Culture

Findings from the RECOVERY trial do not support use of lopinavir-ritonavir to treat patients admitted to hospital with COVID-19

Lopinavir-ritonavir treatment does not significantly reduce deaths, length of hospital stay, or the risk of needing to be placed on a ventilator

The authors recommend that clinical guidelines be updated based on findings from the RECOVERY trial

The drug combination lopinavir-ritonavir is not an effective treatment for patients admitted to hospital with COVID-19, according to the results of a randomised controlled trial published in The Lancet.

Many clinical care guidelines have recommended lopinavir-ritonavir - an antiviral medication approved to treat HIV/AIDS - for the treatment of patients hospitalised with COVID-19. However, these guidelines should now be updated, authors say.

The Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial, under way at 176 UK hospitals, is the first large-scale randomised clinical trial to report the effects of lopinavir-ritonavir in patients admitted to hospital with COVID-19.

Professor Martin Landray from the Nuffield Department of Population Health at the University of Oxford, UK, who co-leads the RECOVERY trial, said: "Treatment of COVID-19 with the drug combination lopinavir-ritonavir has been recommended in many countries. However, results from this trial show that it is not an effective treatment for patients admitted to hospital with COVID-19." [1]

"Since our preliminary results were made public on June 29, 2020, the World Health Organization has halted lopinavir-ritonavir treatment groups involved in its SOLIDARITY trial and reported that their interim results are in line with those presented here." [1]

Between March 19 and June 29, 2020, 1,616 patients in the RECOVERY trial were randomised to receive lopinavir-ritonavir while 3,424 patients received usual care alone. Those on lopinavir-ritonavir received 400 mg of lopinavir and 100 mg of ritonavir by mouth every 12 hours for 10 days or until discharge, if sooner. The primary outcome was 28-day all-cause mortality.

Findings from the trial indicate that using lopinavir-ritonavir to treat patients hospitalised with COVID-19 does not reduce deaths within 28 days of treatment beginning. 23% (374/1,616 patients) who received lopinavir-ritonavir and 22% (767/3,424 patients) allocated to usual care died within 28 days.

Professor Peter Horby, from the Nuffield Department of Medicine at the University of Oxford, UK, co-Chief Investigator of the RECOVERY trial, said: "The result from the RECOVERY trial is clear. When combined with findings from an earlier, smaller trial and with the WHO interim results, this provides strong evidence that lopinavir-ritonavir is not an effective treatment for patients hospitalised with COVID-19." [1]

"Whilst it is disappointing that there was no significant benefit from lopinavir-ritonavir for patients in hospital, these findings have allowed us to focus our efforts on other promising treatments, and have informed the way in which individual patients are treated." [1]

The authors also found that lopinavir-ritonavir did not reduce the length of patients' hospital stay, with 69% (1,113/1,616 patients) in the lopinavir-ritonavir group leaving hospital within 28 days, compared with 70% (2,382/3,424 patients) of those receiving usual care. Both groups had a median stay of 11 days.

No significant difference was observed in the risk of needing to be placed on a ventilator, with 10% (152/1,556 patients) of those in the lopinavir-ritonavir group needing ventilation, compared with 9% (279/3,280 patients) in those receiving usual care.

Results were consistent across all patient subgroups - including age, sex and ethnicity - with no evidence of any benefit from lopinavir-ritonavir treatment.

The authors note that few patients who had undergone intubation - insertion of a tube into the airway to aid breathing using a ventilator - took part in the trial due to difficulties in giving the treatment to patients who could not swallow, and so it is not possible to draw conclusions about the effectiveness of lopinavir-ritonavir for mechanically ventilated patients.

Results from the large-scale RECOVERY clinical trial - combined with findings from an earlier, smaller trial and with the WHO interim results - provide strong evidence that lopinavir-ritonavir is not an effective treatment for patients hospitalised with COVID-19, and clinical care guidelines should be updated accordingly.

Writing in a linked Comment, lead authors Bin Cao and Frederick G Hayden (who were not involved the study), from the China-Japan Friendship Hospital and Capital Medical University, China, and the University of Virginia School of Medicine, USA, say: "Compared with the first randomised trial to investigate lopinavir-ritonavir in patients with COVID-19 by Cao and colleagues (including the authors of this Comment), the size of the lopinavir-ritonavir group in the RECOVERY trial was much larger and hence provides a more solid evidence base regarding possible lopinavir-ritonavir treatment effects. [...] The findings of these two open-label studies support each other and conclude that lopinavir-ritonavir is not effective in improving outcomes for patients admitted to hospital with COVID-19."

Ambitious efforts at UVA Cancer Center to improve care delivered to patients with cancer that has spread to the brain have yielded important insights and tools that can benefit other hospitals, a new publication reports.

The tools include the first set of metrics to assess care provided for these secondary tumors, known as brain metastasis. The UVA team says its findings will help doctors and patients make better-informed treatment decisions, enhance the care of brain metastases, and enable hospitals to improve the coordination and effectiveness of their interdisciplinary treatment programs.

"The proposed set of measurements serves as the framework to gauge the performance of multidisciplinary programs, with the goal of providing optimal consistent and coordinated care to patients with brain metastasis," said Camilo E. Fadul, MD, a neuro-oncologist at UVA Health and UVA Cancer Center.

Quality Care for Brain Metastases

Brain metastases are the most common tumors affecting the central nervous system. Although any type of cancer can spread to the brain, the most frequent are lung cancer, breast cancer and melanoma.

As patients with cancer are living longer, the frequency of brain metastasis is on the rise. So doctors are seeking to personalize treatment from a menu of options that include surgery, radiation (either targeted stereotactic radiosurgery or whole brain radiation), chemotherapy, targeted oral therapies and immunotherapy. Because of the complexity of treatment decisions and the need to provide safe and consistent patient-centered care, UVA takes an interdisciplinary approach, which brings together providers with expertise in radiation oncology, neuro-oncology, medical oncology, neurosurgery and palliative care.

