Culture

A new comprehensive analysis on the effect of Mozart's music on epilepsy has confirmed that listening to his piano music can reduce the frequency of epilepsy attacks. The results of this comprehensive meta-analysis (a study of studies), which may overturn current scepticism about the effect, are presented at the ECNP congress after recent publication in a peer-reviewed journal*.

The idea that listening to Mozart may have beneficial effects on mental health arose from early findings in the 1990s. There have been several studies since, but many involved small numbers of people, or have been of variable quality, leading to mixed evidence overall. This has meant that the "Mozart Effect" has been treated with some scepticism by many clinicians. Now two Italian Researchers, Dr Gianluca Sesso and Dr Federico Sicca from the University of Pisa have conducted a systematic review of works related to the effect of Mozart's music on epilepsy.

Working according to accepted standard methods for analysing clinical treatment, they looked at 147 published research articles, which they then evaluated according to such things are relevance and quality of the research. This allowed them to select 12 pieces of research which they gathered into 9 separate groups, representing the best available science on the effect of Mozart's music on epilepsy.

They found that listening to Mozart, especially on a daily basis, led to a significant reduction in epileptic seizures, and also to a reduced frequency of abnormal brain activities in epileptic patients (called interictal epileptiform discharges, which are commonly seen in epileptic patients). These effects occurred after a single listening session and were maintained after a prolonged period of treatment.

Gianluca Sesso said "This isn't the first such review of the effect of Mozart's music on epilepsy, but there has been a flow of new research in the last few years, so it was time to stand back and look at the overall picture. The design of the studies varies, for example some people look at a single listening session, others at daily listening sessions, so it's not easy to form a conclusion.

Epilepsy is surprisingly common, affecting just under 1 person in a hundred worldwide. This means that it has significant social and personal costs. Mostly it's treated by drugs, but these drugs don't work in around 30% of patients, so we need to be open to other therapies: the important thing is that these therapies can be tested and shown to work, and this is what we have shown here".

The meta-analysis indicates that a period of listening to Mozart can give an average reduction in epileptic seizures ranging from between 31% to 66%, but this varies from person to person and according to the music stimulus used. The original studies on the Mozart Effect used the sonata for 2 pianos, K448, and this has remained the music most used in studies. The K545 piano sonata has also been shown to have an effect.

Dr Sesso said "All cultures have music, so it obviously fulfils some psychological need. The mechanisms of the Mozart Effect are poorly understood. Obviously other music may have similar effects, but it may be that Mozart's sonatas have distinctive rhythmic structures which are particularly suited to working on epilepsy. This may involve several brain systems, but this would need to be proven.

This is a review of research, and not original research. One thing it shows is that we need more consistent studies into the effect of music on the mind"

Commenting, Dr Vesta Steibliene, Lithuanian University of Health Sciences, and member of the ECNP Abstract and Poster Committee said:

"There is growing interest in non-invasive brain stimulation techniques in the treatment of neuropsychiatric disorders. This review revealed that Mozart music could be an effective non-invasive method of neurostimulation, reducing the frequency of epileptic seizures, even in hard to treat patients. However, in order to use this method in clinical settings, the exact mechanism of the Mozart music effect on the brain regions should be better understood".

Dr Steibliene was not involved in this work, this is an independent comment.

For the first time doctors have shown that measuring changes in 24-hour heart rate can reliably indicate whether or not someone is depressed. In practical terms, this may give clinicians an objective "early warning" of potential depression, as well as a rapid indication whether or not treatment is working, so opening the way to more rapid and responsive treatment. Presenting results of this pilot study at the ECNP virtual congress, lead researcher, Dr Carmen Schiweck (Goethe University, Frankfurt) said "Put simply, our pilot study suggests that by just measuring your heart rate for 24 hours, we can tell with 90% accuracy if a person is currently depressed or not".

Scientists have known that heart rate is linked to depression, but until now they have been unable to understand exactly how one is related to the other. In part this is because while heart rates can fluctuate quickly, depression both arrives and leaves over a longer period, with most treatments taking months to take effect. This makes it difficult to see whether or not changes in one's depressive state might be related to heart rate.

"Two innovative elements in this study were the continuous registration of heart rate for several days and nights, and the use of the new antidepressant ketamine, which can lift depression more or less instantly. This allowed us to see that average resting heart rate may change quite suddenly to reflect the change in mood", said Carmen Schiweck.

Ketamine has a history as both an anaesthetic and a party drug (a drug of abuse). However in December last year it was licenced to treat major depression in Europe, after having been introduced in the USA a few months earlier. Traditional antidepressants can take weeks to show an effect, in contrast ketamine is rapid acting, with results often being seen in minutes.

As Carmen Schiweck said "We knew that something was going on to link heart rate to psychiatric disorders, but we didn't know what it was, and whether it would have any clinical relevance. In the past researchers had shown that depressed patients had consistently higher heart rates and lower heart rate variability, but because of the time it takes to treat depression it had been difficult to follow up and relate any improvement to heart rate. But when we realized that ketamine leads to a rapid improvement in mood, we knew that we might be able to use it to understand the link between depression and heart rate".

Dr Schiweck performed this work in the Mind Body Research group at KU Leuven, Belgium, with Dr Stephan Claes as the principal investigator. The team worked with a small sample of 16 patients with Major Depressive Disorder, none of who had responded to normal treatment, and 16 healthy controls. They measured their heartrates for 4 days and 3 nights, and then the volunteers with depression were given either ketamine treatment or a placebo.

"We found that those with depression had both a higher baseline heart rate, and a lower heart rate variation, as we expected. On average we saw that depressed patients had a heart rate which was roughly 10 to 15 beats per minutes higher than in controls. After treatment, we again measured the heart rates and found that both the rate and the heartrate fluctuation of the previously depressed patients had changed to be closer to those found in the controls".

The most striking finding was that the scientists were able to use 24-hour heart rate as a "biomarker" for depression. Heart rates were measured using a wearable mini-ECG. The data was fed to an Artificial Intelligence programme, which was able to classify nearly all controls and patients correctly as being depressed or healthy.

"Normally heart rates are higher during the day and lower during the night. Interestingly, it seems that the drop in heart rate during the night is impaired in depression. This seems to be a way of identifying patients who are at risk to develop depression or to relapse." said Carmen Schiweck.

