Culture

UNIVERSITY PARK, Pa. -- The number of human tuberculosis (TB) cases that are due to transmission from animals, as opposed to human-to-human transmission, may be much higher than previously estimated, according to an international team of researchers. The results could have implications for epidemiological studies and public health interventions.

"Tuberculosis kills 1.4 million people every year, making it the most deadly disease arising from a single infectious agent," said Vivek Kapur, professor of microbiology and infectious diseases and Huck Distinguished Chair in Global Health, Penn State. "India has the largest burden of human tuberculosis globally, with more than 2.6 million cases and 400,000 deaths reported in 2019. Additionally, the cattle population in India exceeds 300 million, and nearly 22 million of these were estimated to be infected with TB in 2017.

Kapur noted that the World Health Organization, World Organisation for Animal Health and Food and Agriculture Organization of the United Nations define zoonotic TB as human infection with Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex (MTBC).

To evaluate the use of M. bovis as a proxy for zoonotic tuberculosis and to investigate the potential role of other MTBC subspecies, Kapur and his colleagues analyzed 940 bacterial samples -- both pulmonary (from lung fluid or tissue) and extrapulmonary (from tissues other than the lungs) -- collected from patients who were visiting a large reference hospital for TB in southern India. The researchers used PCR to speciate M. tuberculosis complex organisms and then sequenced all the non-M. tuberculosis samples. Next, they compared the sequences to 715 sequences from cattle and humans that had previously been collected in south Asia and submitted to public databases.

"Surprisingly, we did not find any evidence for the presence of M. bovis in any of the samples," said Sreenidhi Srinivasan, postdoctoral scholar in the Huck Institutes of the Life Sciences. "Instead, we found that seven of the patient samples contained M. orygis. Six of these came from patients with extrapulmonary TB."

They describe their findings in a paper published June 1 in The Lancet Microbe.

As expected, most of the remainder of the sequences from the patients belonged to M. tuberculosis -- the TB bacterium that is generally thought to be transmitted only among humans.

"Our findings suggest that M. bovis might be uncommon in India, and that its detection may not be an adequate proxy for zoonotic TB infection in humans," said Srinivasan. "These data indicate that members of the TB complex other than M. bovis might be more prevalent in livestock in India."

Kapur added that the operational definition of zoonotic TB should be broadened to include other MTBC subspecies capable of causing human disease.

"By 2035, the World Health Organization is aiming to reduce the incidence of tuberculosis by 90% as a part of its End TB Strategy," he said. "The increasing evidence supporting M. orygis endemicity in south Asia and the identification of M. tuberculosis in cattle highlight the importance of using a One Health approach, involving multisectoral collaboration across the veterinary and clinical sectors, to meet the WHO's goal in India."

Tower block games such as Jenga can be used to explain to schoolchildren how lithium-ion batteries work, meeting an educational need to better understand a power source that has become vital to everyday life.

While lithium-ion batteries are abundant in so many of our electronic devices, from smart phones to electric vehicles, the resources available to teach children how they work and why they are important are limited.

A team in the University of Birmingham's School of Chemistry, has devised an educational tool which uses the tower block game Jenga to explain the processes at work inside the battery cells and the electrochemistry behind them. Their method is published in the Journal of Chemical Education.

A rechargeable Li-ion battery consists of an oxide and a graphite electrode. These are commonly built in layers separated with an electrolyte. When the battery is charged, lithium ions move from the graphite to the oxide electrode via the electrolyte. Current collectors, which the electrodes are coated onto, allow electrons to move via an external circuit, providing power.

By using the layers of blocks, children can get a sense of how the battery is constructed and how the different components interact with each other. The battery Jenga can show battery operation and key characteristics. The intercalation, or layered, chemistry of charging and discharging this type of battery can be easily visualised. Through removing a few blank blocks in the graphite electrode (these blocks represent empty space between the layers of graphite), a student can move the Li-ion blocks from the oxide electrode to the graphite electrode. The reverse process will occur on discharge.

The simplicity of this demonstration provides a basis for complex chemistry and redox reactions to be explained. The importance and safety of rate of charge for differing applications can be shown too, when students remove the lithium ion blocks from the oxide electrodes at varying rates. The faster charge invariably leads to the Jenga structure collapsing.

The tower block game can also demonstrate how the performance of the battery reduces over continued use by showing how the blocks become slightly displaced as the lithium blocks are removed and reinserted.

Researcher Elizabeth Driscoll explains: "Hands-on demonstrations are known to be a useful way of supporting learning - teachers often use lemons or potatoes to explain conventional non-rechargeable batteries, for example. But we know that electrochemistry is a tricky area for teachers, which often leads to misconceptions among students. We wanted to design a hands-on activity that would help address this and explain this rechargeable-type."

By introducing tower block sets with strong contrasting colours and different textures, the team were also able to devise teaching tools that would be more inclusive for students who are blind or partially-sighted.

The activities have been trialled with multiple visiting schools over the past year, including: the Royal Society of Chemistry's Top of the Bench demonstration lecture, with positive feedback from both teachers and students. The sets have also made an appearance at public events at museums, from the ThinkTank science museum in Birmingham to the Manchester Science Museum and the Royal Institution in London.

