translational research by an international team coordinated by researchers from Karolinska Institutet in Sweden. The findings, published in the journal Science Advances, support the continuation of ongoing randomized clinical trials.

"We are pleased to report a 71 percent reduction in mortality for the group receiving baricitinib in addition to standard care," says Volker Lauschke, corresponding author and associate professor of personalized medicine and drug development at the Department of Physiology and Pharmacology, Karolinska Institutet. "These results are especially encouraging seeing as the study included a large cohort of elderly patients, a group that is often excluded in other trials."

In the study, 83 patients hospitalized with COVID-19 pneumonia in Italy and Spain were treated with baricitinib in addition to standard care. Of these, 17 percent suffered an adverse outcome that resulted in death or invasive mechanical ventilation. This compared to 35 percent in the matched control group of 83 patients who received standard care only. The patients had a median age of 81 years.

The drug was generally well tolerated with a reduction in inflammation from the first treatment days, according to the researchers. Previously reported side-effects of long-term baricitinib use, including coagulopathy and thrombosis, were not evident in any of the patients, possibly due to treatment with anti-coagulating medicine. However, some adverse events including bacterial infections and gastrointestinal and cardiovascular complications were noted, although these were also observed in the control group so it is unclear what, if anything, can be ascribed to baricitinib.

In a prior study, the same team of researchers reported how they used artificial intelligence (AI) to identify baricitinib as a promising repurposing candidate for COVID-19. That study also showed how the drug inhibited inflammation and reduced the viral load of SARS-CoV-2.

In the current study, the researchers elaborated on those findings by demonstrating that interferons, cytokines made and released by host cells in response to viruses, significantly increases the expression of the ACE2 receptor, which acts as an entry point for SARS-CoV-2 into human cells. While liver injury is commonly observed in severe COVID-19, mechanisms and dynamics of SARS-CoV-2 infections had not been investigated in this organ.

By combining 3D mini organs of human liver cells, RNA sequencing and super-resolution microscopy, the scientists were able to show that barcitinib reversed ACE2 gene expression changes triggered by interferons and reduced SARS-CoV-2 infectivity. Interestingly, interferons did not have the same effect on the ACE2 receptor in lung organoids, suggesting that these signaling proteins affect pulmonary and liver organs differently.

"Our findings explain the dual anti-cytokine and anti-viral actions of baricitinib and support further evaluation in randomized control trials," says Ali Mirazimi, adjunct professor at the Department of Laboratory Medicine, Karolinska Institutet, and co-author of the study.

The researchers note that a limitation of the study was the lack of a placebo control group, which is included in industry-sponsored randomized controlled trials that are currently ongoing.

A clinical study involving 601 patients in Italy and Spain suggests that the JAK inhibitor drug baricitinib may enhance survival rates of patients with severe COVID-19, primarily by blunting the runaway immune inflammation known as "cytokine storm." While the authors are careful to note that their study was not a fully randomized trial with a placebo control group, the drug nonetheless had a notable effect, particularly in the Spanish treatment cohort, composed entirely of elderly patients over the age of 70. This suggests the treatment could address high rates of COVID-19 morbidity and mortality observed in this demographic worldwide. Further in vitro experiments in liver cell spheroids suggest the drug may also restrain abnormally high expression of the ACE2 receptor - required for entry of the SARS-CoV-2 virus - in these cells, helping to reduce viral infection of the liver, and likely other organs and tissues that do not normally express high levels of the ACE2 receptor. Using AI-based analyses, Justin Stebbing and colleagues had previously identified baricitinib, approved for the treatment of rheumatoid arthritis, as a promising treatment for COVID-19. They also previously found that the drug can reduce levels of the pro-inflammatory cytokine IL-6 in rheumatoid arthritis patients. Noting that levels of IL-6 have been reported to correlate with symptom severity in patients with COVID-19, Stebbing et al. enrolled a total of 179 hospitalized patients from Pisa, Italy, and 422 from Albacete, Spain. In the Pisa cohort, 37 patients were given baricitinib once daily for two weeks; of the 142 controls, 37 were matched with the drug recipient group using a "propensity score" based on the patients' age, sex, and several parameters related to their medical history. In Albacete, 46 patients were given a lower dose of the drug for shorter periods of time, due to safety considerations in this elderly cohort. As in Pisa, 46 of the 376 control patients were matched with the drug recipient cohort using the propensity score method. Overall, across both cohorts matched by propensity score, the patients who received baricitinib either died or received invasive mechanical ventilation at roughly half the rate (16.9%) of the untreated group (34.9%). Stebbing et al. note that randomized trials of the drug are currently underway. Based on their own results - including their additional experiments in liver cell spheroids - the authors note that they "eagerly await" the results of these trials.

