Culture

Florida State University Professor of Biological Science David Gilbert is using the latest information about the human genome as a guide to better understand cancer.

Gilbert and his FSU colleagues were part of a team that compared different cancer cell types to a database of normal human cells using a new method he developed that can identify the cell type from which cancers derive. By comparing various cancer cells to the collection of normal cells, they were able to tell which cancers mostly closely matched different cell types.

"Cancer cells come from a cell in your body, but they have changed," Gilbert said. "Knowing what cell type they came from is particularly important when evaluating whether a new tumor in a relapsed patient is derived from the original tumor or is a new cancer altogether."

Their work, published in Nature Communications , is a companion piece to a large series of publications resulting from an international effort to understand how the human genome works, funded by the National Institutes of Health, called the Encyclopedia of DNA Elements (ENCODE). Because only 1 percent of human DNA codes for any known proteins, understanding the function of the rest of our genome has been a huge challenge.

Gilbert and his colleagues also are contributors to the larger ENCODE publication, published in Nature , summarizing the efforts of the latest cycle of ENCODE funding. The highlight of this study is the mapping of nearly one million elements in the human genome, covering 8 percent of the genome, that regulate the genes. That is, they determine how much and in what body tissue a gene will be expressed.

"The complexity in an organism is not in the number of protein-coding genes it has," Gilbert said. "It's in in the combination of those genes. We have almost the same number of genes as worms and flies, but we express them in more complex combinations."

His laboratory adds replication -- the process of DNA making a copy of itself -- to the picture.

"People don't often think of replication as something that would be regulated differently in different cell types because DNA is the same in all cells," he said. "However, it's not just DNA that replicates. Rather, all the components of chromosomes that regulate the DNA are completely dismantled and re-assembled when DNA replicates. We've shown that the order in which segments of DNA replicate is unique to each cell type and also different in diseased cells. It can even be unique to a specific patient's cancer."

Jared Talbot is part of a 32-member international research team that identified a gene that, when altered, can cause bent fingers and toes, clubfoot, scoliosis, and short stature. 
 

The team discovered that partial loss of the protein coding gene MYLPF (myosin light chain, phosphorylatable, fast skeletal muscle) results in a disorder called distal arthrogryposis (DA) that's present at birth.
 

July 23, The American Journal of Human Genetics (AJHG) published the team's paper "Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis" that details the findings. In May, bioRxiv -- a free online and distribution service -- also posted a preprint of the paper.
 

Talbot, an assistant professor in the University of Maine School of Biology and Ecology, is the study's second author. He contributed equally with Jessica Chong, the first author and an assistant professor of human genetics at the University of Washington.
 

The discovery has several exciting implications. 
 

"Before a disease can be effectively treated, its cause needs to be understood," says Talbot. "Right now, DA is treated through surgery, which often has to be repeated several times over a lifetime. By understanding the disease better we may be able to discover longer-lasting and less-invasive ways to treat it."
 

More broadly, the breakthrough adds to scientists' knowledge about how prenatal muscle formation affects health throughout a lifetime, he says.
 

Chong began the project while working with Dr. Michael J. Bamshad in the University of Washington's Division of Genetic Medicine. They identified the initial cases and headed an international team that, so far, has identified MYLPF mutations in 19 people with DA in eight families.
 

Their results also could provide insight into arthrogryposes, which occurs in about 1 in 3,000 births. Arthrogryposes are a larger group of conditions characterized by multiple joint contractures at birth, including in the shoulders, hips and knees. The most common type of arthrogryposis is amyoplasia, which involves muscle loss.
 

"We hope that our findings may help to shed light on potential genetic causes of amyoplasia, because to date, the etiology of most cases of amyoplasia remains unknown," says Chong.
 

Chong and Bamshad also learned of a person with DA who had no muscle in one of their feet, which indicates there may be more similarity than previously thought between DA and amyoplasia.     
 

Bamshad and Chong contacted Talbot, who studies the same gene in zebrafish embryos.
 

Zebrafish have a similar genetic structure to humans. They share 70% of genes with people and 84% of genes known to be associated with human disease have a zebrafish counterpart. Zebrafish muscle development also mirrors that of people and their embryos grow quickly and are see-through.
 

Talbot investigated how muscle development is affected by loss of this gene's function, to understand the "why" behind the human findings. He began work on MYLPF while a postdoc in Dr. Sharon Amacher's laboratory at The Ohio State University. 
 

There, he mentored Emily Teets, who studied MYLPF function as part of her undergraduate honors thesis. They generated mutations that remove one of the two zebrafish MYLPF genes, called mylpfa, and found that this gene is needed for normal muscle structure and function. 
 

Last fall, Talbot began research at UMaine, where he uses zebrafish to investigate muscle formation and model this human muscle disease.
 

"MYLPF protein acts in the muscle. We think the crooked joints of DA arise because of reduced muscle function when those joints are forming in the womb," he says. 

"We can't study people's muscle strength before they're born, but we can study zebrafish in their early development and use these fish to model what happens in people." 
 

Talbot found that zebrafish with mylpfa knocked out had complete paralysis in their pectoral fin and reduced overall muscle strength. 
 

In addition, he and Teets discovered that muscle eventually degenerated in the zebrafish. This, he says, suggests that some muscle loss that people with DA experience may be due to degeneration in utero.
 

Talbot used protein models to understand why some of the specific mutations found in humans have dominant inheritance (where one copy of a mutation can cause disease) and other mutations have recessive inheritance, (where two copies must be mutated for a disease to occur). 
 