The team also found that patients with a higher resting heart rate responded better to the treatment with Ketamine, which may help identify which patients are likely to respond to which treatment.

Carmen Schiweck said "We need to remember that this is a small proof-of-concept study: 6 of our of our 16 initial patients responded to treatment with at least a 30% reduction on the Hamilton Rating scale for depression, so we need to repeat the work with a larger, anti-depressant free sample. Our next step is to follow up depressed patients and patients who are in remission, to confirm that the changes we see can be used as an early warning system".

Commenting, Professor Brenda Penninx of the Department of Psychiatry at Amsterdam University Medical Centre, said:

"This is an innovative proof-of-concept study. My own group had previously studied short-term heart rate variability in over a thousand depressed patients and controls, and we did not detect a consistent differentiation, and found antidepressants to have more impact than depression status itself. However, this study monitored heart rate variability in the ambulatory setting for several days and nights, which gives unique night and day information on the autonomic nervous system. It needs to be examined whether these interesting findings hold in larger, more diverse treatment settings".

Professor Penninx was not involved in this work, this is an independent comment.

Recent protests across the United States and the world have put a magnifying glass on issues of diversity and equity. A new study explores the ways in which these issues go all the way to the top of the corporate ladder.

In "At the Table but Can't Break Through the Glass Ceiling," led by the University of Delaware's Laura Field, found that even when corporate boards include directors who are women and/or racial minorities, these diverse directors are significantly less likely to serve in positions of leadership. This is despite diverse directors being more likely to possess stronger qualifications.

"While specialized skills such as prior leadership or finance experience increase the likelihood of appointment, that likelihood is reduced for diverse directors," wrote Field, who is Donald J. Puglisi Professor of Finance at UD's Alfred Lerner College of Business and Economics, and her coauthors, the University of South Carolina's Matthew E. Souther and the University of Missouri at Columbia's Adam S. Yore.

In a question-and-answer interview, Field provided more information on these results. She also discusses why this inequity could be occurring and how it could be solved.

Can you talk more about the data that your team found?

Prior research has shown that women and minorities are underrepresented in corporate boards, and we've seen increasing calls from institutional investors and regulators for firms to diversify their boards. U.S. firms seem to be responding to these calls for greater board diversity: The percentage of female and minority directors has increased substantially over the past 20 years. In our paper, we examined the extent to which female and minority (diverse) directors served in board leadership roles, as chairman of the board, lead director or as chairman of one of the four major committees (audit, compensation, governance and nominating).

We studied a large sample of directors on U.S. corporate boards over the period from 2006 to 2017. Our sample was extensive, including 126,044 director-firm-year observations, which represented 19,686 individual directors serving at 2,254 unique firms. We found that diverse directors were highly qualified; they had a greater number of professional credentials, they had more extensive outside board and other firm committee experience and they came from larger director networks than their white male counterparts. Nonetheless, we found that women and minority directors were significantly less likely to be appointed to board leadership roles. In each year of our sample period, female and minority directors were less likely to serve in leadership roles, while white males were more likely to serve as board leaders.

When we looked at how specific experience increases the likelihood of appointment to a leadership role, we found that diverse directors were at a disadvantage. For example, while a white male director with prior chairman/lead director experience was 10.5% more likely to be appointed as chairman/lead director, a diverse director with the same experience was only 6.1% more likely to be chosen. Regardless of the experience measure we considered, diverse directors were less likely to serve in leadership roles than their white male counterparts.

Why might this be happening?

There are several possible explanations for why diverse directors are less likely to serve in board leadership roles. As previously discussed, qualifications or experience do not explain the results: Diverse directors are generally as qualified as non-diverse directors. There are several other possible explanations for why diverse directors may not serve in board leadership roles in the same proportion as white males:

Given the recent focus on board diversity, diverse directors may choose to serve on more boards rather than commit substantial resources to serving in leadership positions on fewer boards.

Diverse directors may not choose to serve in board leadership positions because they are risk-averse or because they live farther from the firm.

Diverse directors may not be effective in board leadership roles.

We thoroughly examined each possible explanation and found no evidence to support any of them. In terms of the effectiveness of diverse directors, we found that the quality of financial reporting was higher with a diverse chair on the audit committee, the sensitivity of CEO turnover to performance was similar for boards with or without a diverse non-executive chairman or lead director, and abnormal CEO pay was similar for boards with or without a diverse chair on the compensation committee. We also examined shareholder voting, and we found that diverse directors receive significantly higher shareholder voting support than do their non-diverse counterparts, suggesting that shareholders view them as effective.

In sum, our evidence points to the conclusions that diverse directors possess at least the same professional skills as their peers and, when serving in leadership roles, diverse directors perform their board duties at least as well as their non-diverse counterparts. Moreover, we found no evidence to suggest that diverse directors avoid serving in board leadership roles. Thus, we posit that biases may at least partially explain the leadership gap we observed for diverse directors.

Does your research team have any suggestions on how to remedy this problem?

To identify possible intermediations to mitigate the diversity leadership gap, we considered three interventions suggested by prior literature to enhance board diversity:

Increasing the proportion of diverse directors on the board

Adopting a diversity policy in director nominations explicitly considering gender and race

Including a diverse director on the nominating committee

We found that firms adopting a diversity policy indicating that they consider race and gender in their board nomination policy were more likely to have diverse directors serving in board leadership roles, as were firms with a diverse director on the nominating committee.

However, our results suggest that merely increasing diverse representation on the board will not mitigate the leadership gap. Thus, our research suggests that if firms wish to mitigate the diversity leadership gap, they should make conscious efforts to do so, by publicly acknowledging their commitment to diversity and by including diverse directors on the board's nominating committee.

Why is this research unique and significant?

Our paper raises important questions about board inequity and lends justification to several recent public concerns on the issue. While most concerns raised by advocates have focused primarily on board composition, we point to evidence of inequity even after these directors have been elected to the board.

September 11, 2020

PHILADELPHIA -- Penn Medicine researchers have found that middle-aged individuals -- those born in the late 1960s and the 1970s -- may be in a perpetual state of H3N2 influenza virus susceptibility because their antibodies bind to H3N2 viruses but fail to prevent infections, according to a new study led by Scott Hensley, PhD, an associate professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania. The paper was published today in Nature Communications.