The Barbegal watermills in southern France are a unique complex dating back to the 2nd century AD. The construction with 16 waterwheels is, as far as is known, the first attempt in Europe to build a machine complex on an industrial scale. The complex was created when the Roman Empire was at the height of its power. However, little is known about technological advances, particularly in the field of hydraulics, and the spread of knowledge at the time. A team of scientists led by Professor Cees Passchier from Johannes Gutenberg University Mainz (JGU) has now gained new knowledge about the construction and principle of the water supply to the mills in Barbegal. The research results were published in Scientific Reports.

A mill complex consisting of a total of 16 water wheels in two parallel rows

Watermills were one of the first sources of energy that did not depend on the muscle strength of humans or animals. In the Roman Empire they were used to make flour and sawing stone and wood. As one of the first industrial complexes in European history, the Barbegal watermills are an outstanding example of the development at that time. The mill complex consisted of 16 water wheels in a parallel arrangement of eight wheels each, separated by central buildings and fed by an aqueduct. The upper parts of the complex were destroyed and no traces of the wooden structures have been preserved, which is why the type of mill wheels and how they worked remained a mystery for a long time.

However, carbonate deposits that had formed from the flowing water on the wooden components remained. These were stored in the archaeological museum in Arles and only recently examined in detail. The researchers found an imprint of an unusual, elbow-shaped flume that must have been part of the mill construction. "We combined measurements of the water basins with hydraulic calculations and were able to show that the flume to which this elbow-shaped piece belonged very likely supplied the mill wheels in the lower basins of the complex with water," said Professor Cees Passchier. "The shape of this flume was unknown from other watermills, either from Roman or more recent times. We were therefore puzzled as to why the flume was designed this way and what it was used for."

An elbow-shaped flume as a unique adaptation for the Barbegal mills

At first glance, the team found such a flume unnecessary and even disadvantageous, because it shortens the height from which the water falls onto the mill wheel. "However, our calculations show that the oddly shaped flume is a unique adaptation for the Barbegal mills," explained Passchier. The distribution of the carbonate deposits in the elbow-shaped flume shows that it was inclined slightly backwards against the direction of the current. This created a maximum flow rate in the first, steep leg of the flume, and at the same time the water jet to the mill wheel obtained the correct angle and speed. In the complicated mill system, with small water basins, this unique solution was more efficient than using a traditional, straight water channel. "That shows us the ingenuity of the Roman engineers who built the complex," emphasized Passchier.

"Another discovery was that the wood of the flume was probably cut with a mechanical, water-powered saw, which is possibly the first documented mechanical wood saw - again evidence of industrial activity in ancient times." The research was carried out by a multidisciplinary team of experts in geology, geochemistry, hydraulics, dendrochronology, and archaeology.

The carbonate deposits that formed on the ancient hydraulic structures are an important tool for the researchers for archaeological reconstructions. In an earlier project, the team led by Professor Cees Passchier was able to show that the flour from the Barbegal mills was probably used to make ship biscuits. "The carbonate deposits give us extremely exciting insights into the skills of Roman technicians at a time that can be seen as the direct predecessor of our civilization," added Passchier, Professor of Tectonic Physics and Structural Geology at the JGU Institute of Geosciences from 1993 to 2019, now Senior Research Professor in Geoarchaeology.

Melatonin is used as a dietary supplement to promote sleep and get over jet lag, but nobody really understands how it works in the brain. Now, researchers at UConn Health show that melatonin helps worms sleep, too, and they suspect they've identified what it does in us.

Our bodies produce melatonin in darkness. It's technically a hormone, but you can readily buy melatonin as a supplement in pharmacies, nutrition stores, and other retail shops. It's widely used by adults and often in children as well.

Melatonin binds to melatonin receptors in the brain to produce its sleep-promoting effects. Think of a receptor as a keyhole, and melatonin as the key. The two keyholes for melatonin are called MT1 and MT2 in human brain cells. But scientists didn't really know what happens when the keyhole is unlocked. Now UConn Health School of Medicine neuroscientists Zhao-Wen Wang and Bojun Chen and their colleagues have identified that process through their work with C. elegans worms, as reported in PNAS on Sept. 21. When melatonin fits into the MT1 receptor in the worm's brain, it opens a potassium channel known as the BK channel.