He found the dominant mutations are caused by changes in parts of the protein that directly contact another protein called myosin, which is the motor protein that contracts muscle. 

And, working with David Warshaw at the University of Vermont, they showed that myosin function is reduced in the zebrafish DA model.
 

Together, these fish and human findings show that MYLPF mutations cause a disease, DA, and they offer insights into how and why that disease arises before birth.
 

"I have investigated several disease models, but this was the first time that I was able to offer insights from a model organism at the same time that the gene's function was being connected to a human condition," says Talbot. 
 

"Our basic-science study paired beautifully with the clinical findings to tell one cohesive story that was enriched by everyone involved."

While Einstein's theory of general relativity can explain a large array of fascinating astrophysical and cosmological phenomena, some aspects of the properties of the universe at the largest-scales remain a mystery. A new study using loop quantum cosmology--a theory that uses quantum mechanics to extend gravitational physics beyond Einstein's theory of general relativity--accounts for two major mysteries. While the differences in the theories occur at the tiniest of scales--much smaller than even a proton--they have consequences at the largest of accessible scales in the universe. The study, which appears online July 29 in the journal Physical Review Letters, also provides new predictions about the universe that future satellite missions could test.

While a zoomed-out picture of the universe looks fairly uniform, it does have a large-scale structure, for example because galaxies and dark matter are not uniformly distributed throughout the universe. The origin of this structure has been traced back to the tiny inhomogeneities observed in the Cosmic Microwave Background (CMB)--radiation that was emitted when the universe was 380 thousand years young that we can still see today. But the CMB itself has three puzzling features that are considered anomalies because they are difficult to explain using known physics.

"While seeing one of these anomalies may not be that statistically remarkable, seeing two or more together suggests we live in an exceptional universe," said Donghui Jeong, associate professor of astronomy and astrophysics at Penn State and an author of the paper. "A recent study in the journal Nature Astronomy proposed an explanation for one of these anomalies that raised so many additional concerns, they flagged a 'possible crisis in cosmology.' Using quantum loop cosmology, however, we have resolved two of these anomalies naturally, avoiding that potential crisis."

Research over the last three decades has greatly improved our understanding of the early universe, including how the inhomogeneities in the CMB were produced in the first place. These inhomogeneities are a result of inevitable quantum fluctuations in the early universe. During a highly accelerated phase of expansion at very early times--known as inflation--these primordial, miniscule fluctuations were stretched under gravity's influence and seeded the observed inhomogeneities in the CMB.

"To understand how primordial seeds arose, we need a closer look at the early universe, where Einstein's theory of general relativity breaks down," said Abhay Ashtekar, Evan Pugh Professor of Physics, holder of the Eberly Family Chair in Physics, and director of the Penn State Institute for Gravitation and the Cosmos. "The standard inflationary paradigm based on general relativity treats space time as a smooth continuum. Consider a shirt that appears like a two-dimensional surface, but on closer inspection you can see that it is woven by densely packed one-dimensional threads. In this way, the fabric of space time is really woven by quantum threads. In accounting for these threads, loop quantum cosmology allows us to go beyond the continuum described by general relativity where Einstein's physics breaks down--for example beyond the Big Bang."

The researchers' previous investigation into the early universe replaced the idea of a Big Bang singularity, where the universe emerged from nothing, with the Big Bounce, where the current expanding universe emerged from a super-compressed mass that was created when the universe contracted in its preceding phase. They found that all of the large-scale structures of the universe accounted for by general relativity are equally explained by inflation after this Big Bounce using equations of loop quantum cosmology.

In the new study, the researchers determined that inflation under loop quantum cosmology also resolves two of the major anomalies that appear under general relativity.

"The primordial fluctuations we are talking about occur at the incredibly small Planck scale," said Brajesh Gupt, a postdoctoral researcher at Penn State at the time of the research and currently at the Texas Advanced Computing Center of the University of Texas at Austin. "A Planck length is about 20 orders of magnitude smaller than the radius of a proton. But corrections to inflation at this unimaginably small scale simultaneously explain two of the anomalies at the largest scales in the universe, in a cosmic tango of the very small and the very large."

The researchers also produced new predictions about a fundamental cosmological parameter and primordial gravitational waves that could be tested during future satellite missions, including LiteBird and Cosmic Origins Explorer, which will continue improve our understanding of the early universe.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Cardiac Endotheliitis and Multisystem Inflammatory Syndrome After COVID-19

Endotheliitis and microangiopathy have been identified as key features of the pathophysiology of severe COVID-19. In addition, a multisystem inflammatory syndrome (MIS) similar to Kawasaki disease has been increasingly reported in association with COVID-19 in children and young adults. Authors from Louisiana State University Health Sciences Center describe a case report on the pathologic findings of vasculitis of the small vessels of the heart, which likely represents MIS, leading to death in a young adult after presumed resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Read the full text: https://www.acpjournals.org/doi/10.7326/L20-0882.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Sharon E. Fox, MD, PhD, can be reached through Leslie Capo at LCapo@lsuhsc.edu. [Please note: the authors will not take specific questions on this individual's case out of respect for the family but can discuss the disease process].

2. Body Mass Index and Risk for Intubation or Death in SARS-CoV-2 Infection

Obesity has been associated with COVID-19 and with pneumonia and acute respiratory distress syndrome but is also associated with comorbidities that place patients at higher risk. Authors from Columbia University Irving Medical Center and Villanova School of Business found that obesity is associated with increased risk for intubation or death from COVID-19 in adults younger than 65 years, but not in adults aged 65 years or older. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-3214.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Michaela R. Anderson, MD, MS, can be reached directly at mdr2140@cumc.columbia.edu.