"We found that different aged individuals have different H3N2 flu virus antibody specificities," Hensley said. "Our studies show that early childhood infections can leave lifelong immunological imprints that affect how individuals respond to antigenically distinct viral strains later in life."

Most humans are infected with influenza viruses by three to four years of age, and these initial childhood infections can elicit strong, long lasting memory immune responses. H3N2 influenza viruses began circulating in humans in 1968 and have evolved substantially over the past 51 years. Therefore, an individual's birth year largely predicts which specific type of H3N2 virus they first encountered in childhood.

Researchers completed a serological survey -- a blood test that measures antibody levels -- using serum samples collected in the summer months prior to the 2017-2018 season from 140 children (ages one to 17) and 212 adults (ages 18 to 90). They first measured the differences in antibody reactivity to various strains of H3N2, and then measured for neutralizing and non-neutralizing antibodies. Neutralizing antibodies can prevent viral infections, whereas non-neutralizing antibodies can only help after an infection takes place. Samples from children aged three to ten years old had the highest levels of neutralizing antibodies against contemporary H3N2 viruses, while most middle-aged samples had antibodies that could bind to these viruses but these antibodies could not prevent viral infections.

Hensley said his team's findings are consistent with a concept known as "original antigenic sin" (OAS), originally proposed by Tom Francis, Jr. in 1960. "Most individuals born in the late 1960s and 1970s were immunologically imprinted with H3N2 viruses that are very different compared to contemporary H3N2 viruses. Upon infection with recent H3N2 viruses, these individuals tend to produce antibodies against regions that are conserved with older H3N2 strains and these types of antibodies typically do not prevent viral infections."

According to the research team, it is possible that the presence of high levels of non-neutralizing antibodies in middle-aged adults has contributed to the continued persistence of H3N2 viruses in the human population. Their findings might also relate to the unusual age distribution of H3N2 infections during the 2017-2018 season, in which H3N2 activity in middle-aged and older adults peaked earlier compared to children and young adults.

The researchers say that it will be important to continually complete large serological surveys in different aged individuals, including donors from populations with different vaccination rates. A better understanding of immunity within the population and within individuals will likely lead to improved models that are better able to predict the evolutionary trajectories of different influenza virus strains.

"Large serological studies can shed light on why the effectiveness of flu vaccines varies in individuals with different immune histories, while also identifying barriers that need to be overcome in order to design better vaccines that are able to elicit protective responses in all age groups," said Sigrid Gouma, PhD, a postdoctoral researcher of Microbiology and first author on the paper.

As missions like NASA's Hubble Space Telescope, TESS and Kepler continue to provide insights into the properties of exoplanets (planets around other stars), scientists are increasingly able to piece together what these planets look like, what they are made of, and if they could be habitable or even inhabited.

In a new study published recently in The Planetary Science Journal, a team of researchers from Arizona State University (ASU) and the University of Chicago have determined that some carbon-rich exoplanets, given the right circumstances, could be made of diamonds and silica.

"These exoplanets are unlike anything in our solar system," says lead author Harrison Allen-Sutter of ASU's School of Earth and Space Exploration.

Diamond exoplanet formation

When stars and planets are formed, they do so from the same cloud of gas, so their bulk compositions are similar. A star with a lower carbon to oxygen ratio will have planets like Earth, comprised of silicates and oxides with a very small diamond content (Earth's diamond content is about 0.001%).

But exoplanets around stars with a higher carbon to oxygen ratio than our sun are more likely to be carbon-rich. Allen-Sutter and co-authors Emily Garhart, Kurt Leinenweber and Dan Shim of ASU, with Vitali Prakapenka and Eran Greenberg of the University of Chicago, hypothesized that these carbon-rich exoplanets could convert to diamond and silicate, if water (which is abundant in the universe) were present, creating a diamond-rich composition.

Diamond-anvils and X-rays

To test this hypothesis, the research team needed to mimic the interior of carbide exoplanets using high heat and high pressure. To do so, they used high pressure diamond-anvil cells at co-author Shim's Lab for Earth and Planetary Materials.

First, they immersed silicon carbide in water and compressed the sample between diamonds to a very high pressure. Then, to monitor the reaction between silicon carbide and water, they conducted laser heating at the Argonne National Laboratory in Illinois, taking X-ray measurements while the laser heated the sample at high pressures.

As they predicted, with high heat and pressure, the silicon carbide reacted with water and turned into diamonds and silica.

Habitability and inhabitability

So far, we have not found life on other planets, but the search continues. Planetary scientists and astrobiologists are using sophisticated instruments in space and on Earth to find planets with the right properties and the right location around their stars where life could exist.

For carbon-rich planets that are the focus of this study, however, they likely do not have the properties needed for life.

While Earth is geologically active (an indicator habitability), the results of this study show that carbon-rich planets are too hard to be geologically active and this lack of geologic activity may make atmospheric composition uninhabitable. Atmospheres are critical for life as it provides us with air to breathe, protection from the harsh environment of space, and even pressure to allow for liquid water.

"Regardless of habitability, this is one additional step in helping us understand and characterize our ever- increasing and improving observations of exoplanets," says Allen-Sutter. "The more we learn, the better we'll be able to interpret new data from upcoming future missions like the James Webb Space Telescope and the Nancy Grace Roman Space Telescope to understand the worlds beyond on our own solar system."

INDIANAPOLIS--Researchers at Indiana University School of Medicine are learning more about how a person's genes play a role in the possibility they'll suffer from alcoholic cirrhosis with the discovery of a gene that could make the disease less likely.

Alcoholic cirrhosis can happen after years of drinking too much alcohol. According to the researchers, discovering more about this illness couldn't come at a more important time.

"Based on U.S. data, alcohol-associated liver disease is on the rise in terms of the prevalence and incidents and it is happening more often in younger patients," said Suthat Liangpunsakul, MD, professor of medicine, dean's scholar in medical research for the Department of Medicine Division of Gastroenterology and Hepatology, and one of the principal investigators of the study. "There's a real public health problem involving the consumption of alcohol and people starting to drink at a younger age."

The team describes their findings in a new paper published in Hepatology. The GenomALC Consortium was funded by the National Institutes on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institute of Health (NIH). This genome-wide association study began several years ago and is one of the largest studies related to alcoholic cirrhosis ever performed. DNA samples were taken from over 1,700 patients from sites in the United States, several countries in Europe and Australia and sent to IU School of Medicine where the team performed the DNA isolation for genome analysis. The patients were divided into two groups--one made up of heavy drinkers that never had a history of alcohol-induced liver injury or liver disease and a second group of heavy drinkers who did have alcoholic cirrhosis.