A major function of the BK channel in neurons is to limit the release of neurotransmitters, which are chemical substances used by neurons to talk to each other. In their search for factors related to the BK channel, the Wang and Chen labs found that a melatonin receptor is needed for the BK channel to limit neurotransmitter release. They subsequently found that melatonin promotes sleep in worms by activating the BK channel through the melatonin receptor. Worms that lack either melatonin secretion, the melatonin receptor, or the BK channel spend less time in sleep.

But wait--worms sleep?

Indeed they do, says Chen. There's actually been quite a lot of research on worm sleep, and researchers found that sleep is similar between worms and mammals like humans and mice.

Wang and Chen next plan to see if the melatonin-MT1-BK relationship holds in mice. The BK channel is involved in all kinds of bodily happenings, from epilepsy to high blood pressure. By learning more about the relationships between the BK channel, sleep, and behavioral changes, the researchers hope both to understand melatonin better and also help people who suffer from other diseases related to the BK channel.

A type of arthritis drug may reduce the risk of dying for elderly patients with COVID-19.

This is the finding of a new international study, led by scientists at Imperial College London and the Karolinska Institutet, Sweden, published in the journal Science Advances.

In the early-stage study, 83 patients, with a median age of 81 and all suffering from moderate to severe COVID-19 infection, were given a drug called baricitinib. This medication is usually used to treat rheumatoid arthritis, and was initially identified by the Imperial team using artificial intelligence as a drug that could have anti-viral and anti-inflammatory effects.

In the study, the patients, who were in multiple hospitals across Italy and Spain, had a 71 per cent reduced risk of dying compared to patients who had not taken the drug. The study also found that 17 per cent of patients who were given the drug died or needed to go on a ventilator, compared to 35 per cent in the control group who were not given the medication.

The research team say the findings are being followed up with large-scale clinical trials.

Professor Justin Stebbing, co-lead author of the study from the Department of Surgery and Cancer at Imperial said: "We urgently need to find more effective treatments for COVID-19 while we wait for a vaccine to become widely available. This is one of the first COVID-19 treatments to go from computer to clinic and laboratory. It was first identified by an AI algorithm in February, which scanned thousands of potential drugs that could work against this virus.

"The study suggests this drug can aid recovery of patients with moderate to severe COVID-19, and may provide a new weapon in our arsenal against the virus. Large-scale clinical trials of this drug, to further investigate its potential, are now under way"

In the research, scientists from the Karolinska Institutet in Sweden together with the Imperial team grew miniature human organs in the lab, called organoids, to investigate how exactly the drug may combat COVID-19.

The findings revealed that the drug may help work in two ways: reduce organ damage caused by inflammation, and blocking the virus entering human cells.

When infected with the COVID-19 virus, called SARS-CoV-2, the body releases different types of inflammatory molecules, called chemokines and cytokines. These molecules act as the early warning system for the body, telling the immune system the body is under attack.

However, in the case of COVID-19, particular cytokine and chemokines, including those called interleukins and interferons, causes this warning system to spiral out of control, and trigger a so-called cytokine storm.

This cytokine storm not only causes significant damage to the body's organs, but the study revealed it also helps the virus gain access inside human cells.

The study showed a particular cytokine, called an interferon, increases the number of receptors, or docking points, for the virus. By doing this it, in effect, lowers the drawbridge and lets the virus into the cells of the body.

The researchers revealed the drug blocks this process occurring and so increases survival from COVID-19. The research also suggested COVID-19 increases the activity of genes related to platelets, which can make the blood sticky and more likely to form clots. The drug baricitinib was shown to reduce the activity of the genes.

Professor Volker Lauschke, co-lead author from Karolinska Institutet in Sweden, explained: "This study confirms what AI predicted, and what we were hearing from patient case reports. For instance one case involved an 87-year-old severely unwell patient from Foggia, Italy, who showed rapid improvement after being given the drug, whereas her husband and son, who did not receive baricitinib, died. This study has also shone a light on exactly how this drug may protect us at the cellular level. This helps us understand why other types of drugs are proving beneficial, or not beneficial, as we as help identify other treatments which may tackle COVID-19."