LOS ALAMOS, N.M., July 29, 2020--A multi-institution team has used positron beams to probe the nature of radiation effects, providing new insight into how damage is produced in iron films. This exploration can improve the safety of materials used in nuclear reactors and other radiation environments.

"Positrons do not damage the material and they can reveal defects involving single atoms at very small concentrations," said Blas Uberuaga, a Los Alamos National Laboratory materials scientist on the project. "They are thus one of the most sensitive probes we can use to analyze radiation damage, providing critical data on the nature of the defects in the material and building our understanding of radiation effects." Positrons, a form of antimatter, annihilate when they come in contact with electrons in the material, giving information about the local configuration of atoms.

Radiation damage occurs when high-energy particles smash into materials, knocking atoms out of position and creating defects in the crystal--either positions missing an atom or an atom in between, or interstitial, positions. This collision cascade is akin to a bowling ball slamming into bowling pins, except the ball may be a neutron and the pins are atoms. The defects that are created are ultimately responsible for failure of these materials in many extreme environments such as those present in the walls and various components of nuclear reactors. Thus, it is essential to understand how defects are created and behave in the material in these environments.

With thin films of iron as a model for steel, the team used ion beams--atoms accelerated in a laboratory--to mimic the type of damage that might be created in a reactor.

These films contained a high number of voids, or pores in the material. The team then used a combination of positrons and electron microscopy to look at the material before and after the ion beam damage. By combining characterization techniques utilizing positrons and electrons, they were able to interrogate both very small and much larger defects. Specifically, they were able to elucidate new mechanisms in which the voids already present in the material modified how damage was produced during the collision cascades.

As schools prepare to reopen and more people are heading back to their offices and shared work spaces, Syracuse University Professor Jianshun "Jensen" Zhang offers a three-step plan to improve indoor air quality (IAQ) and help prevent the spread of COVID indoors.

Zhang's plan is detailed in a recent editorial published in the journal "Science and Technology for the Built Environment" called "Integrating IAQ control strategies to reduce the risk of asymptomatic SARS CoV-2 infections in classrooms and open plan offices."

"Classrooms and open-space offices present a special challenge because of their relatively large occupant density, which can lead to a higher chance of person-to-person cross infection in the space via airborne transmission as well as through direct or indirect contacts," Zhang says. "As schools and businesses are making plans to reopen, how can the risk of such cross infection be minimized or prevented?"

The coronavirus disease is a respiratory illness that can spread from person to person. The virus that causes COVID-19 spreads, typically through respiratory droplets from coughing, sneezing, or talking. Some people without symptoms are able to spread the disease without knowing that they have it.

Dr. Zhang, a professor in the Department of Mechanical and Aerospace Engineering and Director of the Building Energy and Environmental Systems Laboratory, writes that source control, ventilation and air cleaning - and combinations of all three - can offer important tools in preventing the spread of COVID within indoor spaces.

Here's a look at his three-step plan:

Source Control

Source control is the first and most important among all IAQ strategies. For preventing the spread of the coronavirus, that means detecting, tracking, and isolating infected persons; and preventing transmission from asymptomatic virus carriers.

"The latter is more challenging in open space office or classroom settings in which air is typically well mixed," Zhang writes. "To reduce the number of virus-containing aerosols emitted to the space from any possible virus carriers present, universal face masking, as well as hand sanitizing before entering the space is essential."

Ventilation

The next step in air quality is ventilation with a focus on supplying enough clean outdoor air to rooms and offices and effectively diluting the concentration of pollutants.

"Mechanically ventilated classrooms and offices typically have about 20 percent of their air supplied from outdoors, and the rest is recirculated air. This is done to save heating and cooling energy while maintaining acceptable levels of IAQ," Zhang says. "To reduce the risk of the SARS CoV-2 virus infection, the outdoor ventilation rate should be increased to the maximum operational capacity of the building ventilation system, which can be two or more times of that under the normal operation mode per the existing standard."

He also writes that any recirculated air needs to be filtered with HEPA filters or MERV 14 filters, to minimize cross-contamination.

Zhang says that proper air distribution is essential for making sure the filtered air is reaching the people where they are. He says, "this is an area so far has been largely neglected in existing guidelines or recommended practices for reducing the SARS CoV-2 virus infection."

He points out that most classrooms and open plan offices in the United States use mixing ventilation (MV) for fresh air delivery. Air diffusers in MV are typically located close to the ceiling level, but Zhang recommends that air supply should be brought in through ground ventilation. The difference is that filtered air from the ceiling mixes with the exhaled breath of people who could be asymptomatic carriers of COVID.

He said to prevent filtered air becoming contaminated, it should be pumped into a room through ground-level vents. Zhang recommends using "displacement ventilation," which simply delivers the air supply at the floor level but exhausts it through vents in the ceiling.

Air cleaning

Air cleaning strategies involve applying air filtration or purification within a building, rooms, or at a personal level, such as a properly worn mask. But among all three, there must be high efficiency filters and sufficient airflow, writes Zhang.

At the building level, high efficiency particulate (HEPA) filters in the recirculated or mixed air duct can reduce the cross contamination between rooms and increase the total clean air delivery rate (outdoor plus filtered air) for diluting the virus concentration in the ventilated space.