The next step for the team will be to enable the activity to be widely accessible to more students and provide support for educators in these topics. Funding from the Faraday Institution and the Royal Society of Chemistry has already enabled 100 small jenga sets to be supplied to a Birmingham secondary school. Tactile classroom sets will also be provided to New College Worcester and Bolton Sensory Support service. Educators interested in producing their own sets can access full instructions via the open access paper in the Journal of Chemical Education.

Six months into the COVID-19 pandemic, more than 7.4 million people have been infected, and more than 410 000 have died. As yet, there is no treatment or vaccine for the disease.

Now, a team of researchers from Norway and Estonia have looked at different possible treatment options -- and found both good and bad news.

The good news is that the team identified six existing safe-in-humans broad-spectrum antivirals that worked against the disease in laboratory tests. Two of the six, when combined, showed an even stronger effect in infected cell cultures.

"This is exciting new data from the work we did," said Magnar Bjørås, a professor in the Norwegian University of Science and Technology's (NTNU) Department of Clinical and Molecular Medicine, and one of the paper's co-authors.

The bad news is that another, non-drug treatment -- the use of antibody-laden plasma from recovered patients to treat the severely ill -- may only work if the donor has recently recovered from COVID-19.

"This means if you collect blood from patients who have recovered from COVID-19 after 2 months from diagnosis of the disease, and transfuse their plasma/serum to severely sick patients, it may not help," said Svein Arne Nordbø, an associate professor at the university's Department of Clinical and Molecular Medicine and an MD at Department of Medical Microbiology at St. Olavs Hospital in Trondheim, and another of the paper's authors.

The study has been published in the journal Viruses.

The research team developed a cell culture that they could use to grow SARS-CoV-2, the name of the coronavirus that causes COVID-19. The culture allowed them to actually test the efficacy of the different drugs in the laboratory.

They determined that a cell type called Vero-E6 was best suited to propagate the coronavirus, and were able to screen 136 drugs using the cell culture.

The screening identified six existing drugs that had some effect, and several combinations of drugs that acted synergistically, the researchers said. The six drugs were nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine, said Denis Kainov, an associate professor at the university's Department of Clinical and Molecular Medicine, and senior author of the article.

A combination of nelfinar and amodiaquine "exhibited the highest synergy," he said.

This last finding was encouraging enough that the researchers hope that others will follow up and start testing the drug combinations in patients.

"This orally available drug combination -- nelfinavir -amodiaquine -- inhibits the virus infection in cell cultures," Kainov said. "It should be tested further in pre-clinical studies and clinical trials now."

The researchers also wanted to look more closely at the efficacy of using blood plasma from recovered patients to treat people with COVID-19.

The Vero-E6 cell line enabled them to develop a "neutralizing antibody" test, which they could use to determine the strength of antibodies from the blood of recovered patients.

The neutralizing antibody test works much like its name suggests.

The researchers took blood plasma from recovered patients and added it to the cell cultures containing the live virus. That allowed them to see how effectively the antibodies in the plasma neutralized or killed the virus that was growing in the cell culture. Researchers call the plasma from recovered patients "convalescent serum."

"Convalescent serum from patients containing antibodies against the virus has been used for treatment of different viral diseases over the last decades with some success, when vaccines or antivirals are not available," Nordbø said. "If used for treatment, it is essential that the convalescent serum contains enough antibodies that are capable of inactivating or killing the virus."

But Nordbø points out that the only way to know if the convalescent serum is strong enough is by adding dilutions of it to a live virus strain and testing the mixtures on cell lines that can propagate the virus, as the researchers did.

Ordinary antibody tests may not reflect the ability of the convalescent serum to actually kill or neutralize the virus, he said. That means the neutralization tests are still the most specific.

The neutralizing antibody tests allowed the researchers to test convalescent sera from a number of recovered patients. They were able to see that some recovered patients didn't produce lots of antibodies at all, a finding that has been confirmed by other research.

They also were able to see that the more recent the recovery from COVID-19, the more effective was the serum. Two months after a patient had been diagnosed, their serum didn't have enough antibodies to combat the virus in the cell culture.

"The conclusion so far is that clinicians need to collect plasma for treatment purposes as soon as patients recover from COVID-19," Nordbø said, because the amounts of antibodies decline with time.

However, this finding is not contrary to the notion of lasting immunity. If the patient was exposed the virus a second time, the cells of the immune system would most likely be prepared to increase the production of antibodies again, said Mona Høysæter Fenstad, a researcher at the Department of Immunology and Transfusion Medicine at St. Olavs Hospital, and another co-author.

The fact that the researchers had been able to diagnose and isolate the virus from Trøndelag patients gave them the chance to identify the origin and evolution of the viral strains. This was achieved with the help of a new nanotechnology-based test for COVID-19 that was spearheaded by Bjørås and adopted by the Norwegian government and that could potentially be exported for use in other countries.

By determining the genetic make-up of the strains, the researchers were able to compare the strains to those registered in an online resource and figure out where the different strains originated.

"We determined that the SARS-CoV-2 strains isolated in Trondheim had originated from China, Denmark, the USA and Canada," said Aleksandr Ianevski, the first author of the paper and a PhD candidate in the university's Department of Clinical and Molecular Medicine.

That raises the question of whether or not Norway's travel restrictions, enacted on March 12, should perhaps have been introduced earlier to prevent the import of the virus to the country, the researchers said.

But seeing how strains are moving across the globe offers potential helpful insights into the virus and its transmission, Ianevski said.

"Monitoring pathogen epidemiology and the evolution of the virus helps with our epidemiological understanding of the disease and may improve outbreak response," he said.