Professor Stebbing added: "We have seen the top line results of a randomized study called the Adaptive Covid Treatment Trial-2 announced recently, showing benefits of baricitinib plus remdesevir, compared to remdesvir alone in over one thousand patients. Other very large trials occurring now include COV-BARRIER, and this will help create a fuller picture of the benefits and side effects of the oral medication (a small number of the patients in our study needed to stop the treatment due to problems with liver function). Further trials comparing baricitinib to other drugs in COVID-19 patients would also be helpful in improving outcomes."

LOS ANGELES (Nov. 13, 2020) -- New research presented today at the American Heart Association Scientific Sessions suggests neither vitamin D nor the omega-3 fatty acids found in fish oil prevent the development of atrial fibrillation, a potentially serious heart rhythm disturbance.

"Our trial results do not support taking fish oil or vitamin D supplements to prevent atrial fibrillation," said Christine M. Albert, MD, MPH, the study's lead author and chair of the Department of Cardiology in the Smidt Heart Institute, who presented the research at the late-breaking science session. "However, these supplements also did not elevate the risk of atrial fibrillation, which is good news for individuals taking them for other health conditions."

Past data from observational studies have been conflicting, leaving both patients and clinicians uncertain on recommendations regarding prevention of atrial fibrillation with these supplements.

"This is the first large-scale trial that led us to a definitive result," said Albert.

Results are based on a randomized clinical trial involving more than 25,000 men and women from all over the United States without a history of atrial fibrillation. During a more than five-year period, 900, or 3.6%, of participants were diagnosed with atrial fibrillation.

There were no statistically significant differences between the participants who were assigned to take vitamin D or fish oil supplements and the participants who were assigned to take a placebo.

Atrial fibrillation, or AF, is the most common type of abnormal heart rhythm, causing the heart to contract irregularly and, sometimes, too quickly. It is estimated to affect 33 million people worldwide.

The condition can lead to clotting inside the atrium chamber of the heart and clots can then travel from the heart to the brain, causing a stroke. Atrial fibrillation can also lead to weakening of the bottom chamber of the heart, resulting in fluid buildup or heart failure. Importantly, it often results in significant symptoms that can adversely affect one's quality of life.

While this research is important in educating patients about effective preventive measures, Albert emphasizes the need for more research directed at avoiding the condition.

"Although these two supplements do not prevent atrial fibrillation, recent studies have suggested that lifestyle modifications such as maintaining a healthy weight, controlling blood pressure, and moderating alcohol intake may lower risk of atrial fibrillation," said Albert. "We need to continue to educate the public on ways to lower their risk as well as search for new ways to prevent this condition."

Researchers from SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute's (NCI) Division of Cancer Diagnosis and Treatment (DCTD), part of the National Institutes of Health, have shown that the immunotherapy combination of ipilimumab and nivolumab shrinks rare angiosarcoma tumors in 25 percent of all patients, with some having an even stronger response to the drug combination.

Results of the SWOG study, led by Michael Wagner, MD, of the University of Washington, the Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance, and conducted by the NCI National Clinical Trials Network (NCTN), were shared in a virtual oral presentation today at The Society for Immunotherapy of Cancer's (SITC) 35th Anniversary Annual Meeting. The findings provide the first rigorous evidence that immunotherapies can treat angiosarcoma, a rare cancer of blood and lymph vessels that often develops in the skin. About 500 Americans are diagnosed with angiosarcoma each year.

Wagner's study is part of a path-breaking clinical trial called DART, short for Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors. Launched in 2017 with sponsorship by the NCI, DART is proving a successful model for the study of rare cancers. Using an innovative "basket" design, DART tests the effectiveness of the ipilimumab and nivolumab combination in a variety of rare tumor types, thanks to a Cooperative Research and Development Agreement (CRADA) between the NCI and Bristol-Myers Squibb, the maker of both immunotherapy drugs. Through DART, the drug combination has completed testing in 36 cohorts of rare cancer patients, with another 12 cohorts still taking the drugs, and four cohorts temporarily closed for data analysis. Promising results have previously been reported in patients with other rare cancers, including neuroendocrine tumors and metaplastic breast cancer, while results from patients with thyroid tumors will also be reported at the 2020 SITC meeting.