While developing this program, the UVA group led by Dr. Fadul identified relevant outcome measurements to inform treatment decisions, evaluate the care process and implement interventions that will improve value. They tested the measurements by looking at hundreds of patients' data to identify strategies that will improve outcomes, and they reviewed every detail of UVA's care for patients, beginning with their brain metastasis diagnosis and ending with the patients' discharge.

They identified relevant outcome measurements for patients receiving brain metastases directed treatment by looking at survival - specifically, survival more than 90 days after the important milestones of diagnosis, surgery, stereotactic radiosurgery and whole-brain radiation therapy. Other measurements examined processes that may translate in better outcomes, such as whether patients had advance directives outlining the type of care they wish to receive documented in their electronic medical record, if they had palliative care consultation and if the drug memantine, which may protect cognitive function from possible radiation injury, was prescribed to patients receiving whole-brain radiation therapy.

"The proposed set of performance measurements serves as the foundation for improving healthcare delivery, for characterizing the structure, processes and functions of the optimal interdisciplinary teams, and for filling the gap associated with disparities in the quality of the care and outcomes after diagnosis of brain metastases," Dr. Fadul said.

He noted the measurements need to incorporate the input and perspective from patients and caregivers -- what are called "patient-reported outcomes." In addition, the metrics have to be refined and validated by other experts in the field. Several projects are already underway to build upon these results and further improve the care provided to patients with brain metastasis at UVA.

"Identification of areas for quality improvement, sharing among hospitals of data and strategies that improve outcomes, and development of consistent treatment guidelines based on continuous performance measurements, like the ones we proposed, will enhance the quality and value of the care provided to the growing population of patients afflicted with brain metastasis," Dr. Fadul said.

HOUSTON -- Researchers at The University of Texas MD Anderson Cancer Center have identified molecular and cellular characteristics of anti-CD19 CAR T cell infusion products associated with how patients with large B-cell lymphoma (LBCL) respond to treatment and develop side effects.

The research team also found that early changes in circulating tumor DNA one week after CAR T cell therapy may be predictive of treatment response in a particular patient. The paper was published online today in Nature Medicine.

"CAR T cell therapy is highly effective against LBCL," said corresponding author Michael Green, Ph.D., associate professor of Lymphoma and Myeloma. "However, we experience two main clinical challenges: achieving long-term remission and managing treatment-associated adverse events."

This study suggests that, within the first week of therapy, clinicians may be able to identify a subset of patients who may experience more poor outcomes or adverse treatment reactions, said Green. This would allow the care team to adjust therapy to improve efficacy or to act to mitigate toxicity.

CAR T cell signature, early molecular response may predict long-term outcomes

For this study, researchers performed single-cell analysis on CAR T cells to study gene expression profiles in the infused cells. CAR T cells were collected from those remaining in infusion bags following treatment of 24 patients with LBCL. These genetic profiles were compared to treatment responses, determined at three months post-infusion by PET/CT scan.

"When we look at the characteristics of the infused CAR T cells, we found that samples from patients who were less responsive to treatment had exhausted T cells, whereas those who experienced complete responses had T cells expressing 'memory' signatures," said co-corresponding author Sattva Neelapu, M.D., professor of Lymphoma and Myeloma. "Additionally, one cellular signature of T cell exhaustion was more commonly found in patients who exhibited a poor molecular response, and poor molecular response is generally associated with less-positive, long-term outcomes."

Further, the researchers analyzed early molecular responses in the patients by monitoring changes in circulating tumor DNA from treatment to one week post-infusion. The magnitude of change in tumor-associated DNA corresponded with response, suggesting that patients who displayed an early molecular response were more likely to experience a clinical response to treatment.

CAR T cell features predict likelihood of severe side effects

Adverse side effects of CAR T cell therapy can include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). These adverse events can delay patients' recovery and can lead to increased need for hospitalization and intensive care.

"When we examined the infusion product, we found that a cell population with characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with development of high-grade neurotoxicity," said Green. "Detecting these cells may subsequently lead us to identify patients who would be at higher risk of developing neurotoxicity, allowing us to provide prophylactic treatment with agents that target the specific cellular features."

Further examination may lead to insights into the types and attributes of the cells present within the CAR T infusion product.

"This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important," said co-corresponding author Linghua Wang, M.D., assistant professor of Genomic Medicine. "Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results."

These findings will help researchers develop clinical interventions that can block or target these cells. They also plan to validate the capacity of circulating tumor DNA to accurately predict patients' long-term outcomes.

October 5, 2020 - Healthcare organizations that can attract and retain talented women executives have the advantage over their peers, finds a special report in the September/October issue of the Journal of Healthcare Management, an official publication of the American College of Healthcare Executives (ACHE). The report presents results from a 2018 survey, the sixth in a series, conducted by the ACHE of its members to compare the career attainments, attitudes, and workplace experiences of men and women healthcare executives.

Data from the survey shows that women with five to 20 years of experience in the healthcare field are significantly less likely than their male peers to see employers as gender-neutral in hiring, promotion, evaluation, and compensation. This special report on the data finds little to no improvement in these outcomes since the ACHE began measuring them in 1990 with the first survey in the series.

A multidisciplinary research team at the National Institute of Standards and Technology (NIST) has developed a way to increase the sensitivity of the primary test used to detect the SARS-CoV-2 virus, which causes COVID-19. Applying their findings to computerized test equipment could improve our ability to identify people who are infected but do not exhibit symptoms.

The team's results, published in the scientific journal Analytical and Bioanalytical Chemistry, describe a mathematical technique for perceiving comparatively faint signals in diagnostic test data that indicate the presence of the virus. These signals can escape detection when the number of viral particles found in a patient's nasal swab test sample is low. The team's method helps a modest signal stand out more clearly.

"Applying our technique could make the swab test up to 10 times more sensitive," said Paul Patrone, a NIST physicist and a co-author on the team's paper. "It could potentially spot more people who are carrying the virus but whose viral count is too low for the current test to give a positive result."