Kainov and Ianevski had previously gone through the academic literature to identify what are called "safe-in-man" broad spectrum antivirals (abbreviated BSAAs). These are drugs that are known to inhibit human viruses that belong to two or more viral families, and have passed the first phase of clinical trials.

That database of the drugs was published in the International Journal of Infectious Diseases and is accessible at https://drugvirus.info/. The authors also identified 46 BSAAs that could potentially act against the SARS-CoV-2 virus including remdesivir and favipiravir, which are currently being studied in different clinical trials across the globe.

The advantage of these drugs is that if they are shown to be able to inhibit the coronavirus in the lab, they can be given to patients without having to first test the drugs for safety.

They would still require clinical trials to see how well they actually work in the human body and what kind of doses are needed for them to control or kill the virus.

June 15, 2020, CLEVELAND: Cleveland Clinic researchers have developed the world's first risk prediction model for healthcare providers to forecast an individual patient's likelihood of testing positive for COVID-19 as well as their outcomes from the disease.

According a new study published in CHEST, the risk prediction model (called a nomogram) shows the relevance of age, race, gender, socioeconomic status, vaccination history and current medications in COVID-19 risk. The risk calculator is a new tool for healthcare providers to aid them in predicting patient risk and tailoring decision-making about care. It provides a more scientific approach to testing which is important for the healthcare community which has faced increased demand for testing and limited resources.

"The ability to accurately predict whether or not a patient is likely to test positive for COVID-19, as well as potential outcomes including disease severity and hospitalization, will be paramount in effectively managing our resources and triaging care," said Lara Jehi, M.D., Cleveland Clinic's Chief Research Information Officer and corresponding author on the study. "As we continue to battle this pandemic and prepare for a potential second wave, understanding a person's risk is the first step in potential care and treatment planning."

The nomogram, which has been deployed as a freely available online risk calculator at https://riskcalc.org/COVID19/ , was developed using data from nearly 12,000 patients enrolled in Cleveland Clinic's COVID-19 Registry, which includes all individuals tested at Cleveland Clinic for the disease, not just those that test positive.

Data scientists, including co-author on the study Michael Kattan, Ph.D., Chair of Lerner Research Institute's Department of Quantitative Health Sciences, used statistical algorithms to transform data from registry patients' electronic medical records into the first-of-its-kind nomogram.

This study revealed several novel insights into disease risk, including:

Patients who have received the pneumococcal polysaccharide vaccine (PPSV23) and flu vaccine are less likely to test positive for COVID-19 than those who have not received the vaccinations.

Patients actively taking melatonin (over-the-counter sleep aid), carvedilol (high blood pressure and heart failure treatment) or paroxetine (anti-depressant) are less likely to test positive than patients not taking the drugs.

Patients of low socioeconomic status (as measured in this study by zip code) are more likely to test positive than patients of greater economic means.

Patients of Asian descent are less likely than Caucasian patients to test positive.

"Our findings corroborated several risk factors already reported in existing literature - including that being male and of advancing age both increase the likelihood of testing positive for COVID-19 - but we also put forth some new associations," said Dr. Jehi. "Further validation and research are needed into these initial insights but these correlations are extremely intriguing."

In a previous network medicine study led by Lerner Research Institute scientists, 16 drugs (including melatonin, carvedilol and paroxetine) and three drug combinations were identified as candidates for repurposing as potential COVID-19 treatments. While these findings suggest an association between taking these medications and reduced risk of testing positive for COVID-19, additional studies are needed to assess how these drugs may affect disease progression.

"The data suggest some interesting correlations but do not confer cause and effect," said Kattan. "For example, our data do not prove that melatonin reduces your risk of testing positive for COVID-19. There may be something else about patients who take melatonin that is indeed responsible for their apparent reduced risk, and we don't know what that is. Consumers should not change anything about their behavior based on our findings."

The nomogram, developed using data from patients tested at Cleveland Clinic for COVID-19 before April 2, 2020, showed good performance and reliability when used in a different geographic region (Florida) and over time (patients tested after April 2, 2020). This suggests that the patterns and predictors identified in the model are consistent across regions and communities and can be potentially adopted for clinical practice in healthcare systems across the country.

"This nomogram will bring precision medicine to the COVID-19 pandemic, helping to enable researchers and physicians to predict an individual's risk of testing positive," said Kattan. "Additionally, while testing solutions continue to be needed, it is so important to make sure we are responsibly and optimally dispatching our resources ¬- including clinical personnel, personal protective equipment and hospital beds. Our risk prediction model stands to greatly assist hospital systems in this planning."

LAWRENCE -- It's been estimated that up to 88% of survivors of rape or molestation suffer from persistent nightmares that can occur multiple times per week, seemingly at random.

A new study from psychologists at the University of Kansas just published in the Journal of Traumatic Stress attempts to shed light on triggers of post-trauma nightmare occurrences - a topic that has received scant study.

The research is the first to show that having difficulty getting to sleep, along with thinking about the trauma or other negative events prior to sleep, could boost the odds of a post-trauma nightmare occurrence.

"We found both 'sleep latency,' or the time it takes someone to fall asleep, and 'pre-sleep cognitive arousal,' or worrying or ruminating prior to going to bed, were the two significant predictors of a nightmare occurring," said lead author Westley Youngren, a doctoral student in clinical psychology at KU.