An expert in sarcoma, Wagner wanted to replace anecdotal reports that immune checkpoint inhibitors like ipilimumab and nivolumab can successfully treat angiosarcoma with a prospective phase II trial. Wagner and his SWOG team enrolled 16 patients, all with advanced or inoperable cancer and all of whom were previously treated with chemotherapy. They found that 25 percent of patients saw their tumors shrink, regardless of where in the body their angiosarcoma occurred. The news was even better for patients whose cancer presented on the face or scalp. Those patients saw a 60 percent response rate to the drugs. In some cases, the response was long lasting. Two patients remain cancer free one year after treatment.

"These results open a new way to treat angiosarcoma - with immunotherapy," Wagner said. "At SWOG, we're planning a larger follow-up study to see if this combination can work as a first line of treatment."

The SWOG team also found that most patients - 75 percent - experienced side effects from the drugs and 25 percent experienced severe side effects.

Rare cancers make up about a quarter of all cancers diagnosed worldwide. But because there are hundreds of types, and because each is so scarce, rare cancers are notoriously difficult to study. With expert advice from the NCI and the SWOG statistical team, the study leadership - Sandip Patel, MD, and Razelle Kurzrock, MD, both of UCSD Moores Cancer Center, and Young Kwang Chae, MD, of Northwestern University - came up with DART's unique basket design. It's proven successful. The study has successfully enrolled 755 with rare disease who may not otherwise have been eligible for a clinical trial. It also is plowing important ground in translational medicine. Tumor and blood specimens from DART patients will soon undergo DNA and RNA sequencing to shed light on their molecular makeup and how immunotherapies may help disarm certain rare cancer types. This work will be done through the Cancer Immune Monitoring and Analysis Centers (CIMACs), which were established by the NCI through its Cancer Moonshot initiative.

Embargoed until 11:05 a.m. CT/12:05 p.m. ET, Friday, Nov. 13, 2020

DALLAS, Nov. 13, 2020 -- Taking omega-3 fatty acids and vitamin D3 supplements does not neither increase nor decrease the risk of developing atrial fibrillation, according to late-breaking research presented today at the American Heart Association's Scientific Sessions 2020. The virtual meeting is Friday, November 13 - Tuesday, November 17, 2020, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide.

Atrial fibrillation is a rapid, irregular heartbeat caused by chaotic electrical signals in the top chambers of the heart. Atrial fibrillation is the most common heart rhythm disturbance, and it can lead to blood clots, strokes, heart failure and other heart-related complications. Atrial fibrillation risk increases with age, high blood pressure and heavy drinking and can be common among multiple, biologically related family members.

Evidence from previous observational studies has been conflicting, suggesting both risks and potential health benefits of fish oil - a source of omega-3 fatty acids - and vitamin D for atrial fibrillation.

"Once established, atrial fibrillation is difficult to treat and results in symptoms that can impair patients' quality of life," said Christine M. Albert, M.D., M.P.H., founding chair of the department of cardiology in the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles and lead author of this study. "Current treatment options have limited long-term success and significant risks, and there is a pressing need for preventive strategies."

The VITAL Rhythm Trial is the first, placebo-controlled, randomized clinical trial investigating preventive therapies for atrial fibrillation. This trial evaluated whether supplementation with vitamin D3 (2000 IU/day) and omega-3 fatty acids (EPA:DHA in 1.2:1 ratio; 840mg/day) can reduce the risk of developing atrial fibrillation compared to placebo.

The five-year study, from 2012 - 2017, included 25,119 adults, ages 50 and older who had no history of atrial fibrillation. About half of the participants were female, 21% were black, and the average age was 67. Atrial fibrillation diagnoses were established both by participant self-report and claims data from the Centers for Medicare and Medicaid Services. Electrocardiogram evidence and/or a physician's report documenting a new diagnosis of atrial fibrillation were required for confirmation.

During the trial follow-up period, 900 participants developed atrial fibrillation, 3.6% of the study population. There were no statistically significant differences between the groups who were assigned to supplemental EPA/DHA and/or vitamin D3 compared to individuals who were assigned to the placebo.

Albert added, "With regards to clinical care, these results do not support using marine omega-3 fatty acids or vitamin D to prevent atrial fibrillation. However, the results do provide reassurance that these supplements do not increase the overall risk of atrial fibrillation and appear to be generally safe for patients who are taking these supplements for other reasons."