Standalone room air cleaners with HEPA filters can also be used as a supplementary measure to further reduce the concentration of virus in the occupied space. Research has shown a range of clean air delivery rate (CADR) from 170 to 800?m3/h (or 100 to 470 CFM) with a median cost of $361 based on a comprehensive survey of off-the-shelf air cleaners available from the most popular online shopping sites. The results were consistent with an earlier laboratory study in which 6 portable air cleaners were tested for both particulate and volatile organic compounds removal performance. Zhang says that an air cleaner with a CADR of 722?m3/h (425 CFM) can double the clean air supply for 25 people in a classroom or open plan office.

Zhang says this can be considered as a cost-effective supplementary measure for rooms where total ventilation airflow rate is insufficient. However, for spaces with displacement ventilation (DV), a room air cleaner should only be used with caution so that the desirable airflow pattern of DV is not disturbed.

Conclusion

Zhang writes that these IAQ strategies can be used and implemented across multiple scales from an entire building to a room to an individual's cubicle or personal space. In his editorial, Dr. Zhang also includes a table that shows the efficiency of different combinations of IAQ strategies and the associated costs.

DALLAS, July 29, 2020 -- After decades of progress in reducing overall, premature cardiac death rates in the U.S., a county-by-county population study has found the decline began slowing in 2011, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Researchers in China and the U.S. accessed multiple databases to analyze county-by-county data on nearly 1.6 million premature cardiac deaths in the U.S. that occurred between 1999 and 2017, among individuals between 35 and 74 years of age. While rates declined between 1999 and 2017, since 2010 the pace of the decline has slowed significantly.

"From the 1960s to 2010s, the United States experienced remarkable decline in cardiovascular disease mortality that was coined as one of the major public health accomplishments of the 20th century," said lead investigator Zhi-Jie Zheng, M.D., Ph.D., a University Endowed Distinguished Professor and chair of the department of global health at Peking University in Beijing, China, who leads studies analyzing global and country-specific trends in diseases of major global health importance. Zheng previously served as a lead epidemiologist at the U.S. Centers for Disease Control and Prevention in Atlanta and a supervisory medical epidemiologist at the National Heart, Lung, and Blood Institute of the National Institutes of Health in Bethesda, Maryland.

"Increasing numbers of out-of-hospital deaths and fatal heart attacks in younger age groups, coupled with a steady widening of disparity of socioeconomic and health environment factors affecting health care at the county level, appear to be the key drivers of the slowdown we have seen since 2010."

The study is one of the first national analyses on factors related to disparities in premature cardiac death rates among U.S. counties.

In 2012, all United Nations-member countries including the U.S. committed to achieving a 25% reduction in premature death from cardiovascular diseases, cancer, diabetes or chronic respiratory diseases by the year 2025, as proposed by World Health Organization (WHO). In addition, The Global Cardiovascular Disease Taskforce, which includes the American Heart Association, American College of Cardiology Foundation and other organizations, set a goal to reducing premature deaths from cardiovascular diseases and stroke (The Heart of 25 by 25).

In this study, premature cardiac death was defined as any death that occurred between ages 35 and 74 attributed to heart disease. Among the key findings:

Of nearly 1.6 million premature cardiac deaths from 1999 to 2017, about 61% occurred outside of a hospital.
Although overall premature cardiac death rates fell, the proportion of out-of-hospital deaths rose from 58.3% to 61.5% in 2017.
Twice as many premature cardiac deaths occurred in men compared to women.
Premature death rates were 3.4 times higher among African Americans than Asians or Pacific Islanders.
"Our findings suggest a need for health care policy changes and programs that can identify high-risk, young populations prone to premature cardiac death and support improved cardiac health," Zheng said.

"The decline in the reduction of premature deaths attributable to heart disease is disheartening and is an urgent call to action," said American Heart Association President Mitchell S. V. Elkind, M.D., M.S., FAHA, FAAN, professor of neurology and epidemiology at Columbia University New York and attending neurologist at Columbia University Irving Medical Center of the NewYork-Presbyterian Hospital. "We must invest and focus public and private efforts to address the disparities in risk factors, access to care and other factors slowing the progress in heart disease so that we can increase the opportunity for all Americans to live longer and healthier lives."

"Heart attacks can occur at any age, not just in older persons," Zheng said. "The slower decline in out-of-hospital rates is alarming and warrants more precision targeting and sustained efforts to integrate lifestyle and behavioral interventions that increase heart health and reduce the risk of premature cardiac death."

Disparities were largely associated with demographic composition and socioeconomic status. Demographic composition, which included population size, rural living, sex, age, racial/ethnic and foreign-born as factors, accounted for just over a third of out-of-hospital and in-hospital premature cardiac deaths.

Differences in socioeconomic factors, which included median household income, unemployment, school enrollment and number of violent crimes per 100,000 population, accounted for about 20% of deaths.

Health care environment, which included density of primary care physicians; diabetic, Medicare enrollees who had diabetes confirmed by an HbA1c test; access to places for physical activity; and access to healthy foods, accounted for 18.6% of out-of-hospital and 13.9% of in-hospital deaths. While population health status, which included scoring according to the cardiovascular disease risk index derived from a set of major cardiovascular risk factors, self-rated poor/fair health and total Medicare reimbursements per enrollee (a measure of health care utilization as a proxy for illness), accounted for 23.7% of out-of-hospital death and 30.2% in-hospital deaths.

The study had several limitations including potential errors in the reporting of cause of death, which is reliant on county-level, government health department data.

Once found in bottles, food containers, cash register receipts and electronics, bisphenol A (BPA) has been phased out of many products because of health concerns and government regulations. As a result, the production and use of BPA analogs, which are unregulated and poorly understood, have increased. Now, by analyzing urine samples and wastewater, researchers report in ACS' Environmental Science & Technology how human exposure to bisphenols has changed over time in an Australian population.