The researchers' findings prove that the data from a positive test, when expressed in graphical form, takes on a recognizable shape that is always the same. Just as a fingerprint identifies a person, the shape is unique to this type of test. Only the shape's position, and importantly, its size, differ when graphed, varying with the quantity of viral particles that exist in the sample.

While it was known previously that the shape's position could vary, the team learned that its size can vary as well. Reprogramming test equipment to recognize this shape, regardless of size or location, is the key to improving test sensitivity.

The swab test employs a lab technique called quantitative polymerase chain reaction, or qPCR, to detect the genetic material carried by the SARS-CoV-2 virus. The qPCR technique takes any strands of viral RNA that exist in a patient's swab sample and then multiplies them into a far larger quantity of genetic material. Each time a new fragment of this material is made, the reaction releases a fluorescent marker that glows when exposed to light. It is this fluorescence that indicates the presence of the virus.

While the test method usually works well in practice, it can lack sensitivity to low viral particle counts. The test starts with the genetic material that is present and doubles it, then doubles it again, up to 40 times over, so that the fluorescent markers generate enough light to trigger a detector. Doubling, as anyone familiar with compound interest knows, is a powerful amplifier, growing slowly at first and then spiking to high numbers. The doublings produce a graph that is initially flat other than the bumps from systemic background noise, and eventually a telltale spike rises from it.

However, when the initial viral count is low, there may be false starts in the first few cycles. In these cases, even 40 doublings may not build a spike tall enough -- or a fluorescence bright enough -- to rise above the detection threshold. This issue can cause problems like inconclusive tests or "false negatives," meaning a person carries the virus but the test does not reveal it.

Preliminary studies indicate that the rate of false negatives may be as high as 30% in qPCR testing for COVID-19, including one study in which chest CT scans indicated positive cases where swab tests had not. Another study shows that asymptomatic and early-disease states are associated with up to 60 times fewer virus particles in patient samples. A JAMA study published in August supports the idea that asymptomatic carriers can spread the virus.

The NIST researchers found that the shape of a positive test graph -- a flat, noisy beginning followed by a spike -- is found even in data that currently does not trigger a positive test result. Their paper offers a formal proof that the shapes are mathematically "similar," akin to triangles that have the same angles and proportions despite being larger or smaller than one another. They apply this theoretical evidence in a routine that a computer can use to recognize the reference shape in the data.

"We're no longer constrained by having to pass a high detection threshold," Patrone said. "The spikes don't need to be large. They need to have the right shape."

Incorporating their findings into tests would immediately help the pandemic response, Patrone said, as it would help determine the number of asymptomatic and presymptomatic cases more accurately.

"In essence, lowering false negatives should help doctors and scientists get a better handle on the actual spread of the virus," he said. "There is a good chance that we're missing asymptomatic cases with the testing. The reduction we project in the number of viral RNA detected could pick up a significant number of asymptomatic cases."

The new test also would be unlikely to generate false positives because it would check that the curve was consistent with a reference shape, not merely that it crossed a detection threshold.

"In standard testing protocols, it is possible to get false positives -- for example, if background effects rise to the detection threshold and no one manually checks the result," Patrone said. "The likelihood of that happening in our analysis is very small because the math automatically rules out such signals."

Pandemic response workers would not need to do anything differently when collecting samples. Because the team's approach uses a mathematical algorithm applied after data collection, programmers could apply it by updating the lab equipment software with a few lines of computer code.

"Our work is a potentially easy fix because it's an advance in the data analysis," Patrone said. "It can easily be incorporated into the protocol of any lab or testing instrument, so it could have an immediate impact on the trajectory of the health crisis."

A new study by Tel Aviv University and the Israel Antiquities Authority indicates that a workshop for smelting copper ore once operated in the Neveh Noy neighborhood of Beer Sheva, the capital of the Negev Desert. The study, conducted over several years, began in 2017 in Beer Sheva when the workshop was first uncovered during an Israel Antiquities Authority emergency archeological excavation to safeguard threatened antiquities.

The new study also shows that the site may have made the first use in the world of a revolutionary apparatus: the furnace.

The study was conducted by Prof. Erez Ben-Yosef, Dana Ackerfeld, and Omri Yagel of the Jacob M. Alkow Department of Archeology and Ancient Near Eastern Civilizations at Tel Aviv University, in conjunction with Dr. Yael Abadi-Reiss, Talia Abulafia, and Dmitry Yegorov of the Israel Antiquities Authority and Dr. Yehudit Harlavan of the Geological Survey of Israel. The results of the study were published online on September 25, 2020, in the Journal of Archaeological Science: Reports.

According to Ms. Abulafia, Director of the excavation on behalf of the Israel Antiquities Authority, "The excavation revealed evidence for domestic production from the Chalcolithic period, about 6,500 years ago. The surprising finds include a small workshop for smelting copper with shards of a furnace -- a small installation made of tin in which copper ore was smelted -- as well as a lot of copper slag."

Although metalworking was already in evidence in the the Chalcolithic period, the tools used were still made of stone. (The word "chalcolithic" itself is a combination of the Greek words for "copper" and "stone.") An analysis of the isotopes of ore remnants in the furnace shards show that the raw ore was brought to Neveh Noy neighborhood from Wadi Faynan, located in present-day Jordan, a distance of more than 100 kilometers from Beer Sheva.

During the Chalcolithic period, when copper was first refined, the process was made far from the mines, unlike the prevalent historical model by which furnaces were built near the mines for both practical and economic reasons. The scientists hypothesize that the reason was the preservation of the technological secret.

"It's important to understand that the refining of copper was the high-tech of that period. There was no technology more sophisticated than that in the whole of the ancient world," Prof. Ben-Yosef says. "Tossing lumps of ore into a fire will get you nowhere. You need certain knowledge for building special furnaces that can reach very high temperatures while maintaining low levels of oxygen."