"Our key finding is a gene called Fas Associated Factor Family Member 2, or FAF2," said Tae-Hwi Schwantes-An, PhD, assistant research professor of medical and molecular genetics and the lead author of the study. "There's this convergence of findings now that are pointing to the genes involved in lipid droplet organization pathway, and that seems to be one of the biological reasonings of why certain people get liver disease and why certain people do not."

The researchers are anticipating to study this gene more closely and looking at its relationship to other, previously-discovered genes that can make a person more likely to develop alcoholic cirrhosis.

"We know for a fact those genes are linked together in a biological process, so the logical next step is to study how the changes in these genes alter the function of that process, whether it's less efficient in one group of people, or maybe it's inhibited in some way," Schwantes-An said. "We don't know exactly what the biological underpinning of that is, but now we have a pretty well-defined target where we can look at these variants and see how they relate to alcoholic cirrhosis."

As their research continues, the team hopes to eventually find a way to identify this genetic factor in patients with the goal of helping them prevent alcoholic cirrhosis in the future or developing targeted therapies that can help individuals in a more personalized way.

Molecules belonging to an almost unknown bioluminescent system found in larvae of the fungus gnat Orfelia fultoni (subfamily Keroplatinae) have been isolated for the first time by researchers at the Federal University of São Carlos (UFSCar) in the state of São Paulo, Brazil. The small fly is one of the few terrestrial organisms that produce blue light. It inhabits riverbanks in the Appalachian Mountains in the eastern United States. A key part of its bioluminescent system is a molecule also present in two recently discovered Brazilian flies.

The study, supported by Paulo Research Foundation - FAPESP, is published in Scientific Reports. Five authors are affiliated with UFSCar and two with universities in the United States.

The bioluminescent systems of glow-worms, fireflies and other insects are normally made up of luciferin (a low molecular weight molecule) and luciferase, an enzyme that catalyzes the oxidation of luciferin by oxygen, producing light. While some bioluminescent systems are well known and even used in biotechnological applications, others are poorly understood, including blue light-emitting systems, such as that of O. fultoni.

"In the published paper, we describe the properties of the insect's luciferase and luciferin and their anatomical location in its larvae. We also specify several possible proteins that are possible candidates for the luciferase. We don't yet know what type of protein it is, but it's likely to be a hexamerin. In insects, hexamerins are storage proteins that provide amino acids, besides having other functions, such as binding low molecular weight compounds, like luciferin," said Vadim Viviani, a professor in UFSCar's Sustainability Science and Technology Center (CCTS) in Sorocaba, São Paulo, and principal investigator for the study.

The study was part of the FAPESP-funded project "Arthropod bioluminescence". The partnership with United States-based researchers dates from a previous project, supported by FAPESP and the United States National Science Foundation (NSF), in partnership with Vanderbilt University (VU), located in Nashville, Tennessee.

In addition to luciferin and luciferase, researchers began characterizing a complex found in insects of the family Keroplatidae, which, in addition to O. fultoni, also includes a Brazilian species in the genus Neoditomyia that produces only luciferin and hence does not emit light.

Because they do not use it to emit light, the luciferin in O. fultoni and the Brazilian Neoditomyia has been named keroplatin. In larvae of this subfamily, keroplatin is associated with "black bodies" - large cells containing dark granules, proteins and probably mitochondria (energy-producing organelles). Researchers are still investigating the biological significance of this association between keroplatin and mitochondria.

"It's a mystery," Viviani said. "This luciferin may play a role in the mitochondrial energy metabolism. At night, probably in the presence of a natural chemical reducer, the luciferin is released by these black bodies and reacts with the surrounding luciferase to produce blue light. These are possibilities we plan to study."

Brazilian cousins

An important factor in the elucidation of the United States insect's bioluminescent system was the discovery of a larva that lives in Intervales State Park in São Paulo in 2018. It does not emit light but produces luciferin, similar to O. fultoni (read more at: agencia.fapesp.br/29066).

In their latest study, the group injected purified luciferase from the United States species into larvae of the Brazilian species, which then produced blue light. The nonluminescent Brazilian species is more abundant in nature than the United States species, so a larger amount of the material could be obtained for study purposes, especially to characterize the luciferin (keroplatin) present in both species.

In 2019, the group discovered and described Neoceroplatus betaryensis, a new species of fungus gnat, in collaboration with Cassius Stevani, a professor at the University of São Paulo's Institute of Chemistry (IQ-USP). It was the first blue light-emitting insect found in South America and was detected in a privately held forest reserve near the Upper Ribeira State Tourist Park (PETAR) in the southern portion of the state of São Paulo. A close relative of O. fultoni, N. betaryensis inhabits fallen tree trunks in humid places (read more at: agencia.fapesp.br/31797).

"We show that the bioluminescent system of this Brazilian species is identical to that of O. fultoni. However, the insect is very rare, and so it's hard to obtain sufficient material for research purposes," Viviani said.

The researchers are now cloning the insect's luciferase and characterizing it in molecular terms. They are also analyzing the chemical structure of its luciferin and the morphology of its lanterns.

"Once all this has been determined, we'll be able to synthesize the luciferin and luciferase in the lab and use these systems in a range of biotech applications, such as studying cells. This will help us understand more about human diseases, among other things," Viviani said.

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.

Counts based on death certificates underestimate COVID-19 mortality rates
Researchers suggest ways to address challenges associated with measuring direct and indirect deaths attributable to COVID-19 pandemic

Estimating deaths from COVID-19 based on death certificate data significantly underestimates the true mortality rate of the pandemic. Authors from Stanford University School of Medicine, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, and Harvard Medical School describe how methods used to assess death tolls from disasters and other pandemics can be used to provide a more accurate picture of COVID-19 death rates now and moving forward. This means measuring direct, indirect, and excess deaths from COVID-19. Their proposed solution is published in Annals of Internal Medicine. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-3100.