BPA is used in the manufacture of polycarbonate plastics and epoxy resins. An endocrine disruptor, the compound readily leaches from these products, and high levels have been linked to health problems in humans and laboratory animals. With increasing regulation and unfavorable public opinion, BPA is being replaced with similar compounds, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB) and bisphenol AF (BP-AF). However, these compounds have not been well studied, and despite their similar chemical structures to BPA, they are largely unregulated. Chang He and colleagues wanted to use pooled urine samples and wastewater collected from South East Queensland, Australia, to estimate exposure to various bisphenols over a 6-year period.

Between 2012 and 2017, the team collected urine samples from a pathology lab and wastewater samples from three wastewater treatment plants. For each 2-year period, they pooled urine samples from the lab by age and sex so that they could determine average levels of bisphenol exposure. Using liquid chromatography/tandem mass spectrometry, the researchers detected BPA in all pooled urine samples, and BPS in 97% of samples, whereas BPB, BPF and BP-AF were not found in any samples. Over the years, urinary levels of BPA decreased, while BPS increased. Higher levels of BPA were measured in younger age groups, which might reflect the presence of BPA in many children's products, such as bottles and toys, manufactured in Australia before 2010. In wastewater, BPA and BPS were detected in all samples, and BPF in 29% of samples. The levels of these bisphenols in wastewater were much higher than predicted from urinary excretion, indicating that most of the compounds arose from leaching from plastic products, industrial input or other sources.

WASHINGTON--COVID-19 may increase the risk of blot cots in women who are pregnant or taking estrogen with birth control or hormone replacement therapy, according to a new manuscript published in the Endocrine Society's journal, Endocrinology.

One of the many complications of COVID-19 is the formation of blood clots in previously healthy people. Estrogen increases the chance of blood clots during pregnancy and in women taking birth control pills or hormone replacement therapy. If infected with COVID-19, these women's risk of blood clotting could be even higher, and they may need to undergo anticoagulation therapy or to discontinue their estrogen medicines.

"During this pandemic, we need additional research to determine if women who become infected with the coronavirus during pregnancy should receive anticoagulation therapy or if women taking birth control pills or hormone replacement therapy should discontinue them," said the study's corresponding author, Daniel I. Spratt, M.D., of Maine Medical Center in Portland, Maine, and Tufts University School of Medicine in Boston, Mass. "Research that helps us understand how the coronavirus causes blood clots may also provide us with new knowledge regarding how blood clots form in other settings and how to prevent them."

Researching and understanding the cause of blood clotting in COVID-19, including the intersecting effects of estrogen therapy or pregnancy, has several hurdles and will require innovative animal and tissue models.

Conversations between clinicians and basic researchers and between endocrinologists and hematologists are necessary to explore potential interactions between SARS-CoV-2--the virus that causes COVID-19--and pregnancy or estrogen therapy that could guide clinical management.

Like the legendary falling apple that hit Isaac Newton and led to his groundbreaking insight on the nature of gravity, COVID-19 could provide unintended glimpses into how complex Earth systems operate, according to a new Stanford-led paper. The perspective, published July 29 in Nature Reviews Earth & Environment, hypothesizes outcomes of unprecedented changes in human activity wrought by worldwide sheltering orders, and outlines research priorities for understanding their short and long-term implications. Getting it right could revolutionize how we think about issues as broad as greenhouse gas emissions, regional air quality, and the global economy's connection to poverty, food security and deforestation, according to the researchers. It could also help ensure an economically, socially and environmentally sustainable recovery from the coronavirus pandemic while helping prevent future crises.

"Without distracting from the most important priority - which is clearly the health and well-being of people and communities - the current easing of the human footprint is providing a unique window into the impacts of humans on the environment, including a number of questions that are critical for effective public policy," said lead author Noah Diffenbaugh, the Kara J Foundation Professor at Stanford's School of Earth, Energy & Environmental Sciences.

For example, the question of how much electrifying the vehicle fleet will improve air quality has until now relied heavily on theoretical arguments and computer models. The scale of recent emissions reductions, however, provides an opportunity to use atmospheric observations to check just how accurate those models are in simulating the impact of pollution-reduction interventions such as electric vehicle incentives.

Predicting pandemic outcomes

The researchers note that although many of the initial impacts of COVID sheltering, such as clear skies resulting from reduced pollutant emissions, could be perceived as beneficial to the environment, the longer-term impacts - particularly related to the economic recession - are less clear. To understand the impacts across both short and long timescales, they propose focusing on cascading effects along two pathways: (1) energy, emissions, climate and air quality; and (2) poverty, globalization, food and biodiversity.

Given the complex interactions along these pathways, the researchers emphasize the need for techniques that can bring together multiple lines of evidence to reveal causes and effects. This includes bolstering and expanding coordinated efforts to study the impacts of the pandemic, including safe deployment of environmental sensors that can track changing conditions, computer models that simulate Earth's response to the sheltering measures and solutions-oriented research trials that lend insight into human behavior and decision making. The authors also call for a coordinated data repository where many different kinds of data can be made openly available to the public in a uniform format.

"Almost overnight, people across the world had to change the way they live, the way they work - with many facing loss of income - commute, buy food, educate their children and other energy-consuming behaviors," said Inês Azevedo, an associate professor of energy resources engineering in Stanford's School of Earth, Energy & Environmental Sciences. "It's critical for us to better understand how future societal disruptions and catastrophes could affect interactions among energy systems and other systems that serve society."

Understanding the human response

A key factor in understanding how the pandemic's effects play out is its influence on human behavior and decision making.