In the study, Youngren and co-authors Nancy Hamilton, KU associate professor of clinical psychology, and Kristopher Preacher of Vanderbilt University, recruited 27 female college students who reported frequent nightmares tied to sexual trauma. In addition to interviews and questionnaires to assess general depression and anxiety-related symptoms, these participants were asked to complete pre- and post-sleep diaries for six days.

"If someone took 60 or 90 minutes to fall asleep and during that time they were worrying or thinking about the trauma, they were then most likely to have a nightmare," Youngren said. "It tended to be the interaction of the two that predicted the occurrence of a nightmare. It's really priming the mind to have dream content of the trauma, which is then going to result in a nightmare."

Youngren said he hoped the findings could be used in a clinical setting to help survivors of sexual trauma reduce or avoid nightmares.

"Recurrent nightmares are pretty frequent in trauma survivors, and they're distressing - often manifesting as nightmares of the exact same event that happened," he said. "If an individual is raped, they can have nightmares of being assaulted again, much the way people who have been in combat have nightmares of combat again."

Post-traumatic nightmares are linked to insomnia and can occur simultaneously with depression, anxiety, cardiovascular risk factors, alcohol abuse, suicidal ideations and suicide attempts.

Currently, interventions include prescribing a heart rate medication called Prazosin and a therapeutic technique where a survivor "re-scripts" nightmares to prime themselves into dreaming differently. Youngren said a more specific grasp of what triggers nightmare occurrences could lead to more effective treatments.

"Re-scripting based therapy does have more effects than using the Prazosin, but it's still not as high as other kinds of treatment options for other psychological disorders," Youngren said.

Youngren's research interest in traumatic nightmares stems from his time as a U.S. Marine.

"While in the military, I was kind of like, 'All right, well, I want to get a job where I can sleep all the time.' Because I wasn't sleeping at all in the military. So, I wanted to do sleep research. I did my undergraduate education at the University of Tulsa with a creator of one of the nightmare treatments. I started working with her and getting involved in trauma work -- and really saw nightmares were the perfect combination of sleep research and trauma work. So, I really fell into that and sought out a graduate experience where I could investigate these post-traumatic nightmares, which brought me to KU."

Youngren plans to earn his doctorate by 2022 and hopes to make a career out of research into post-traumatic nightmares.

"Currently, we just got a research grant from American Psychological Association's Division 19 -- their military psychology unit -- in order to continue the kind of study we've just published," he said. "We're going to make it bigger and use physiological monitors as the second step."

The employment prospects of some ethnic minorities in the UK have improved since the 1970s but still lag behind the white majority because of "persistent racism", a major new study says.

Three researchers found that, despite progress, most ethnic minority groups studied are still more likely to be in manual work or unemployed or sick than their white counterparts.

Dr Saffron Karlsen, of the University of Bristol, Professor James Nazroo, University of Manchester, and Dr Neil Smith, National Centre for Social Research, analysed national census data on more than 70,000 people in England and Wales.

An article to be published shortly in the journal Sociology, run by the British Sociological Association, says that the most disadvantaged groups were men and women of Bangladeshi and Pakistani ethnicity, who were 1.5 and 1.3 times more likely to be in manual work than their white counterparts in 2011.

In 2011, women of Bangladeshi, black Caribbean, black African and Pakistani ethnicity were between 1.6 and 5.3 times more likely to be unemployed or off sick than white women. For men the figures were between 1.8 and 2

Among men the ethnic groups with a relatively strong position were men of Chinese and Indian ethnicity, who were more likely to work in manual occupations than white men in 1971, but less likely in 2011. Also, women of Chinese ethnicity were less likely to be in manual work than white women in 2011, as they were in 1971.

Men and women of Irish ethnicity had about the same likelihood of being in a manual occupation in 2011 as non-Irish ethnicity white men and women.

In most cases where the rate of manual labour or of unemployment or sickness was higher among ethnic minorities in 2011 than among white people, the difference was less dramatic than it was in 1971.

"The evidence for the socioeconomic disadvantage experienced by most, although not all, people with ethnic minority backgrounds in England and Wales compared with the ethnic majority is indisputable," says Dr Karlsen.

"These findings would appear in keeping with work exposing the ethnic penalty which continues to affect the access of minority groups to employment... and the ways in which persistent racism limits access to positive socioeconomic outcomes including social mobility.

"There is sufficient consistency to suggest that this is a problem produced and perpetuated at the societal level.

"Addressing these inequalities will not be resolved by a focus on particular individuals or cultures and their perceived limitations, rather the focus should be racism, discrimination and their consequences."

The researchers also found that:

In the 1971 census men in five of the seven ethnic minority groups studied had a rate of unemployment or sickness higher than that of white men, a figure that rose to six groups in the 2011 census.

Women in six of the seven ethnic minority groups had a rate of unemployment or sickness higher than white women in the 1971 census, a figure that stayed the same in the 2011 census.

In the 1971 census men in six of the seven ethnic minority groups were more likely to be in a manual job than white men, a figure that fell to four groups in the 2011 census.

In 1971 women in six of the seven ethnic minority groups were more likely to be in a manual job than white women, a figure that fell to four groups in the 2011 census.

The seven ethnic minority groups were: Bangladeshi, black African, black Caribbean, Chinese, Indian, Irish and Pakistani. In the text above, 'white' refers to people who gave their ethnicity as white British (and not Irish, who are classed as one of the ethnic minorities). The researchers used ONS Longitudinal Study data.