Overcoming challenges when calculating direct deaths will require a consensus among health care institutions, medical examiners, and public health agencies. The authors endorse counting all deaths from pneumonia, influenza-like illness, and COVID-19 and subtracting the expected seasonal number of cases of pneumonia and influenza computed from trends in the previous 5 years, as currently done by the Centers for Disease Control and Prevention (CDC). To calculate indirect deaths, the researchers recommend employing the CDC's "but for" principle, which is used when ascertaining disaster-related deaths: "But for the [pandemic], would the person have died when he/she did?" Expected recommendations from the National Academies of Sciences, Engineering, and Medicine, could help with this. And to calculate excess deaths, publicly available, well-curated historical data, with published application programming interfaces is needed. According to the authors addressing these issues is critical to our understanding of the pandemic and its effect on human life.

The author of an accompanying editorial from Merck & Co. agrees that reliable and timely information about both direct and indirect mortality attributable to the COVID-19 pandemic is essential. The most accurate data to assess mortality in the United States from any cause are derived from the National Vital Statistics System (NVSS). Seeing as these data are crucial to informing health and emergency preparedness systems in the United States, they are worth greater investment.

The bulk of the DNA in the cells of higher organisms is confined to the nucleus, while all other organellar DNAs are restricted to defined intracellular compartments in the cytoplasm. The appearance of DNA in the soluble phase of the cytoplasm is therefore interpreted by the innate immune system as signaling the presence of intracellular pathogens - usually bacteria or viruses, although tumor cells and senescent cells can also release nuclear or mitochondrial DNA into the cytosol. Misplaced DNAs - whether nuclear, mitochondrial or extracellular in origin - elicit a strong immune reaction, which is initiated by the enzyme cGAS. Researchers had long assumed that cGAS is itself localized exclusively in the cytosol. However, recent studies have shown that the protein is in fact preferentially found in the cell nucleus. This finding naturally raises the question of what prevents cGAS from binding to nuclear DNA and triggering an autoimmune reaction. Now a team of scientists in LMU's Gene Center, led by Professor Karl-Peter Hopfner, in collaboration with Professor Veit Hornung and his colleagues, has shown that the nature of the interaction of cGAS with the chromosomal DNA in the nucleus explains why the interaction fails to activate the innate immune system. The new findings appear in the leading journal Nature.

Upon binding to cytosolic DNA, cGAS synthesizes a messenger molecule which triggers an intracellular signaling cascade that results in the production of proteins that mediate an inflammatory reaction. This process is essential for the elimination of infectious pathogens. However, it is also implicated in the development of autoimmune diseases - some of which in fact involve the generation of antibodies directed against the cell's own DNA. The fact that the cGAS occurs in the nucleus therefore seems at odds with the protective function of the innate immune system, as activation of the enzyme in the nucleus itself would be expected to lead to autoimmune reactions against the nuclear DNA itself. "Curiously, recent data actually suggest that tight binding of cGAS to the DNA-protein complex found in the nucleus - which is known as chromatin - is crucial for the prevention of DNA-based autoimmunity," says Hopfner.

In the chromatin complex, the DNA is wrapped around disk-like particles made up of proteins called core histones. The resulting 'nucleosomes' are connected by 'linker DNA' that is not directly associated with core histones. By means of cryo-electron microscopy, Hopfner and colleagues were able to show that cGAS binds exclusively to the protein component of chromatin, and does not interact with the DNA itself. "That was a big surprise," says joint lead author Carina de Oliveira Mann. "Moreover, its mode of binding ensures that the DNA recognition site of cGAS is occluded. As a result, the enzyme is rendered inactive in the nucleus, even when the DNA in its vicinity becomes accessible to other proteins in the course of gene activation. Paradoxically, this implies that, by trapping the enzyme in an inactive state, chromatin actually serves as a reservoir for cGAS."

In fact, cGAS is most effectively inhibited in less tightly packaged regions of the chromatin, in which most of the genes reside. "That could explain why cGAS is activated in what are known as micronuclei in the cytosol, in which chromatin is thought to be densely packed," says Hopfner. Micronuclei consist of chromosome fragments surrounded by nuclear envelope. They are the product of errors in chromosome segregation in fast-growing tumor cells or DNA damage caused by ionizing radiation. "Our study represents an important step forward in our understanding of how cGAS interacts with chromatin," says Hopfner, "and will help us to clarify the inflammatory reaction initiated by the enzyme in the context of cancers and autoimmune diseases."

When volcanos erupt, these geologic monsters produce tremendous clouds of ash and dust--plumes that can blacken the sky, shut down air traffic and reach heights of roughly 25 miles above Earth's surface.

A new study led by the University of Colorado Boulder suggests that such volcanic ash may also have a larger influence on the planet's climate than scientists previously suspected.

The new research, published in the journal Nature Communications, examines the eruption of Mount Kelut (or Kelud) on the Indonesian island of Java in 2014. Drawing on real-world observations of this event and advanced computer simulations, the team discovered that volcanic ash seems to be prone to loitering--remaining in the air for months or even longer after a major eruption.

"What we found for this eruption is that the volcanic ash can persist for a long time," said Yunqian Zhu, lead author of the new study and a research scientist at the Laboratory for Atmospheric and Space Physics (LASP) at CU Boulder.

Lingering ash

The discovery began with a chance observation: Members of the research team had been flying an unmanned aircraft near the site of the Mount Kelut eruption--an event that covered large portions of Java in ash and drove people from their homes. In the process, the aircraft spotted something that shouldn't have been there.

"They saw some large particles floating around in the atmosphere a month after the eruption," Zhu said. "It looked like ash."

She explained that scientists have long known that volcanic eruptions can take a toll on the planet's climate. These events blast huge amounts of sulfur-rich particles high into Earth's atmosphere where they can block sunlight from reaching the ground.

Researchers haven't thought, however, that ash could play much of a role in that cooling effect. These chunks of rocky debris, scientists reasoned, are so heavy that most of them likely fall out of volcanic clouds not long after an eruption.

Zhu's team wanted to find out why that wasn't the case with Kelut. Drawing on aircraft and satellite observations of the unfolding disaster, the group discovered that the volcano's plume seemed to be rife with small and lightweight particles of ash--tiny particles that were likely capable of floating in the air for long periods of time, much like dandelion fluff.

"Researchers have assumed that ash is similar to volcanic glass," Zhu said. "But what we've found is that these floating ones have a density that's more like pumice."

Disappearing molecules

Study coauthor Brian Toon added that these pumice-like particles also seem to shift the chemistry of the entire volcanic plume.