It's a decision being made thousands of times over inside hospitals all around the country: is it time to place a patient struggling to breathe on a ventilator? For all of the attention ventilators have received during the COVID-19 pandemic, deciding when to place patients on them--and when to take them off--is complex. Michigan Medicine researchers have been investigating best practices for mechanical ventilation for years, never knowing how applicable their work would become.

In a new paper in the journal CHEST, lead author and clinical lecturer Jennifer Ervin, Ph.D., MSc of the division of pulmonary and critical care medicine at Michigan Medicine and her team outline 20 evidence-based practices shown to reduce time spent on a ventilator and death in patients with acute respiratory failure and acute respiratory distress--conditions that have many overlaps with severe COVID-19. "Hopefully, this work will inform clinical decision-making in these complex care settings," says Ervin.

The trigger points for ventilation, she explains are "junk in the lungs" or congestion visible on an X-ray and the inability to maintain normal oxygen levels in the blood. "Ventilation gives the body and lungs time to heal," she says.

Optimizing how long a patient is on a ventilator can help prevent negative outcomes both immediately and later on, Ervin says. And putting someone on a ventilator and then monitoring them is a team sport, she says. "You have attending physicians working with registered nurses, respiratory therapists, pharmacists, and trainees."

Mechanical ventilated patients typically must be sedated and/or paralyzed so that the machine can do the work of breathing. But over-sedation can lead to a host of problems, including delirium and later on, post intensive care syndrome, which has many of the same features as being reported by those with "long COVID."

Best practices that have emerged include prone position, or placing a ventilated patient on their stomach, to give the lungs more room to inflate--a practice that should be done early, says Ervin. Lung protective ventilation, which involves avoiding over-inflating the lungs, has also been shown to improve outcomes. However, "anywhere from 30-60% of patients are potentially having their lungs over-inflated," she says.

Furthermore, several practices revolve around frequently checking to see whether it is time to take a patient off the ventilator, including turning down sedation to check for delirium and doing breathing exercises to see how well a person is doing without the machine's help.

The team's next step has been to prioritize the 20 best practices they've identified, acknowledging that it's near impossible for healthcare providers to do them all, especially during the stress of a pandemic. "None of these happen in a vacuum. It's a continuum of care and a lot of practices are contingent on one another," says Ervin. "We are trying to give the tools...here's everything in one place. This is just one step, though."

Critical care at Michigan Medicine is a well-oiled machine because everyone understands what their role is, she says. She notes that in a time of crisis you have to do the best you can, but doing even three or four of these evidence-based practices is better than none. "This is a very important resource for clinicians who may not be familiar with how to optimize mechanical ventilation, as well as for future trainees."

BOSTON - A public health strategy that combines contact tracing and community-based screening with isolation and quarantine centers can substantially reduce infections, hospitalizations and deaths from COVID-19 while being cost-effective in low-and-middle-income countries like South Africa, a study by Massachusetts General Hospital (MGH) has found. In a paper published in The Lancet Global Health, the research team reported that this battery of health interventions, implemented either fully or partially, could offer good value for the money and, in some scenarios, even reduce health care expenditures in South Africa.

"Our results demonstrate to public policymakers that a multi-faceted COVID-19 strategy can prevent infections and save lives even where budgets and resources are constrained," says investigator Krishna Reddy, MD, with the Medical Practice Evaluation Center at MGH, and corresponding author of the study.

By September 2020, 16 countries in sub-Saharan Africa (SSA) had each reported more than 10,000 COVID-19 cases. Raising the health risk to populations in this region are high urban density, limited opportunities for physical distancing, and poor access to hygiene and health care facilities. In the past, the World Health Organization has issued recommendations for disease surveillance and control in low- and middle-income countries, and some have implemented programs like contact tracing and community-based screening in response to previous infectious disease epidemics like Ebola and tuberculosis.

The MGH research team, in collaboration with the Africa Health Research Institute, developed a COVID-19 microsimulation model to evaluate clinical and economic outcomes of various combinations of five complementary epidemic control interventions in KwaZulu-Natal, South Africa. Those interventions are health care testing, where diagnostic testing is performed at designated health care centers; contact tracing to identify those who may have come in close contact with someone with COVID-19; isolation centers for people with COVID-19; mass symptom screening of local populations by community health workers; and quarantine centers for people who have been in close contact with someone with COVID-19 but have tested negative.