Prof. Ben-Yosef notes that the archeology of the land of Israel shows evidence of the Ghassulian culture. The culture was named for Tulaylât al-Ghassûl, the archeological site in Jordan where the culture was first identified. This culture, which spanned the region from the Beer Sheva Valley to present-day southern Lebanon, was unusual for its artistic achievements and ritual objects, as evidenced by the copper objects discovered at Nahal Mishmar and now on display at the Israel Museum in Jerusalem.

According to Prof. Ben-Yosef, the people who lived in the area of the copper mines traded with members of the Ghassulian culture from Beer Sheva and sold them the ore, but they were themselves incapable of reproducing the technology. Even among the Ghassulian settlements along Wadi Beer Sheva, copper was refined by experts in special workshops. A chemical analysis of remnants indicates that every workshop had its own special "recipe" which it did not share with its competitors. It would seem that, in that period, Wadi Beer Sheva was filled with water year-round, making the location convenient for smelting copper where the furnaces and other apparatus were made of clay.

Prof. Ben-Yosef further notes that, even within Chalcolithic settlements that possessed both stone and copper implements, the secret of the gleaming metal was held by the very few members of an elite. "At the beginning of the metallurgical revolution, the secret of metalworking was kept by guilds of experts. All over the world, we see metalworkers' quarters within Chalcolithic settlements, like the neighborhood we found in Beer Sheva."

The study discusses the question of the extent to which this society was hierarchical or socially stratified, as society was not yet urbanized. The scientists feel that the findings from Neveh Noy strengthen the hypothesis of social stratification. Society seems to have consisted of a clearly defined elite possessing expertise and professional secrets, which preserved its power by being the exclusive source for the shiny copper. The copper objects were not made to be used, instead serving some ritual purpose and thus possessing symbolic value. The copper axe, for example, wasn't used as an axe. It was an artistic and/or cultic object modeled along the lines of a stone axe. The copper objects were probably used in rituals while the everyday objects in use continued to be of stone.

"At the first stage of humankind's copper production, crucibles rather than furnaces were used," says Prof. Ben-Yosef. "This small pottery vessel, which looks like a flower pot, is made of clay. It was a type of charcoal-based mobile furnace. Here, at the Neveh Noy workshop that the Israel Antiquities Authority uncovered, we show that the technology was based on real furnaces. This provides very early evidence for the use of furnaces in metallurgy and it raises the possibility that the furnace was invented in this region.

"It's also possible that the furnace was invented elsewhere, directly from crucible-based metallurgy, because some scientists view early furnaces as no more than large crucibles buried in the ground," Prof. Ben-Yosef continues. "The debate will only be settled by future discoveries, but there is no doubt that ancient Beer Sheva played an important role in advancing the global metal revolution and that in the fifth millennium BCE the city was a technological powerhouse for this whole region."

HOUSTON -- (Oct. 5, 2020) -- NASA's James Webb Space Telescope is still more than a year from launching, but the Gemini South telescope in Chile has provided astronomers a glimpse of what the orbiting observatory should deliver.

Using a wide-field adaptive optics camera that corrects for distortion from Earth's atmosphere, Rice University's Patrick Hartigan and Andrea Isella and Dublin City University's Turlough Downes used the 8.1-meter telescope to capture near-infrared images of the Carina Nebula with the same resolution that's expected of the Webb Telescope.

Hartigan, Isella and Downes describe their work in a study published online this week in Astrophysical Journal Letters. Their images, gathered over 10 hours in January 2018 at the international Gemini Observatory, a program of the National Science Foundation's NOIRLab, show part of a molecular cloud about 7,500 light years from Earth. All stars, including Earth's sun, are thought to form within molecular clouds.

"The results are stunning," Hartigan said. "We see a wealth of detail never observed before along the edge of the cloud, including a long series of parallel ridges that may be produced by a magnetic field, a remarkable almost perfectly smooth sine wave and fragments at the top that appear to be in the process of being sheared off the cloud by a strong wind."

The images show a cloud of dust and gas in the Carina Nebula known as the Western Wall. The cloud's surface is slowly evaporating in the intense glow of radiation from a nearby cluster of massive young stars. The radiation causes hydrogen to glow with near-infrared light, and specially designed filters allowed the astronomers to capture separate images of hydrogen at the cloud's surface and hydrogen that was evaporating.

An additional filter captured starlight reflected from dust, and combining the images allowed Hartigan, Isella and Downes to visualize how the cloud and cluster are interacting. Hartigan has previously observed the Western Wall with other NOIRLab telescopes and said it was a prime choice to follow up with Gemini's adaptive optics system.

"This region is probably the best example in the sky of an irradiated interface," he said. "The new images of it are so much sharper than anything we've previously seen. They provide the clearest view to date of how massive young stars affect their surroundings and influence star and planet formation."

Images of star-forming regions taken from Earth are usually blurred by turbulence in the atmosphere. Placing telescopes in orbit eliminates that problem. And one of the Hubble Space Telescope's most iconic photographs, 1995's "Pillars of Creation," captured the grandeur of dust columns in a star-forming region. But the beauty of the image belied Hubble's weakness for studying molecular clouds.

"Hubble operates at optical and ultraviolet wavelengths that are blocked by dust in star-forming regions like these," Hartigan said.

Because near-infrared light penetrates the outer layers of dust in molecular clouds, near-infrared cameras like the Gemini South Adaptive Optics Imager can see what lies beneath. Unlike traditional infrared cameras, Gemini South's imager uses "a mirror that changes its shape to correct for shimmering in our atmosphere," Hartigan said. The result: photos with roughly 10 times the resolution of images taken from ground-based telescopes that don't use adaptive optics.

But the atmosphere causes more than blur. Water vapor, carbon dioxide and other atmospheric gases absorb some parts of the near-infrared spectrum before it reaches the ground.

"Many near-infrared wavelengths will only be visible from a space telescope like the Webb," Hartigan said. "But for near-infrared wavelengths that reach Earth's surface, adaptive optics can produce images as sharp as those acquired from space."

The advantages of each technique bode well for the study of star formation, he said.

"Structures like the Western Wall are going to be rich hunting grounds for both Webb and ground-based telescopes with adaptive optics like Gemini South," Hartigan said. "Each will pierce the dust shrouds and reveal new information about the birth of stars."