Toon, a professor in LASP and the Department of Atmospheric and Oceanic Sciences at CU Boulder, explained that erupting volcanos spew out a large amount of sulfur dioxide. Many researchers previously assumed that those molecules interact with others in the air and convert into sulfuric acid--a series of chemical reactions that, theoretically, could take weeks to complete. Observations of real-life eruptions, however, suggest that it happens a lot faster than that.

"There has been a puzzle of why these reactions occur so fast," Toon said.

He and his colleagues think they've discovered the answer: Those molecules of sulfur dioxide seem to stick to the particles of ash floating in the air. In the process, they may undergo chemical reactions on the surface of the ash itself--potentially pulling around 43% more sulfur dioxide out of the air.

Ash, in other words, may hasten the transformation of volcanic gases in the atmosphere.

Just what the impact of those clouds of ash are on the climate isn't clear. Long-lasting particles in the atmosphere could, potentially, darken and even help to cool the planet after an eruption. Floating ash might also blow all the way from sites like Kelut to the planet's poles. There, it could kickstart chemical reactions that would damage Earth's all-important ozone layer.

But the researchers say that one thing is clear: When a volcano blows, it may be time to pay a lot more attention to all that ash and its true impact on Earth's climate.

"I think we've discovered something important here," Toon said. "It's subtle, but it could make a big difference."

Highest among cleaners and acute medical and BAME staff

Type of PPE worn may be key, say researchers

Findings relevant for any second coronavirus surge and/or seasonal flu this winter

Contrary to expectations, the risk of COVID-19 infection among hospital staff at the height of the coronavirus pandemic was lowest among intensive care clinicians, reveals a study of one major UK medical centre, published in the journal Thorax.

Infection risk was highest among cleaners, acute and general medicine clinicians, and those of Black, Asian and Minority Ethnic (BAME) backgrounds at University Hospitals Birmingham NHS Foundation Trust (UHBFT).

The findings prompt the researchers to suggest that the type of personal protective equipment (PPE) worn may be key to these differences, which are likely to be relevant for any second surge in COVID-19 and/or seasonal flu this winter.

UHBFT is one of the largest hospital trusts in the UK, with over 20,000 employees caring for 2.2 million people every year. As lead study author Professor Alex Richter explains in a linked podcast, at the height of the pandemic, 5 patients with serious COVID-19 infection were being admitted every hour.

At the time, there was no national NHS staff testing capacity, so no way of knowing who was infected, and therefore at risk of passing it on to patients, or who had already had the infection. "You've got to remember that we are all key workers, so travelling on public transport, and out and about," she says.

To find out, she offered to test staff with no COVID-19 symptoms for both current (throat and nose swabs to detect antigen) and previous (blood test to detect antibodies) infection. "I've never recruited to a study so fast in my life. We recruited 545 staff in 20 hours," she comments.

All the staff were at work over the course of 24 hours between 24 and 25 April 2020, around a month after the UK went into lock down. They were asked to report any illnesses consistent with COVID-19 that they had had in the previous 4 months. Information on ethnicity and department of work was also collected.

Nearly 2.5% (13 out of 545) staff with no symptoms tested positive for SARS-CoV-2, the virus responsible for COVID-19 infection. Of these, 38% (5) subsequently developed COVID-19 symptoms.

Around 1 in 4 (26%; 136) of the 516 for whom serum samples were available said they had previously had symptoms consistent with COVID-19 infection.

Staff with previous symptoms were significantly more likely to have antibodies than those who hadn't had symptoms: 37% (of 136 staff) vs 17% (of 281 staff). And they had higher levels of antibodies.

The overall prevalence of antibody positivity (seroprevalence) was 24% (126/ 516): this compares with 6% generally in the Midlands at the time.

When the researchers looked at the figures by staff area, striking differences in antibody positivity emerged.

Cleaners had the highest seroprevalence (34.5%; 10/29), followed by clinicians working in acute medicine (33%; 10/30) or general internal medicine (30%; 30/99). The lowest seroprevalence was found among staff working in intensive care medicine (15%; 9/61), emergency medicine (13%; 2/15), and general surgery (13%; 3/23).

There was also an ethnic divide: workers of BAME backgrounds were nearly twice as likely to have already had the infection as their White colleagues.

"We presumed intensive care workers would be at highest risk.. But workers in ITU are relatively well protected compared with other areas," explains Professor Richter.

"The reasons underlying this are likely to be multifactorial: in accordance with national guidelines, intensive care units were designated high-risk environments and the use of enhanced personal protective equipment (PPE) including filtered face piece (class 3) respirators mandated. In contrast, fluid-resistant surgical masks were recommended in other clinical areas," note the researchers.

This is an observational study, and not all participants provided all the information requested. Nor is it known whether symptomless infection among staff puts hospital patients at risk.

"However, our data would support the assessment of widespread healthcare worker testing, including track and trace, on viral transmission during future waves of a pandemic," conclude the researchers.

"All these factors are important for considering what's going to happen this winter," suggests Professor Richter. "Cases [of coronavirus] are on the rise. Are we going to have another surge? If there is one, how do we protect healthcare workers this winter?" she asks.

"And let's think not just about SARS-CoV-2 and the lessons we can learn for other pandemics, but seasonal infection. Influenza has a massive impact on the NHS every winter," she adds.

The NHS would spend billions of pounds more on drugs if it had to pay US prices following a US/UK trade deal. According to a new study by researchers at Brigham and Women's Hospital in Boston, Harvard Medical School, and the University of Oxford, published by the Journal of the Royal Society of Medicine, NHS England would have spent over £5 billion more on 50 brand-name prescription drugs widely used in primary care if it had paid US prices in 2018. Drugs on the list included a variety of commonly used medicines, including treatments for diabetes, inhalers and anticoagulants.

Prescription drug prices in the US far exceed prices in the UK, where there are price controls in place to limit NHS spending and restrict the profits that drug manufacturers can earn. The analysis shows that if NHS England had paid US prices for the 50 costliest drugs used in primary care in 2018 it would have spent 4.6 times as much, an increase from £1.39 billion to £6.42 billion.

It is currently unclear whether prescription drug prices will be included in any trade deal between the US and UK following Brexit. The UK government has previously stated that the NHS would not be part of a trade deal with the US, but a recent summary of negotiating objectives stated that the US Trade Representative is pursuing 'full market access' for US pharmaceuticals in the UK.