HOUSTON - (June 15, 2020) - Mixing and matching computational models of 2D materials led scientists at Rice University to the realization that excitons -- quasiparticles that exist when electrons and holes briefly bind -- can be manipulated in new and useful ways.

The researchers identified a small set of 2D compounds with similar atomic lattice dimensions that, when placed together, would allow excitons to form spontaneously. Generally, excitons happen when energy from light or electricity boosts electrons and holes into a higher state.

But in a few of the combinations predicted by Rice materials theorist Boris Yakobson and his team, excitons were observed stabilizing at the materials' ground state. According to their determination, these excitons at their lowest energy state could condense into a superfluidlike phase. The discovery shows promise for electronic, spintronic and quantum computing applications.

"The very word 'exciton' means that electrons and holes 'jump up' into a higher energy," Yakobson said. "All cold systems sit in their lowest-possible energy states, so no excitons are present. But we found a realization of what seems a paradox as conceived by Nevill Mott 60 years ago: a material system where excitons can form and exist in the ground state."

The open-access study by Yakobson, graduate student Sunny Gupta and research scientist Alex Kutana, all of Rice's Brown School of Engineering, appears in Nature Communications.

After evaluating many thousands of possibilities, the team precisely modeled 23 bilayer heterostructures, their layers loosely held in alignment by weak van der Waals forces, and calculated how their band gaps aligned when placed next to each other. (Band gaps define the distance an electron has to leap to give a material its semiconducting properties. Perfect conductors -- metals or semimetals like graphene -- have no band gap.)

Ultimately, they produced phase diagrams for each combination, maps that allowed them to view which had the best potential for experimental study.

"The best combinations are distinguished by a lattice parameter match and, most importantly, by the special positions of the electronic bands that form a broken gap, also called type III," Yakobson said.

Conveniently, the most robust combinations may be adjusted by applying stress through tension, curvature or an external electric field, the researchers wrote. That could allow the phase state of the excitons to be tuned to take on the "perfect fluid" properties of a Bose-Einstein condensate or a superconducting BCS condensate.

"In a quantum condensate, bosonic particles at low temperatures occupy a collective quantum ground state," Gupta said. "That supports macroscopic quantum phenomena as remarkable as superfluidity and superconductivity."

"Condensate states are intriguing because they possess bizarre quantum properties and exist on an everyday scale, accessible without a microscope, and only low temperature is required," Kutana added. "Because they are at the lowest possible energy state and because of their quantum nature, condensates cannot lose energy and behave as a perfect frictionless fluid.

"Researchers have been looking to realize them in various solid and gas systems," he said. "Such systems are very rare, so having two-dimensional materials among them would greatly expand our window into the quantum world and create opportunities for use in new, amazing devices."

The best combinations were assemblies of heterostructure bilayers of antimony-tellurium-selenium with bismuth-tellurium-chlorine; hafnium-nitrogen-iodine with zirconium-nitrogen-chlorine; and lithium-aluminum-tellurium with bismuth-tellurium-iodine.

"Except for having similar lattice parameters within each pair, the chemistry compositions appear rather nonintuitive," Yakobson said. "We saw no way to anticipate the desired behavior without the painstaking quantitative analysis.

"One can never deny a chance to find serendipity -- as Robert Curl said, chemistry is all about getting lucky -- but sifting through hundreds of thousands of material combinations is unrealistic in any lab. Theoretically, however, it can be done."

The brain is our most energy-hungry and metabolically active organ. It is responsible for our thoughts, ideas, movement and ability to learn. Our brain is powered by 600 km of blood vessels that bring it nutrients and remove waste products. However, the brain is also very fragile. Thus, the blood vessels in the brain have evolved to form a tight protective barrier - the blood-brain barrier - that restrict the movement of molecules in and out of the brain. It is essential that the brain can regulate its environment. On the one hand, pathogens or toxins are effectively prevented from entering the brain, but on the other hand, required messengers or nutrients can pass through them unhindered.

Epigenetics turns on the nutrition program

Given their close relationship, it is important that the brain and its vessels talk extensively to one another. Recent work in the lab of Asifa Akhtar in Freiburg has shown that blood vessels can sense the metabolic state of neighboring neural cells.

The researchers found that the epigenetic regulator MOF is required for equipping neurons with the right metabolic enzymes needed for processing fatty acids. "Something has to tell neural cells that there are nutrients around and they should turn on the programs needed to process them," explains Bilal Sheikh, lead author of the study. "MOF goes to the DNA and switches on the genetic programs that allow cells to process fatty acids in the brain".

Fatty acids are found in food and are used for generating energy and assembling complex lipids required in cell membranes. When the activity of MOF is defective, as occurs in neural developmental disorders, the neurons cannot process fatty acids. This leads to their accumulation in the interstitial spaces between the brain cells. In their studies, Asifa Akhtar's team uncovered that this imbalance in fatty acids is sensed by the neural blood vessels, stimulating them to mount a stress response by loosening the blood-brain barrier. If the metabolic imbalance remains, the leaky blood-brain barrier can induce a diseased state.