When the riders set off to climb Mount Etna on the 3rd stage of Giro d'Italia today, they have definitely eaten large amounts of carbohydrates in the form of pasta, rice or potatoes during the past few days. It is well known that large amounts of carbohydrates in the diet lead to increased storage of sugar molecules inside the muscle cells called glycogen, which enables our muscles to work at a very high intensity for a long period of time.

A new Danish study from the Department of Sports Science and Clinical Biomechanics at the University of Southern Denmark recently showed, that if athletes can place their glycogen close to the structures that produce the force in the muscle cells, they can cycle for a longer time, than if their glycogen is placed elsewhere in the muscle cells.

Placement is more important than amount

In other words, the research results suggest that it is more important where the sugar is stored than how much there is:

"The better you are at placing the energy source, meaning the sugar, as close to the place of consumption as possible, the more endurance you have", explains PhD student Rasmus Jensen.

Since the sugar is stored in very small molecules called glycogen, the researchers had to use a powerful electron microscope, which makes it possible to examine the tiniest structures of only a few nanometres (one-millionth of a millimetre). In order to make these observations representative of the whole body, many muscle cells must be examined, and therefore the research team has spent more than 2,000 hours on the microscopy work in order to complete the study.

In the footsteps of August Krogh

In this way, researchers now take another step in a 100-year process of understanding the importance of carbohydrates for our endurance on the bike. At that time, Danish Nobel Prize winner August Krogh made a number of experiments with both a high-fat and a carbohydrate-rich diet in relation to cycling. Due to his world-renowned ability to build research equipment with unprecedented precision, he discovered that not only carbohydrate but also fat could be used as fuel in the muscles.

August Krogh often used himself as a trial subject and therefore also made another important finding, namely that many days on a high-fat diet caused significant tiredness during cycling at a high intensity. This was the start of a long period of intensive research into the muscles' choice of fuel between fat and carbohydrate, and a number of studies have now shown that a diet high in carbohydrates increases the glycogen content of the muscles, which can be burned faster than fat, allowing muscles to work harder and for a longer period of time.

Will examine how diet changes can optimize placement of glycogen

With the new study, we now know that it is also crucial for your endurance where the glycogen is placed within the muscle cells. It is still too early to make specific recommendations to riders and other athletes on how to place their glycogen in the best possible way.

"The potential of this finding is that the riders of the Giro d'Italia and other endurance athletes of the future will not only eat a lot of carbohydrates but also make sure to 'place' the glycogen molecules of their muscles at the best locations", says Rasmus Jensen.

The researchers have now initiated a number of experiments, some in collaboration with the government-funded initiative Team Denmark, where they will investigate how different forms of exercise combined with diet changes can optimise the placement of glycogen in the muscles and thus improve performance during prolonged hard work such as road cycling. In addition, the researchers have initiated laboratory experiments in an effort to understand why the placement of glycogen is important for the muscles' ability to work hard for a long time.

ST. LOUIS, MO -- For years, Elizabeth (Toby) Kellogg, PhD, member and Robert E. King Distinguished Investigator and other researchers at the Donald Danforth Plant Science Center (Danforth Center) drove up and down the highways of the continental United States, occasionally pulling over to the side of the road to collect small weedy plants and bring them back to the lab. The weedy grass was green millet (Setaria viridis), a small model grass with a short lifecycle that uses a carbon fixation process known as the C4 pathway, which particularly helps plants thrive in warm, arid environments. Corn and sugarcane are among the major high-yield C4 crops, as are the candidate biofuel feedstocks Miscanthus and switchgrass.

Innumerable road trips and hundreds of plants have resulted in a paper, "A genome resource for green millet Setaria viridis enables discovery of agronomically valuable loci," in Nature Biotechnology. Kellogg and her colleagues, along with researchers at the HudsonAlpha Institute for Biotechnology and the U.S. Department of Energy (DOE) Joint Genome Institute (JGI), a DOE Office of Science User Facility located at Lawrence Berkeley National Laboratory (Berkeley Lab), generated genome sequences for nearly 600 green millet plants and released a very high quality reference S. viridis genome sequence. Analysis of these plant genome sequences also led researchers to identify a gene related to seed dispersal in wild populations for the first time.

"To our knowledge, nobody has ever discovered a dispersal gene that way," said Kellogg, a senior author of the paper. "This paper is the first one to survey a huge amount of natural diversity and say, 'Yeah, there are genes out there that affect this phenotype.'"

Results from A "Massive Amount" of Sequencing

Seed dispersal is critical for plants in the wild, but it is an undesirable trait for domesticated crops because it leads to reduced harvest yields. Over thousands of years, farmers have selected for cereal plants without this shattering trait - referring to the moment when the cluster of seeds at the tip of each branch breaks apart so the seeds can disperse - so that the seeds remain atop the plant to be collected.

Association mapping led the team to identify a gene called Less Shattering 1 (SvLes1); gene editing studies led by co-first author Pu Huang confirmed that it was involved in shattering by turning it off. "It's a new shattering gene variant identified in a natural population. Not very many of these shattering genes have been discovered that let a plant go all the way to seed but prevent the seeds from falling," said JGI Plant Program head Jeremy Schmutz, who is also a HudsonAlpha Faculty Investigator. "This could be another mechanism to turn off shattering and domesticate crops." How shattering occurs varies widely between crops, Kellogg added, and shattering genes may be specific to species or groups of species.

The genome data also revealed that green millet was introduced into the United States multiple times from Eurasia. The team also identified a gene associated with leaf angle, which determines how much sunlight leaves can get and in turn serves as a predictor of yield. The gene is an ortholog of known genes, "The gene has now been mapped back in maize as involved in leaf angle," noted Schmutz. "It's a nice example of de novo discovery and then mapping back to identify candidate genes."