"Human behavior contributes to, but is also affected by, changes in the Earth system, and COVID-19 is creating new challenges for ensuring people and corporations act to protect the planet," said co-author Margaret Levi, the Sara Miller McCune Director of Stanford's Center for Advanced Study in the Behavioral Sciences and a professor of political science. "While government was not a central focus in this paper, it clarifies the roles that laws, regulations and investments play in the safety of the food supply and food workers, emissions controls and many other aspects of the health of the Earth and its inhabitants."

Some of the pandemic's most lasting impacts on climate and air quality could occur via insights it provides into the calculation of policy parameters that measure the value that individuals and society place on different environmental trade-offs. The COVID-19 crisis is making these tradeoffs more explicit, the researchers point out. This is because governments, communities and individuals are making historic decisions reflecting underlying preferences for current and future consumption, as well as the tradeoff between different types of economic activity and individual and collective risk.

These decisions can help quantify the parameters that are routinely used in environmental policymaking (such as the cost of human lives lost to air pollution or of climate change associated with carbon dioxide emissions). As those updated parameters are incorporated into actual policy decisions, they will have lasting effects on the regulations that impact the long-term trajectory of climate and air quality.

Studying policy interventions designed to prevent socio-environmental damage - such as the role of poverty in driving deforestation - could also help vulnerable people weather poverty shocks from COVID-19 by providing a deeper understanding of how and where poverty and environmental degradation are most tightly linked. The researchers propose using the kinds of solution-oriented research trials that were awarded this year's Nobel Prize in Economics to study whether interventions such as payments for protection of natural resources are effective in staving off deforestation, over-fishing and other environmental damages.

"COVID-19 poses some of the biggest challenges we have faced in the last century," said paper co-author Chris Field, the Perry L. McCarty Director of the Stanford Woods Institute for the Environment and Melvin and Joan Lane Professor for Interdisciplinary Environmental Studies. "With every challenge, there are opportunities for learning, and this paper provides a map for expanding the set of opportunities."

WASHINGTON, D.C. and SAN DIEGO, CA -- People of color are far more likely to worry about their ability to pay for healthcare if diagnosed with COVID-19 than their White counterparts, according to a new survey from nonprofit West Health and Gallup. By a margin of almost two to one (58% vs. 32%), non-White adults report that they are either "extremely concerned" or "concerned" about the potential cost of care. That concern is three times higher among lower-income versus higher-income households (60% vs. 20%).

The data come from the West Health/Gallup U.S. Healthcare Study, an ongoing survey about Americans' experiences with and attitudes about the healthcare system. The latest findings are based on a nationally representative sample of 1,017 U.S. adults interviewed between June 8 and June 30.

Additionally, the survey finds a disturbing trend when it comes to medication insecurity. Overall, 24% of U.S. adults say they lacked money to pay for at least one prescribed medicine in the past 12 months, an increase from 19% in early 2019. Among non-White Americans, the burden is growing even more quickly. Medication insecurity jumped 10 percentage points, from 21% to 31%, compared with a statistically insignificant three-point increase among White Americans (17% to 20%).

"We're seeing a significant and increasing racial and socioeconomic divide when it comes to Americans' views on the cost of healthcare and its impact on their daily lives," said Tim Lash, chief strategy officer for West Health. "When we started polling in early 2019, close to 1 in 5 Americans were unable to pay for prescribed medication in the last 12 months. Today it's 1 in 4, and disparities between race and income are growing and will continue to grow without more action from providers and policymakers."

"The statistically significant rise in Americans experiencing medication insecurity is by itself a noticeable shift," said Dan Witters, Gallup senior researcher. "The 10-percentage-point increase among non-White Americans between early 2019 and today serves as strong evidence that the situation is worsening more acutely for those who are already most at risk."

Non-White Workers Twice as Likely to Report Staying in Unwanted Job

Amid broad concern about paying for the cost of COVID-19 or other medical expenses, health insurance benefits are likely more important than ever to U.S. workers. The West Health/Gallup survey finds that 12% of workers are staying in a job they want to leave because they are afraid of losing healthcare benefits, a sentiment that is about twice as likely to be held by non-White workers versus White workers (17% vs. 9%).

High Public Support for Government Negotiation and for Banning Political Contributions from Pharma

Americans step across racial lines in their overwhelming support for disallowing political contributions by pharmaceutical companies and for government intervention in setting price limits for government-sponsored research and a COVID vaccine.

Nearly 9 in 10 U.S. adults (89%) think the federal government should be able to negotiate the cost of a COVID-19 vaccine while only 10% say the drug company itself should set the price. Similarly, 86% of U.S. adults say there should be limits on the price of drugs that government-funded research helped develop. Regarding the influence of pharmaceutical companies on the political process, 78% of U.S. adults say political campaigns should not be allowed to accept donations from pharmaceutical companies during the coronavirus pandemic.

In the case of an infection, the SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defense. During this process, infected body cells release messenger substances known as type 1 interferons. These attract natural killer cells, which kill the infected cells.

One of the reasons the SARS-CoV-2 virus is so successful - and thus dangerous - is that it can suppress the non-specific immune response. In addition, it lets the human cell produce the viral protein PLpro (papain-like protease). PLpro has two functions: It plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. The German and Dutch researchers have now been able to monitor these processes in cell culture experiments. Moreover, if they blocked PLpro, virus production was inhibited and the innate immune response of the human cells was strengthened at the same time.