Neural blood vessel breakdown

The study sets the foundation for a better understanding of how neural cells and blood vessels talk to each other in the brain and illustrates how changes in the metabolic milieu of one cell type in a complex organ can directly impact the functionality of surrounding cells and thereby affect overall organ function. "Our work shows that proper metabolism in the brain is critical for its health. A defective neural metabolic environment can induce vascular inflammation, dysfunction of the cells forming the blood-brain barrier, and increased permeability. What can follow is neural blood vessel breakdown," explains Asifa Akhtar. This is particularly important, as neural blood vessel breakdown is a characteristic feature of the onset of age-related diseases such as Alzheimer's disease and vascular dementia. Better characterization of the molecular changes that induce vascular dysfunction will help design better treatments for these debilitating pathologies.

A new study led by researchers from The Irish Longitudinal Study on Ageing (TILDA) at Trinity College Dublin challenges claims from some international scientific circles, that having high blood levels of folate (folic acid) increases the risk of poor cognition in older adults, especially in those with low levels of vitamin B12.

The study published today (Monday, 15th June 2020) in the British Journal of Nutrition, forms part of the largest representative study of its kind conducted among older persons.

Both vitamin B12 and folate are essential vitamins for the nervous system and healthy blood cells. Deficiency of folate in early pregnancy can lead to neural tube defects (NTDs) in new-born babies. This is the reason for mandatory fortification of the food supply with folic acid in the US and other countries (but not Ireland or Europe). While fortification is proven to reduce NTDs, several influential publications in the US suggest that very high folate levels in older persons, if coupled with low vitamin B12, leads to poorer brain function and a faster rate of cognitive decline. Largely because of such fears, no country in Europe has implemented mandatory folic acid fortification, although the NTD rates have not declined in two decades and may be rising in Ireland, according to recent data.

What has the new research unveiled?

Using blood samples from over 3,700 Irish older adults aged 50 and over, the study compared cognitive health in individuals grouped by their combinations of vitamin B12 and folate blood levels. It found no evidence that having high blood levels of folate affected the risk of cognitive decline in those with low levels of vitamin B12. Moreover, having higher folate seemed to be associated with better cognitive function in these older adults.

Key findings:

Cognitive performance was not worse in older people with low vitamin B12 combined with high folate (representing 1.5% of older adults in Ireland)

Those with normal vitamin B12 levels and high folate levels (7.6% of older adults) performed better cognitively than the others

The use of folic acid - containing supplements was uncommon, with higher rates among women than men but less than 4% overall taking supplements

Why do the findings matter?

Older adults at significant risk of deficiency

TILDA has previously reported high rates of deficiency: 1 in 8 older adults are deficient in vitamin B12, while 1 in 7 are deficient in folate. Vitamin B12 deficiency is associated with cognitive impairment and nerve damage. Older adults can have difficulty in absorbing vitamin B12 due to diminished digestive function or medications. Folate deficiency causes anaemia and is associated with heart disease, stroke, and possibly certain cancers.

New-born babies at significant risk

Folate is critical to the healthy development of the brain and spinal cord in the growing foetus, and deficiency can cause NTDs, such as spina bifida. Consequently, public health authorities world-wide recommend that women of childbearing age consume folic acid from fortified foods and/or supplements. Voluntary food fortification is permitted in Ireland but is not effective in this regard. Ireland has one the highest rates of NTDs in Europe but does not have mandatory fortification largely because of concerns detailed above.

Lead author Deirdre O'Connor, Registered Nutritionist and TILDA researcher said,

"Concerns surrounding associations between high intakes of folic acid and cognitive decline in older adults with low vitamin B12 have impeded mandatory folic acid fortification in Ireland. Our study shows that a small percentage of older people in the community have this potentially adverse combination, but they are not at increased risk of poorer cognition. In fact, older adults with normal vitamin B12 and high folate levels performed better in cognitive tests than their counterparts with normal folate. This implies that elevated folate may benefit cognitive health in older persons in Ireland."

Professor Anne Molloy, senior author of the study said:

"Ireland does not have mandatory food fortification with folic acid. We know that folic acid fortification is an effective population strategy if it is carefully established, controlled and monitored. We can learn from up to two decades of experience in North and South America and Australia. It reduces NTD prevalence and eliminates folate deficiency - a much bigger health problem. Our study on this important Irish cohort of almost 4,000 older individuals indicates that improving folate levels in the population would have positive health consequences for both young and old."

Professor Rose Anne Kenny, Principal Investigator of TILDA, said:

"This is the largest study of the interaction between vitamin B12 and folate and cognitive function world-wide. The high rates of vitamin B12 and folate deficiency in the older adult population are of concern and, given that this can be easily treated with fortification, this has significant policy implications for Government and health services. TILDA has consistently assisted policy makers by providing strong evidence-based data on which to make recommendations and this study provides such data to energize policy decisions on this important topic for all ages and reopen the public discourse regarding the proposition of mandatory fortification."

NEW YORK - June 15, 2020--Emily Sims, M.D. today shared new findings that a breakthrough drug significantly delays the onset of type 1 diabetes (T1D).

The data presented at the American Diabetes Association (ADA)'s 80th Scientific Sessions details the Phase 2 Teplizumab Prevention Study Clinical Trial findings that showed a two-week course of teplizumab delayed the onset of clinical T1D by three years as compared to those taking a placebo.

These results add another year to the average time reported to reach insulin dependence in teplizumab treated subjects compared to placebo treated controls. The primary results of this trial, led by Kevan C. Herold, M.D. and colleagues, were presented at the 2019 ADA conference and published in the New England Journal of Medicine demonstrating a two year delay in T1D onset for those using the drug.