Through JGI's Community Science Program, sequences of several hundred green millet plant genomes were generated, though the final analyses focused on 598 individuals. Schmutz and his team assembled and annotated the genomes at HudsonAlpha. Sujan Mamidi and Adam Healey, two of the co-first authors, led the data analyses and assembled the green millet "pan-genome" (a set of 51,000 genes that represent all the genes that are present in a given species).

"This is a great example of developing a large-scale genome infrastructure with a reasonably accessible system," said Schmutz. "Building the pan-genome and accessions allow us to see presence/absence variation easily and to find genes missing in particular accessions, and to confirm phenotypes, which validate traits."

"The number of lines sequenced is not trivial, and they were all assembled de novo, which let the team look at presence/absence of whole genes," Kellogg agreed. "Getting that information is hard. There's a good reason nobody's done it; it's a heck of a lot of work. I wouldn't have done it without the contribution of Jeremy's group. It's just a massive amount of sequencing."

A Resource for Many Applications

Kellogg noted that C4 crops have gotten a lot of interest because they're very productive even in high heat while C3 crops have become less efficient at photosynthesis, a concern as extreme weather events become more frequent. "A big part of the Danforth Center's mission is to feed the hungry and improve human health. So there's a major question: how to turn a C3 crop into a C4 crop. There should be a master regulator but no one has found it," Kellogg mused. "[The S. viridis genome] is a resource for many different applications. The JGI group has been wonderful to collaborate with, and this [project] wouldn't have been possible without their involvement; it's something we wouldn't have even started."

The reference genome of Setaria viridis is available on JGI's plant portal Phytozome.

Children appear to be at greater risk of having high blood pressure when their mothers had the high blood pressure condition called preeclampsia during pregnancy--but this adverse association may be reduced or even eliminated for children who were exposed to higher levels of vitamin D in the womb, according to a study from researchers at Johns Hopkins Bloomberg School of Public Health.

The findings, based on an analysis of data on 754 mother-child pairs in Massachusetts, suggest that higher vitamin D levels in pregnancy may help protect children born to preeclamptic women from developing high blood pressure. High blood pressure in childhood is associated in turn with hypertension and heart disease in adulthood.

The study was published online October 5 in JAMA Network Open.

"There is increasing evidence that cardiovascular disease risk is, to a great extent, programmed in the womb, and we now see that it may be vitamin D that alters this programming in a beneficial fashion," says study senior author Noel Mueller, PhD, an assistant professor in the Department of Epidemiology at the Bloomberg School.

Preeclampsia, which can lead to strokes and/or organ failure, is a major cause of illness and death for pregnant women, and also is associated with a greater risk of stillbirth and preterm birth. Researchers have estimated that preeclampsia occurs in 2-8 percent of pregnancies worldwide. It is associated with maternal obesity, and the rate of severe preeclampsia in the U.S. has risen sharply since the 1980s.

At the same time, the rate of high blood pressure among children in the U.S. has risen by about 40 percent between 1988 and 2008. Studies have suggested that maternal preeclampsia may be a factor in that increase.

Studies also have linked maternal vitamin D deficiency to a higher risk of preeclampsia, and have suggested that lower levels of vitamin D in adulthood or even early in life bring a greater risk of hypertension.

"We wanted to know if vitamin D levels in the womb would modify this association between maternal preeclampsia and hypertension in childhood," says study first author Mingyu Zhang, a PhD candidate in Mueller's research group.

To investigate this question, the team analyzed data that had been gathered on 754 mother-child pairs from 1998 to 2018 in a large epidemiological study conducted at the Boston Medical Center in Massachusetts. The dataset included information on preeclampsia during pregnancy, tests on blood from the umbilical cord at birth, and the children's blood pressure from age 3 to 18.

About 62 percent of the mothers in the study group were Black, and 52 percent were overweight or obese. Previous studies suggest that mothers who were Black or overweight or obese were at higher risk for preeclampsia. Darker-skinned people living in higher latitudes also are more likely to be deficient in vitamin D--a cholesterol-derived molecule that is present in some foods but also is synthesized in skin with the help of ultraviolet light.

Roughly ten percent of the women in the study group had preeclampsia, and the analysis revealed that their children on average had higher systolic blood pressure than the children born to non-preeclamptic mothers--about 5 percentile points higher, when all the blood pressure readings were arranged on a 0 to 100 percentile scale.

Cord-blood vitamin D levels clearly modified these associations, and in a dose-related manner. Children in the lowest 25 percent range of vitamin D levels (lowest "quartile") were about 11 percentile points higher in blood pressure, on average, if their mothers had had preeclampsia, compared to children of non-preeclamptic mothers.

For children in the highest vitamin D quartile, there appeared to be no difference in average blood pressure if their mothers had had preeclampsia--in other words, the results suggest that having relatively high vitamin D levels at birth, which could be achieved through dietary supplements, may completely mitigate the risk brought by preeclampsia.

"If other epidemiological studies confirm these findings, then randomized trials would be needed to determine conclusively if higher vitamin D in mothers at risk of preeclampsia protects against childhood high blood pressure," Mueller says.

When exploring data on Washington workers during the pandemic -- demographics, working conditions, wages and benefits, and risks of exposure to disease -- the authors of a new report found that women hold two-thirds of the jobs in the harshest category of work.

"The big takeaway from our research," said David West, a co-author of the report and an analyst at the Washington Labor Education and Research Center, "is how particularly women are working under precarious conditions -- a large number of women are both facing safety risks at high-hazard jobs and are economically at risk."

The report, authored by researchers from the labor center at South Seattle College's Georgetown campus and the University of Washington's School of Public Health, initially set out to understand the risks faced by workers in jobs deemed essential by Gov. Jay Inslee as the pandemic took hold in Washington, asking people to remain in their homes and closing many businesses.

But as the state began its phased reopening, nonessential workers started returning to the workplace, and the researchers found that many of those workers also faced a high risk of exposure to disease and economic stress.

In the end, the researchers identified 55 of the 694 occupations on which they had data as both precarious -- facing economic and health care stress -- and high risk of exposure to the coronavirus. Out of a total Washington workforce of 3.3 million workers, some 900,000 fill positions in these 55 occupations. These workers, 70% in essential jobs, were not only mostly female, but also disproportionately workers of color.