Professor Ivan Dikic, Director of the Institute of Biochemistry II at University Hospital Frankfurt and last author of the paper, explains: "We used the compound GRL-0617, a non-covalent inhibitor of PLpro, and examined its mode of action very closely in terms of biochemistry, structure and function. We concluded that inhibiting PLpro is a very promising double-hit therapeutic strategy against COVID-19. The further development of PLpro-inhibiting substance classes for use in clinical trials is now a key challenge for this therapeutic approach."

Another important finding from this work is that the viral protein PLpro of SARS-CoV-2 cleaves off ISG-15 (interferon-stimulated gene 15) from cellular proteins with a higher level of activity than the SARS equivalent, which leads to greater inhibition of type I interferon production. This is concordant with recent clinical observations which show that COVID-19 exhibits a reduced interferon response in comparison to other respiratory viruses such as influenza and SARS.

To understand in detail how inhibiting PLpro stops the virus, researchers in Frankfurt, Munich, Mainz, Freiburg and Leiden have worked closely together and pooled their biochemical, structural, IT and virological expertise.

Donghyuk Shin, postdoctoral researcher and first author of the paper, says: "Personally, I would like to underline the significance of science and research and in particular emphasize the potential generated by a culture of collaboration. When I saw our joint results, I was immensely grateful for being a researcher."

Professor Sandra Ciesek, Director of the Institute of Medical Virology at University Hospital Frankfurt, explains that the papain-like protease is an extremely attractive anti-viral goal for her as a physician because its inhibition would be a "double strike" against SARS-CoV-2. She highlights the excellent collaboration between the two institutes: "Especially when investigating a new clinical picture, everyone profits from interdisciplinary collaboration as well as different experiences and viewpoints."

Researchers have shown how a blend of old tyres and building rubble could be used as a sustainable road-making material, in a zero-waste solution to boost recycling and support the circular economy.

Construction, renovation and demolition account for about half the waste produced annually worldwide, while around 1 billion scrap tyres are generated globally each year.

The new material, developed by researchers at RMIT University in Melbourne, Australia, is the first to combine recycled rubble and rubber in a mix that is precisely optimised to meet road engineering safety standards.

Designed to be used for base layers, the recycled blend is more flexible than standard materials, making roads less prone to cracking.

Lead researcher Dr Mohammad Boroujeni said the rubble-rubber mix could deliver both environmental and engineering benefits.

"Traditional road bases are made of unsustainable virgin materials - quarried rock and natural sand," Boroujeni said.

"Our blended material is a 100% recycled alternative that offers a new way to reuse tyre and building waste, while performing strongly on key criteria like flexibility, strength and permanent deformation.

"As we push towards a circular economy that can eliminate waste and support the continual use of resources, our recycled blend is the right choice for better roads and a better environment."

In Australia, only 16% of scrap tyres are domestically recycled. About 3.15 million tons of processed building rubble - known as recycled concrete aggregate (RCA) - is added to stockpiles each year rather than being reused.

In 2019, federal and state governments agreed to ban the export of certain waste materials, with the aim of building Australia's capacity to generate high value recycled commodities and associated demand. As part of the agreement, whole used tyres will be banned from export by December 2021.

On the road to a circular economy

Roads are made of four layers - a subgrade, base and sub-base, with asphalt on top.

All the layers must be strong enough to withstand the pressures of heavy vehicles, while being flexible enough to allow the right amount of movement so a road doesn't easily crack.

RCA can potentially be used on its own for road base layers, but adding recycled rubber can significantly enhance the finished product.

In previous research, the RMIT School of Engineering team has shown their rubble-rubber blend performs well when tested for stress, acid and water resistance, as well as strength, deformation and dynamic properties. Its low shrinkage and good flexibility reduce the risk of cracking.

The new study published in Construction and Building Materials looked at how the mix would withstand the pressures of being driven over by countless vehicles over its lifetime.

Researchers used special machinery to assess the blended material's performance under frictional force, or shear stress, and compared different types of crumb rubber (fine and coarse) mixed into the RCA at different ratios.

The team identified an optimal mixture - 0.5% fine crumb rubber to 99.5% RCA - that delivered on shear strength while maintaining good cohesion between the two materials.

Chief investigator Professor Jie Li said while the recycling of construction waste and scrap tyres was growing, both industries continued to produce significantly more waste than is currently reused.

"Solutions to our waste problems will come not only from reducing how much goes to landfill and increasing how much we recycle; developing new and innovative uses for our recycled materials is absolutely vital," Li said.

'An experimental study on the shear behaviour of recycled concrete aggregate incorporating recycled tyre waste' is published in Construction and Building Materials (DOI: 10.1016/j.conbuildmat.2020.120266).

A team of researchers investigating how a certain type of drugs can kill cells has discovered that these drugs can do more harm than good when used in combination with other cancer treatments.

The researchers wanted to know more about how the drugs, which are called pan-Bcl-2 or Bcl-xL-specific inhibitors, help encourage cell death, specifically cells that have damaged RNA, DNA or proteins.

They had a hunch that chemical and physical factors that damage the DNA, RNA or proteins of otherwise healthy cells -- such as cancer treatments like radiation -- might also predispose formerly healthy cells to die if they were exposed to the pan-Bcl-2 or Bcl-xL-specific inhibitor drugs. A number of cancer treatments use combinations of drugs and other treatments to try to combat cancers that have become resistant to single drug treatments.

It turns out that their hunch was correct.

"Our study explains why clinical trials with 31 drug combinations with Bcl-2 inhibitors have been terminated, withdrawn or suspended," said Denis E. Kainov, the senior author of the new study, which has been published in MDPI Cancers.