A public health program built on all five interventions in response to the pandemic could reduce COVID-19 deaths by 94% compared to the use of health care testing alone over one year, the study found. It also estimated that a program combining all interventions would cost an additional $340 per year of life saved, which represents similar or better value than many other established public health initiatives in South Africa, including tuberculosis diagnostic testing and cervical cancer screening. In some epidemic growth scenarios, combinations of interventions saved health care costs over one year compared with health care testing alone. "Our results show that these upfront investments can both save lives and actually lower health care costs by substantially reducing the need for hospitalizations for COVID-19," says Mark Siedner, MD, MPH, with the MGH Medical Practice Evaluation Center, and senior author of the study.

Many countries have the infrastructures in place for some or all of these interventions, the researchers pointed out. Contact tracing and community-based screening, for example, have frequently been deployed in the past through networks of community health workers. And isolation centers, which are likely to require the greatest investment, have been implemented successfully in response to Ebola epidemics in West Africa and the Democratic Republic of Congo, where health care resources are among the scarcest in the world. According to the MGH research team, isolation centers would be particularly effective in areas with high household density and limited capacity for in-home isolation. Quarantine centers were also shown by the MGH microsimulation model to be a cost-effective way to reduce the health impact of epidemics, but their implementation must recognize social and human rights issues that have plagued mandatory quarantine in some settings.

"Even where quarantine centers are not feasible due to lack of public support, implementing the other interventions we described can provide major clinical benefits in an economical manner," stresses Reddy. "The bottom line is that prevention goes a long way, and we're hopeful that decision makers will work to translate the evidence we've uncovered into effective public policy and interventions for pandemic control."

As almost any new parent will attest, the issue of infant sleep can be a nightmare. But the challenges and consequential health effects of infant sleep problems may, like so many other health disparities, disproportionately affect families of different racial/ethnic backgrounds and household socioeconomic statuses. A new study led in part by researchers from Brigham and Women's Hospital takes a look at 24-hour sleep-wake cycles for infants across racial/ethnic and socioeconomic categories. The team found several distinct differences in sleep-wake patterns, largely explained by discrepancies in socioeconomic status. Findings are published in Sleep.

"What we knew before this study was that, in general, individuals with low socioeconomic backgrounds, as well as children and adults who are minorities, had shorter sleep than white individuals and higher socioeconomic individuals," said senior author Susan Redline, MD, MPH, of Brigham's Division of Sleep and Circadian Disorders. "What wasn't so clear was when those differences first emerged."

Previous studies have used responses from surveys of parents to draw conclusions about how sleep duration varies by race and socioeconomic status, but when such disparities arise was previously unknown. This study characterized sleep-wake patterns in infants at 1- and 6-months old using ankle-placed actigraphs and parent-completed sleep diaries, examining differences among infants with different racial/ethnic backgrounds and household socioeconomic statuses.

The study consisted of 306 infants -- 42.5 percent non-Hispanic white, 32.7 percent Hispanic, 17.3 percent Asian, and 7.5 percent Black. Between the ages of 1 and 6 months, night sleep duration increased by 65.7 minutes, night awakenings decreased by 2.2 episodes, and daytime sleep duration decreased by 73.3 minutes, confirming that night sleep increases and day sleep decreases overall in the first six months of life.

The team found several distinct differences in sleep-wake patterns across these categories:

Black and Hispanic infants experienced less of an increase in night sleep length when compared to white infants;

infants in families with lower maternal education and household income experienced less of an increase in night sleep duration;

Asian infants exhibited more frequent night awakenings than all other racial categories.

Additionally, Asian infants were the only group to still have a night sleep duration deficit compared to white infants at 6 months after adjusting for household socioeconomic status, meaning, unlike Hispanic and Black infants, Asian infant night sleep duration may not be explained by corresponding SES.

Car rides, parental rocking, and other environmental factors may reduce the accuracy of a sleep-wake assessment. Additionally, the numbers of Black and Asian families were relatively low, driving Redline to conclude that the disproportionate night awakenings recorded in Asian infants may have been by sheer chance. Such discrepancies still intrigue Redline, as they point to other avenues for exploration: parenting styles, environmental cues, maternal stress, and more.

"We know that there are these significant differences in sleep duration and sleep consolidation in older children and adults; we know those are associated with negative health outcomes and behaviors," said Redline. "Now we see that they emerge early in life, pointing to a totally new set of risk factors."

This study is one of four in a longitudinal collaborative effort to investigate the sleep-wake cycles of children ages 1 month through 2 years, with the primary goal of tracking weight gain.