"There are a lot of workers in Washington who are at increased risk for exposure to COVID-19 and still going to work. And those workers tend to also be workers who have a lack of workplace protections and are either women or workers of color," said Marissa Baker, co-author of the labor report and an assistant professor in the UW Department of Environmental & Occupational Health Sciences.

"So, we really need to ensure that there are targeted policies or regulations to help these workers, especially since we now know who they are and what occupations and industries they fall into," Baker said.

In order to determine which occupations were at higher risk of exposure to COVID-19 and to make specific recommendations related to workplace safety, the researchers looked at the importance of these "key dimensions" of a job:

Physical proximity to others

Dealings with external customers

Face-to-face discussions

Contact with others

Exposure to disease/infections

Work with a team or group

Dealings with physically aggressive people

Assisting/caring for others

Performing for/working directly with the public

Use of common or specialized safety equipment (gloves, masks, hazmat suits)

The authors list in their report a series of policies designed to address these health risks as well as the economic challenges they recommend policymakers and business leaders adopt.

Here are their key recommendations:

Airborne transmissible disease (ATD) standard: Washington should follow the lead of states such as California that have enacted ATD standards for their workplaces, instead of relying on voluntary guidance.

Workplace coronavirus disclosure, testing and tracking: Support comprehensive notification of positive workplace COVID tests, workplace testing, and prioritize workplace follow-up tracking.

Safety committees: Promote and widely enforce the Washington state requirement that workplaces with more than 11 employees have safety committees in order to involve workers in identifying and preventing COVID risk factors.

Economic security: Ensure that all Washington at-risk/precarious workers have affordable access to health insurance, hazard pay, paid leave for quarantine periods, and affordable child care to reduce stress and ensure prompt care.

"Even though this has been a devastating time for the American workforce," Baker said, "we can harness this moment and make big structural changes that can forever improve the relationship between work and health."

RIVERSIDE, Calif. -- A postdoctoral researcher at the University of California, Riverside, has discovered human papillomavirus, or HPV, vaccination mandates fall short of ensuring both higher levels of uptake and equal uptake of the vaccine across socioeconomic and racial-ethnic groups.

The findings could help facilitate equal access to and compliance with uptake of COVID-19 vaccines, once they are available.

"For the first time in history we have a safe and effective vaccine with the potential to eliminate cervical cancer -- yet uptake remains well below national targets," said researcher Andrea Polonijo, a Chancellor's Postdoctoral Fellow in the Department of Social Medicine, Population, & Public Health at the School of Medicine and the research paper's sole author.

Policies that merely aim to increase knowledge or standardize the age of uptake are not enough to facilitate equal or widespread uptake, she explained.

"Without widespread public support, surveillance, sanctions for noncompliance, incentives for uptake, or efforts to improve access, flu and COVID-19 vaccine requirements are unlikely to be successful. It will be interesting to see if the University of California's 2020-21 flu vaccine order improves uptake, given unvaccinated students, faculty, and staff are still able to work remotely without a flu vaccine."

Published in SSM - Population Health, the study found HPV vaccination mandates help reduce some differences in provider recommendations and initiation of the vaccine series. Polonijo found receiving a recommendation from a health provider greatly increased the odds that teens got their first HPV shot.

"Non-Hispanic whites and higher socioeconomic status girls tend to receive physician recommendations more often than their racial-ethnic minority and lower socioeconomic status peers," she said. "My findings suggest school-entry HPV vaccination mandates helped equalize recommendations -- likely by providing the motivation for providers to consistently recommend HPV vaccines as part of routine care."

Polonijo used 2008-09 and 2011-13 data from the National Immunization Survey-Teen, a nationally representative cross-sectional survey that identifies adolescent vaccination coverage. She was surprised to find mandates did not improve rates of HPV vaccine series completion or lead to more equal vaccine series completion across racial-ethnic and socioeconomic groups.

"HPV vaccine mandates were accompanied by pharmaceutical manufacturer lobbying, political debate, and controversial news coverage, which made them unpopular among parents who may have questioned whether compliance was in their daughter's best interest and opted them out," she said. "Mandates also did not make it any easier for teens to access HPV vaccines and there was no widely used surveillance or reminder system in place to recall teens who were due for shots."

According to Polonijo, one reason HPV vaccine mandates were unpopular is that HPV is a sexually transmitted infection that cannot be transmitted through casual contact.

"Given that flu and COVID-19 are more easily spread, people might be more willing to be vaccinated against these respiratory illnesses," she said. "Earning public trust and ensuring universal provider recommendations and easy access are crucial for the success of flu or COVID-19 vaccination programs, which need to target all individuals, regardless of socioeconomic status, race-ethnicity, gender, or life stage."

NASA's Terra satellite obtained visible imagery of Tropical Storm Chan-hom as it continued moving though the Northwestern Pacific Ocean. The imagery revealed that the center of circulation was exposed and its strongest storms were south of the center.

Tropical Depression 16W formed on Oct. 4 and strengthened into a tropical storm on Oct 5. Once it reached tropical storm strength, it was re-named Chan-hom. Laos submitted the name Chan-hom to the World Meteorological Organization list. The name is a type of tree in Laos.

NASA Satellite View: Chan-hom's Organization

The Moderate Resolution Imaging Spectroradiometer or MODIS instrument that flies aboard NASA's Terra satellite captured a visible image of Tropical Storm Chan-hom on Oct. 5 that showed a couple of things were occurring in the storm. First, bands of thunderstorms were wrapping into a partially exposed low-level circulation center. Second, there was building convection and thunderstorms occurring over the southern quadrant of the storm, giving it an appearance of a backwards letter "C" on satellite imagery. The storm is expected to strengthen over the next three days and when it does, it will likely develop a more circular shape.

The satellite imagery was created using NASA's Worldview product at NASA's Goddard Space Flight Center in Greenbelt, Md.