Kainov is an associate professor at the Norwegian University of Science and Technology's (NTNU) Department of Clinical and Molecular Medicine.

Kainov specifically identified trials with the pan-Bcl-2 drug navitoclax plus bendamustine and rituximab in patients with relapsed diffuse large B cell lymphoma, and navitoclax plus abiraterone acetate with or without hydroxychloroquine in patients with progressive metastatic castrate refractory prostate cancer (NCT02471391, NCT01423539).

"We think that clinicians and patients should be aware of adverse effects of certain drugs like navitoclax," said Aleksandr Ianevski, the first author of the study, and a PhD candidate at NTNU. "This information has the potential to save lives and improve care of cancer patients."

The researchers tested their idea by exposing healthy small roundworms (C. elegans) to a DNA-damaging substance plus a Bcl-xl specific inhibitor.

The roundworms that were treated with the two substances died faster than those that had been given only one or no substances. They also found reproductive and developmental defects in the roundworms given the combination treatment.

They also tested the toxicity of the combined treatment on healthy, non-malignant human, monkey and dog cells, and found that the treatment killed all the cells. A similar test on malignant cells also showed that the combined treatment would kill these cells, too. But since the goal of a successful cancer treatment is to kill the cancer cells while leaving healthy cells alone, the combination doesn't meet that goal.

When cells are infected by a virus, the virus inserts its own RNA or DNA into the cell and turns the cell into a virus-making factory.

The pan-Bcl-2 or Bcl-xL-specific inhibitors can cause these infected cells to die.

Kainov said that the pan-Bcl-2 or Bcl-xL-specific inhibitors could have adverse effects because cancer patients could be infected with different viruses (such as herpes, coronavirus or influenza).

Safety new medical providers can substantially increase their telemedicine services with modest investments in new staff and technology, a move that can help them expand patients' access to specialized medical care, according to a new RAND Corporation study.

But sustaining gains created by expanded telemedicine will require more-generous reimbursement policies from payers or ongoing revenue from other sources such as government grants, according to researchers.

While the study focused on the experiences of nine community health centers in California that provided telemedicine access to medical specialists from their primary care clinics, the findings have implications about how to sustain the rapid expansion of telemedicine that has been prompted by the social distancing efforts triggered by the novel coronavirus pandemic.

"We found that telemedicine services can extend care for services such as psychiatry and diabetic retinopathy screening in settings that reach underserved populations," said Lori Uscher-Pines, lead author of the study and a senior policy researcher at RAND, a nonprofit research organization. "But in order to sustain such improvements, the federal government and others who pay for medical care need to increase their long-term support for telemedicine services."

There are about 1,400 community health centers across the nation that serve 29 million patients who are mostly low-income. The federally supported centers provide comprehensive primary care to medically underserved populations, regardless of their insurance status or ability to pay for services.

RAND researchers examined the experiences of clinics enrolled in the Sustainable Models of Telehealth in the Safety Net, which was funded by the California Health Care Foundation from 2017 to 2020. The project's goal was to help transform participating health centers from low-volume to high-volume telemedicine providers that are dedicated to improving access to specialty care through technology.

The nine community health centers in the project operated health clinics mostly in rural areas of California.

On average, the health centers had experienced a slight downward trend in telemedicine use prior to the start of the initiative. But there was a large and significant increase in telemedicine volume at the beginning of the initiative, which continued to increase over time.

The majority of participating health centers contracted with third parties (typically a
telemedicine vendor or independent group of specialists) for telemedicine services. In this model, a patient visits the health center where they typically receive primary care and is connected to a remotely located specialist who is employed by another organization.

Two of the health centers primarily used their own clinicians to provide telemedicine services. In this model, multisite health centers that employ specialists such as mental health providers connect patients -- via telemedicine -- at clinics that do not have the specialists.

The community health centers spent between $4,400 and about $250,000 to establish expanded telemedicine programs, with most of the money going to new equipment. During the project, telemedicine volume at the clinics ranged from fewer than 500 visits per year to more than 7,000 per year.

Nearly half of the telemedicine visits were with a behavioral health provider, while another quarter were for eye care. Other common specialists providing telemedicine care included endocrinologists, rheumatologists and dermatologists.

Staff from most health centers reported that the telemedicine services were likely permanent, but that financial factors would determine the scope of services. Administrators at all of the clinics said that telemedicine was a cost center for their organizations and identified several factors that make it difficult for health centers to break even on telemedicine.

Barriers that increased costs include a high no-show rate, limited connectivity, restrictions that do not allow some providers to provide telemedicine services, telemedicine visits taking up space that could be used for more-profitable visits, and the costs associated with switching telemedicine providers.

The RAND evaluation recommends that clinics hire a telemedicine coordinator to head their efforts and that they consider offering telemedicine services to patients from their homes.

The home model, which has been widely implemented during the COVID-19 pandemic, allows health centers to serve patients who live farther away and may be more sustainable because it uses less physical clinic space and can allow salaried providers employed by a clinic to work at full capacity.

"Most community health centers involved in the project were committed to sustaining telemedicine programs, regardless of profitability, in order to provide their patients access to medical specialists," Uscher-Pines said. "Nevertheless, during and after the COVID-19 pandemic, new reimbursement policies could allow for greater flexibility in the type of visits that qualify for reimbursement, which could increase revenue for these visits."

In addition to overall findings, RAND researchers prepared companion reports that provide in-depth recommendations about how to expand telemedicine services. Those reports cover the ideal duties for a telemedicine coordinator, promising practices for adoption of telemedicine and a detailed analysis of the financial costs of expanding telemedicine.