Lead researcher Michael Liu said: "The UK is working towards a range of external trade deals, which is great news. Our paper sounds a note of caution around the NHS medication spend: if drug prices were to be included in a US/UK trade deal, and current cost-containment mechanisms were compromised, this could result in drug prices more similar to those of the US."

"Because the scale of this difference in pricing is so substantial, we have modelled the possible excess costs, applying current US price data to current UK medicines usage data. We hope this provides helpful context for those evaluating different trade options."

As the first wave of the COVID-19 pandemic was receding in mid-May, some 1.3 million working-age adults reported being home sick with symptoms they attributed to the coronavirus. A new analysis finds that, compared to those still working or those absent with other illnesses or disabilities, the adults home sick with COVID-19 had lower incomes, were more likely to be racial/ethnic minorities, and had less education -- national-level evidence of the disparate impact of the COVID-19 pandemic that bolsters other studies based on diagnosed cases and deaths. The study, published September 10 in the Journal of General Internal Medicine, also found that these adults had very high rates of uninsurance and food insecurity that could compound the health harms of the pandemic, findings with relevance to ongoing debates over coronavirus relief legislation in Washington.

The researchers analyzed the Census Bureau's Household Pulse Survey, a new survey that provides information on the health and financial impact of the COVID-19 pandemic in the U.S. Using data from two weeks of the survey conducted in April and May, the researchers identified working-age adults who reported being out "sick with coronavirus symptoms" (previous research has found that some 83.0% of Americans correctly identify the leading coronavirus symptoms). Compared to those at work the previous week, researchers found that these individuals were more likely to be Black (24.2% vs. 11.5%), Asian (11.7% vs. 5.6%), and Hispanic (26.5% vs. 17.2%). The study authors observed similar patterns when comparing the adults home sick with coronavirus to those not working because of a non-coronavirus illness or disability. Those reporting coronavirus symptoms also had lower incomes and less education, and tended to live in larger households and states with high levels of COVID-19 incidence.

The researchers additionally found that those out sick with coronavirus symptoms had disturbingly high levels of social vulnerability: 29.2% of these individuals were uninsured, compared to 8% among the two comparison groups; and 36.2% reported not being able to obtain enough food, compared to 7.5% of those working and 20.8% of those out of work for another illness or disability.

"We know that Black and Hispanic communities have been the hardest hit by the COVID-19 pandemic, as measured in diagnoses and deaths," noted study author Dr. Steffie Woolhandler, distinguished professor at City of University Hunter College and a Lecturer at Harvard Medical School. "But our study suggests that the disparate impact is larger yet, because many people recover at home without ever being diagnosed. Our study also reveals remediable social vulnerabilities -- lack of health insurance and food insecurity -- that could further compound the inequitable health impact of the coronavirus," she added.

The study builds on previous studies from this research group. An earlier study, also published in the Journal of General Internal Medicine using data that predated the pandemic, found that some 18.2 million adults who were at increased risk of severe COVID-19 because of age or chronic disease were either uninsured or underinsured, and that these individuals were disproportionately people of color and lower income. In another study, published in JAMA: Internal Medicine, the researchers identified a historic rise in work absence for illness of any cause, with a disproportionate impact on immigrants, in April.

"The COVID-19 pandemic has been a disaster for working class Americans of all backgrounds, and for Black and Hispanic communities in particular," noted study author Dr. Adam Gaffney, a pulmonary and critical care physician at Harvard Medical School and the Cambridge Health Alliance. "But in so many ways, this disaster has been manmade. The high levels of uninsurance and food insecurity we observed in those reporting coronavirus symptoms is not an act of nature -- it could be solved today by action from Washington. Universal health coverage, and economic aid to American workers, is an urgent necessity."

UCLA researchers and colleagues who analyzed electronic health records found that there was a significant increase in patients with coughs and acute respiratory failure at UCLA Health hospitals and clinics beginning in late December 2019, suggesting that COVID-19 may have been circulating in the area months before the first definitive cases in the U.S. were identified.

This sudden spike in patients with these symptoms, which continued through February 2020, represents an unexpected 50% increase in such cases when compared with the same time period in each of the previous five years.

The findings, the study authors say, demonstrate the importance of analyzing electronic health records to monitor and quickly identify irregular changes in patient populations. The researchers' novel approach, in which they focused not only on hospitalization data but also on data from outpatient settings, may help epidemiologists and health systems detect future epidemics sooner.

The study appears in the peer-reviewed Journal of Medical Internet Research.

"For many diseases, data from the outpatient setting can provide an early warning to emergency departments and hospital intensive care units of what is to come," said Dr. Joann Elmore, the study's lead author and a professor of medicine in the division of general internal medicine and health services research at the David Geffen School of Medicine at UCLA. "The majority of COVID-19 studies evaluate hospitalization data, but we also looked at the larger outpatient clinic setting, where most patients turn first for medical care when illness and symptoms arise."

As scientists and doctors continue to learn more about SARS-CoV-2, the virus that causes COVID-19, health systems and public health agencies are also attempting to predict and monitor cases. Analyzing electronic patient records, the researchers say, could help health authorities more effectively identify and control outbreaks like the current pandemic, which has killed hundreds of thousands worldwide and disrupted billions of lives.

"The pandemic has really highlighted our need for agile health care analytics that enable real-time symptom and disease surveillance using electronic health records data," said Dr. Michael Pfeffer, a study co-author and chief information officer for UCLA Health. "Technology, including artificial intelligence powered by machine learning, has further potential to identify and track irregular changes in health data, including significant excesses of patients with specific disease-type presentations in the weeks or months prior to an outbreak."

The researchers evaluated more than 10 million health system and patient visit records for UCLA Health outpatient, emergency department and hospital facilities, comparing data from the period between Dec. 1, 2019, and Feb. 29, 2020 -- the months prior to increased public awareness of COVID-19 in the U.S. -- with data from the same period over the previous five years.

They found that outpatient clinic visits by UCLA patients seeking care for coughs increased by over 50% and exceeded the average number of visits for the same complaint over the prior five years by more than 1,000. Similarly, they discovered a significant excess in the number of patients seen in emergency departments for reports of coughs and of patients hospitalized with acute respiratory failure during this time period. These excesses remained even after accounting for changes in patient populations and seasonal variation.