In ongoing analysis of trial data, Sims and colleagues found that subjects treated with teplizumab had higher rates of insulin secretion and C-peptide levels than those taking a placebo, indicating a change in the normal progression of T1D. Study participants taking a placebo showed no change since last year's reporting in the median time to clinical diagnosis of T1D during this follow-up period and maintained a decline in insulin and C-peptide production, which is consistent with beta-cell destruction caused by the disease. The trial involved individuals at high risk of developing T1D, based on the presence of two or more autoantibodies, which are detected through a screening blood test.

"We are excited and hopeful about what the newly released trial results mean for the type 1 diabetes community. This is the first disease-modifying drug with data showing a long-term delay to insulin dependence," said Aaron J. Kowalski, Ph.D., President, and CEO of JDRF. "This is a major milestone in the global effort to comprehensively understand T1D and support the advancement towards prevention and cures for this disease."

The study was conducted by TrialNet, a clinical trial network focused on T1D prevention, and funded the National Institute of Diabetes and Digestive and Kidney Diseases, primarily through the Special Diabetes Program. Provention Bio provided study drugs and additional site monitoring.

In 2019 the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation and the European Medicines Agency (EMA) granted PRIority MEdicines (PRIME) designation to teplizumab, for the prevention or delay of T1D in individuals at-risk of developing the disease. CD3 is a blood marker that helps to activate the immune cells--called T cells--which are thought to be responsible for the disease. Type 1 diabetes, a life-long autoimmune disease, affects nearly 1.6 million Americans and 18 million people globally.

JDRF, the leading global organization funding T1D research, has supported the research of teplizumab for many years, including studies that have informed the mechanistic analysis ongoing with teplizumab trial samples. In 2017, the JDRF T1D Fund made an equity investment in Provention Bio, which is developing teplizumab for the prevention or delay of T1D.

Philadelphia, June 15, 2020 - Pulmonary hypertension (PH) is a serious problem associated with a wide variety of lung diseases, which can lead to right ventricular dysfunction and death. Currently, there is no drug therapy to cure PH and the condition may necessitate lung transplantation. The management and prognosis of PH heavily relies on whether the pathology is localized in pulmonary arteries or veins. In particular, at early stages, it is challenging to distinguish pulmonary arterial hypertension (PAH) from the rare subtype of pulmonary veno-occlusive disease (PVOD) because clinical presentations of PAH and PVOD can be similar. A new study in the American Journal of Pathology, published by Elsevier, reports gene expression analysis of lung explant tissue can accurately differentiate PAH from PVOD.

"The pathogenesis of PVOD and PAH is poorly understood and the clinical differentiation between both diseases remains challenging because of similar clinical presentation," explained lead investigator Lavinia Neubert, MD, Institute of Pathology, Hannover Medical School, and Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany. "Our study is the first to put forward a molecular model with the ability to differentiate between the PH subtypes PAH and PVOD. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases."

Patients with PH often experience narrowing, blockage, or destruction of lung blood vessels, a process referred to as vascular remodeling. In this study, researchers analyzed lung samples from patients with PAH, PVOD, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and healthy controls. As anticipated, patients with PAH had pathological changes predominantly in pulmonary arteries and arterioles, whereas samples from patients with PVOD were characterized by alterations of the post-capillary pulmonary vasculature (veins).

Using deep-learning algorithms to analyze the molecular findings, the researchers were able to successfully differentiate disease entities with 100 percent sensitivity and 92 percent specificity, based on six target genes. Interestingly, samples from PVOD patients shared more regulatory characteristics with samples from patients with IPF than with PAH.

"We are confident that the classification accuracy of our molecular approach is close to the gold standard, of histopathological diagnosis," said Dr. Neubert. "Since lung biopsies remain as high-risk interventions for PH patients and non-invasive approaches currently do not allow for a definite diagnostic accuracy, these findings may facilitate diagnosis of PVOD by molecular analysis, provided that our findings are reproducible in blood or urine samples."

Additional analyses using quantitative proteomics and multiplex immunohistochemistry identified a variety of dysregulated genes. Some of the gene changes were common to all patients with severe pulmonary vascular remodeling regardless of the afflicted lung compartments, while others were more specific.

The investigators believe genetic signaling changes in various forms of severe PH might serve as novel pharmaceutical targets with the potential to address severe vascular remodeling. They recommend further studies to investigate the diagnostic value of the identified markers in the clinical setting.

PH is a condition in which blood pressure from the heart to the lungs is higher than normal. Symptoms of PH include breathing impairment (dyspnea), chest pain, light-headedness, and weakness. Impaired gas exchange, right heart overload, and death by right heart failure result in high mortality and morbidity for those with PH. Medications, surgical interventions, and exercise may help control symptoms.

Philadelphia, June 15, 2020 - Nearly one out of every 10 African Americans has a genetic variant that puts them inherently at an increased risk for ventricular arrhythmias and sudden cardiac death. Writing in the journal Heart Rhythm, the official publication of the Heart Rhythm Society and the Cardiac Electrophysiology Society, published by Elsevier, investigators observe that along with socioeconomic and cultural factors, this genetic risk factor may contribute to the racial health disparities that have been documented in victims of the COVID-19 pandemic. They also note that the unwanted effects of therapies such as hydroxychloroquine may put African Americans with the variant at increased risk of drug-induced ventricular arrhythmias. Therefore, they urge particular caution.