Chan-hom's Status on Oct. 5

At 11 a.m. EDT (1500 UTC) on Oct. 5, Chan-hom was centered near latitude 23.0 degrees north and longitude 139.2 degrees east. That is about 738 miles south of Yokosuka, Japan. Chan-hom is moving north and has maximum sustained winds of 35 knots (40 mph/64 kph).

Chan-hom's Forecast

The Joint Typhoon Warning Center noted, "Chan-hom is forecast to track generally northwestward along the southwestern periphery of a sub-tropical ridge (elongated area of high pressure) over the next three days. During this time, the system will steadily intensify to a peak intensity of 85 knots (98 mph/157 kph) by three days largely due to the continued low vertical wind shear and warm sea surface temperatures."

Closed-canopy rainforests are a vital part of the Earth's modern ecosystems, but tropical plants don't preserve well in the fossil record so it is difficult to tell how long these habitats have existed and where rainforests might have once grown. Instead, scientists look to the diets of extinct animals, which lock evidence of the vegetation they ate into their teeth. A new study led by scientists at the American Museum of Natural History finds that the paradigm used to identify closed-canopy rainforests through dietary signatures needs to be reassessed. The findings are published this week in the journal Proceedings of the National Academy of Sciences.

"The Amazon is the world's most diverse rainforest, home to one in 10 known species on Earth," said Julia Tejada-Lara, who led the study as a graduate student at the Museum and Columbia University. "Closed-canopy rainforests have been proposed to occur in this area since at least the Eocene, some 50 million years ago, but we know very little about their extent and evolution through time."

To reconstruct ancient ecosystems, including rainforests, researchers often use stable carbon isotope (δ13C) analyses on extinct and living herbivores. Stable carbon isotopes, which form in specific proportions inside plants, are preserved in the body tissues of the animals that eat those plants. Samples from the animal's bones, teeth, toenails, or other biological material can help scientists determine the kinds of plants that were consumed.

In the new study, Tejada and her colleagues analyzed specimens from the American Museum of Natural History and the Museum of Natural History in Lima representing 45 modern herbivores and 12 species of "secondary consumers" (meat-, insect-, and fish-eaters) that live in western Amazonia. The authors then compared their results with a landmark analysis of modern mammals in equatorial Africa, a generally accepted proxy used to identify past closed-canopy rainforests on all continents. The researchers also determined nitrogen isotope values from 35 Amazonian mammal species, finding greater than expected complexity in how nitrogen from macromolecules (carbohydrates, proteins, and fats [lipids]) is incorporated into body tissues in animals from different levels of the food chain.

"Up to this point, there had only been one other broad isotopic sampling--and inferences of food sources--of a tropical closed-canopy rainforest mammal community, and that was in central Africa," said co-author John Flynn, Frick Curator of Fossil Mammals in the Museum's Division of Paleontology. "So we knew that if we wanted to learn more about both modern and ancient Amazon ecosystems, we had to test whether we should expect the tropical forest conditions to be roughly the same in these two continents that separated more than 90 million years ago and have a 1,600-mile-wide ocean between them today."

The comparison reveals that Amazonian and African closed-canopy rainforests have a very similar mean dietary carbon isotopic value, and it may be representative of mammalian herbivores in any closed-canopy rainforest. Beyond this newly discovered way of recognizing ancient rainforests, Amazonian mammals in this study lacked highly negative dietary values found in a few of the African animals. These negative values are often used outright to infer closed-canopy rainforests in fossil records.

"We have found that these negative isotopic values can no longer be used as an indispensable indicator of a rainforest," Tejada said. "And further, that many of the longtime assumptions about ecological niches, feeding habits, and isotopic signatures characterizing tropical communities likely need to be reassessed."

Similarities among individuals living in the same communities can dramatically change their risk of dying by suicide, according to a new study by Indiana University researchers.

The study, published in the Proceedings of the National Academy of Sciences, examined the relationship between suicide and social "sameness" -- living in communities with other individuals who share common social characteristics, such as employment and marital status, ethnicity or place of birth.
Researchers found that social similarity reduced well-known individual risks of suicide for those younger than 45, unemployed, widowed, white, Black or not born in the United States.

But sameness was not always protective. Social similarity increased suicide risk for individuals who were born in the United States, had never married, or were Alaska Native, Native American, Hispanic or Asian, according to the study.

"This study breaks a longstanding barrier to understanding the link between individual suicide risk and community-based risk," said Bernice Pescosolido, co-author of the study and a Distinguished Professor of Sociology in the College of Arts and Sciences at IU Bloomington. "This offers new insights into how complex the relationship between suicide and cultural and social connections is. Science has been challenged to get beyond the split between looking at individuals and looking at communities in the U.S. Sameness allows us to think about the role of connectedness in new ways."

Researchers merged data from a number of sources, including the National Violence Data Reporting System and the American Community Survey, to examine whether "sameness" between individuals and where they live affected their risk of suicide in the U.S. between 2005 and 2011.

Suicide in America has been on the rise, according to the U.S. Centers for Disease Control and Prevention, pressing the need for new approaches to reduce risk. While individual suicide risks have been previously documented in individuals, the finding that those risks change depending on social geography has previously been difficult to establish in the U.S., Pescosolido said.

"These findings challenge the idea of a 'one size fits all' approach to programs trying to reduce suicide -- even for targeted groups like teens, where the increase has been great," she said. "We need to consider where they are."

Traditional treatment and prevention efforts have focused around the idea that strong social ties protect people from suicide, and those who lose or do not have those connections are thought to be more at risk of suicide.

But according to Pescosolido and her colleagues, social similarity is not always a strong lever to reduce suicide risk. For example, their findings suggest that in isolated communities or those communities where socio-economic devastation has been great, similarity can actually increase the risks of suicide.

"With the burdens that people are experiencing due to the pandemic, this study reinforces calls for fresh approaches to understanding suicide risk," Pescosolido, said. "Knowing how social context alters individual suicide risk provides a path toward personalized and tailored strategies for anti-suicide programs, policies and treatment."