The researchers noted that other factors could be responsible for some of this unexpected increase. For instance, their search of outpatient visit records included only the word "cough" as the reason for clinic visits, which may not have been sufficiently specific, and respiratory illnesses could have been due to vaping, though the use of e-cigarettes had been declining since September 2019. In addition, they could not rule out that the excess cases were due to flu.

"We may never truly know if these excess patients represented early and undetected COVID-19 cases in our area," Elmore said. "But the lessons learned from this pandemic, paired with health care analytics that enable real-time surveillance of disease and symptoms, can potentially help us identify and track emerging outbreaks and future epidemics."

Scientists from the Genotype-Tissue Expression (GTEx) project, a National Institutes of Health-funded consortium including researchers from the Broad Institute of MIT and Harvard, have completed a wide-ranging set of studies documenting how small changes in DNA sequence can impact gene expression across more than four dozen tissues in the human body.

These studies, released in a set of 15 papers published in Science and other journals, constitute the most comprehensive catalog to date of genetic variations that affect gene expression. They also highlight the importance of cell type as a factor in understanding how genes are regulated in human tissues, and provide a rich resource for connecting the functional dots between genetic variation and human traits and diseases.

The NIH launched GTEx in 2010 to identify and map quantitative trait loci (QTLs), namely, associations between genetic variants at specific locations in the genome and gene expression within a variety of tissues. Researchers have mapped the vast majority of genetic variants discovered through genome-wide association studies -- which scan the genome to identify variants linked to traits or disease -- to regions of the genome's non-coding DNA (which does not directly instruct the construction of proteins). This suggests that these variants act by influencing genes' expression, rather than by altering the proteins they encode.

To shed light on these relationships, GTEx set out to genotype and measure gene expression in samples of up to 50 tissue types (brain, heart, lung, prostate, uterus, etc.) from as many as 1,000 deceased donors, with a goals of identifying QTLs for as many genes as possible, and determining whether or not their effects are shared among multiple tissues or cell types.

"GTEx attempted to map, across as many individuals as possible, the basis of gene regulation, starting from how a genetic change might affect how a gene is expressed or how a protein is produced," said Kristin Ardlie, who directs the GTEx Laboratory Data Analysis and Coordination Center at Broad, and who served as co-corresponding author on the project's flagship Science paper with Broad computational biologist François Aguet and Tuuli Lappalainen of the New York Genome Center (NYGC).

A resource for the future

The flagship Science paper details the results of the GTEx Consortium's 10 years of work, efforts that have helped reveal much about the immense complexity underlying genetic control of gene expression. It presents the results of the consortium's analysis of 15,201 samples representing 52 tissues, collected from 838 donors -- a dataset nearly twice the size of that behind the most recent prior GTEx papers published in 2017. Each donor underwent whole genome sequencing to identify the genetic variants present, along with RNA sequencing of all tissue samples to establish the pattern of gene expression within the tissue.

The resulting dataset -- available via the GTEx portal -- catalogs QTLs governing the expression of more than 23,000 genes, with multiple QTLs regulating many genes. These included variants that directly affect expression of (eQTLs) or splicing within genes (sQTLs), both for variants close to the genes they control (cis-QTLs) and ones located on chromosomes other than the one harboring their target gene (trans-QTLs).

The data also confirmed that QTLs tend to be either very tissue-specific in their expression effects, or shared quite broadly across all tissues; and revealed some differences in QTL effects between sexes and across populations.

Mechanistically, the findings suggest that QTLs may often affect how a cell's transcription factors bind to the genome at a gene's promoter or enhancer, which in turn affects that gene's expression. And they also provide a baseline for deeper insights into functional roles QTLs play.

"At this larger sample size, and with the diverse tissues and donors we have, we can start to see that there is more than one regulatory effect per gene, and that these differ not just by tissue but by cell type," Ardlie said. "We can start to map at high resolution the variants that actually impact a trait. And we can begin to relate GWAS signals to QTLs and see whether what appear to be random GWAS hits might actually fall within functional elements that affect gene regulation and complex trait and disease phenotypes."

Tuning in

A key focus for this latest set of GTEx studies was to understand how QTLs mapped not just to tissues, but to specific cell types. With hundreds of samples sequenced from many tissues, GTEx researchers found that many genes were influenced by multiple QTLs. This phenomenon, called "allelic heterogeneity," reflects the fact that the GTEx tissue samples represent mixtures of many types of cells.

To gain a more nuanced understanding of QTLs' cellular specificity and learn the extent to which QTLs from different cell types contributed to their tissue-level observations, a GTEx team led by Aguet at Broad and Lappalainen and Sarah Kim-Hellmuth at NYGC used the project's RNA profiling data to computationally identify the cell types present within GTEx's tissue samples. They then checked whether QTLs mapped within those tissues were likely to be specific to the inferred cell types.

These analyses, reported in a companion Science paper, pinpointed thousands of "cell type interaction QTLs," many of which had not been previously characterized. The results indicate that many more cell type specific QTLs are likely to exist but cannot yet be detected without additional samples or improved methods. They also showed that the patterns of QTL sharing and specificity across tissues could be tied back to whether those tissues shared cell types in common.

The findings also revealed that even at the cell type-level, multiple QTLs can influence any given gene, sometimes acting together to boost expression, sometimes in opposition to tamp expression down, depending on an individual's genotype.

"In a sense, QTLs act like a dial on expression, one that can be adjusted up or down," Aguet explained. "One QTL might increase expression, but another might turn it back down a little. It all adds to the complexity of how genetic variation regulates gene expression."

An end, but also a beginning

This collection of studies comprises the consortium's final analysis of the GTEx dataset, though a great deal of work remains to be done and a great deal of knowledge remains to be gleaned from the catalog of QTLs. For instance, Ardlie noted, QTL analysis provides only one lens through which to view the functional implications of genetic variation, one that complements epigenomic, proteomic, and other forms of genomic and transcriptomic analysis.

"GTEx was an ambitious, complex undertaking, and it remains very difficult to access this breadth of tissues from individuals, and in that sense GTEx was unique and has helped pave the way for studies like the Human Cell Atlas," she said. "But we really need large-scale resources like this and others, such as ENCODE, from which we can glean complementary information to get a more complete picture of the molecular mechanisms that drive biology."