"Without a definitive explanation for the increased COVID 19-related mortality rates observed among individuals of African descent, we need to consider all potential contributors, including the possibility of genetic predispositions," explained first author John R. Giudicessi, MD, PhD, Department of Cardiovascular Medicine (Clinician-Investigator Training Program and Division of Heart Rhythm Services), Mayo Clinic, Rochester, MN, USA. "The African-specific p.Ser1103Tyr-SCN5A common ion channel variant is a reasonable place to start, as its proarrhythmic potential is awakened by risk factors observed in hospitalized COVID-19 patients - namely, hypoxemia, electrolyte abnormalities, and QT-prolonging drug use."

The investigators note that the proarrhythmic potential associated with p.Ser1103Tyr-SCN5A can be enhanced by drugs that can cause irregular heartbeat (QTc-prolonging medications), including some antiarrhythmic drugs but also, importantly, some antibiotics and antifungal medications.

Direct and/or indirect myocardial injury or stress has emerged as a prominent, prognostic feature in COVID-19. Acute myocardial injury in patients with COVID-19 may be caused by a direct SARS-CoV-2 myocardial infection; the exaggerated immune response known as the cytokine storm; or hypoxia, dangerously low levels of oxygen and high levels of carbon dioxide in the blood. African American infants with the p.Ser1103Tyr-SCN5A variant are over-represented in sudden infant death syndrome, and mechanisms underlying hypoxia may be responsible. The profound hypoxia observed in many COVID-19 patients, raises reasonable concern that p.Ser1103Tyr-SCN5A could produce a similar, African-American susceptibility to ventricular arrhythmia and sudden cardiac death from the SARS-CoV-2 infection.

Taken together, the data suggest that one in 13 African Americans may be at substantially increased risk for potentially lethal ventricular arrhythmia during the COVID-19 pandemic. Whether population-specific genetic risk factors are contributing to the spike in sudden deaths and racial health disparities observed in COVID-19 epicenters remains to be proven, and given the lack of banked DNA in these epicenters, the investigators question whether the speculation may even be testable.

"The genetic variant p.Ser1103Tyr-SCN5A, is a potentially proarrhythmic, sudden cardiac death marker for African Americans, and seeking its presence and respecting it is long overdue," asserted senior author and genetic cardiologist Michael J. Ackerman, MD, PhD, Department of Cardiovascular Medicine (Division of Heart Rhythm Services), Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Windland Smith Rice Cardiovascular Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.

As recent studies have shown that hydroxychloroquine is not effective in the treatment of sick, hospitalized COVID-19 patients, the authors advocate against its use in that setting. Nevertheless, if COVID-19-directed, QTc-prolonging agents such as hydroxychloroquine are to be used, the investigators recommend careful cardiac monitoring, preferably in a way that spares personal protective equipment.

The authors call for research into the link between p.Ser1103Tyr-SCN5A and rates of sudden death and COVID-19-related mortality, suggesting the use of existing DNA biobanks such as the United Kingdom Biobank, a study that investigates the contribution of genetic and environmental factors to the development of disease, and the Jackson Heart Study, a large, community-based investigation into the causes of cardiovascular disease in African Americans. Point-of-care genetic testing for p.Ser1103Tyr-SCN5A should be investigated.

And finally, the authors recommend studies of medications that may better protect at-risk individuals, especially African Americans, in the context of the ongoing COVID-19 pandemic.

Throughout history, portraits featuring the human profile have evolved to reflect changing cultural norms. A new study led by Helena Miton, a Santa Fe Institute Omidyar Fellow, and co-authored by Dan Sperber of Central European University and Miko?aj Hernik, of UiT the Artic University of Norway, shows that human cognition plays a critical role in the evolution of human portraiture.

"These cognitive factors cause greater spontaneous attention to what is in front of -- rather than behind -- a subject, Miton says. "Scenes with more space in front of a directed object are both produced more often and judged as more aesthetically pleasant. This leads to the prediction that, in profile-oriented human portraits, compositions with more space in front of depicted subjects (a 'forward bias') should be over-represented."

To test their prediction, the research team looked at 1831 paintings by 582 unique European painters from the 15th to the 20th century. They not only found evidence that this forward bias -- where painters put more open space in front of their sitters than behind them -- was widespread, they also found evidence that the bias became stronger when cultural norms of spatial composition favoring centering became less stringent.

In the accompanying image, the portrait on the left (Adrian Brouwer, 1630) is an example of a composition with the sitter centered. On the right, a portrait by Pierre Auguste Renoir (1905) shows the forward bias, with more free space in front of the sitter than behind her. The study showed this type of spatial composition increased over time.

"Culture and cognition are two interacting domains," Miton explains. "With most cultural phenomena, you're going to have some kind of influence from cognition. Our idea is to work out how we identify these factors and how we work with that type of causality."

The research team identified cultural norms that favored centering portraits, especially in the earlier periods. These preferences clearly loosened over time, resulting in more diverse portrait composition.

The widespread presence of a forward bias was robust. Previous studies found some evidence of a forward bias in the production of a handful of painters, but these results suggest that this bias in spatial composition was widespread--particularly remarkable since it goes against a cultural norm that favors centering sitters.

According to Miton, this research approach can be extended to quantify in a more general way (and with a more general painting data set) how much artistic norms loosen and how much variation increases over time. Beyond the art world, the approach can also look at the role cognition plays in other cultural phenomena, from writing systems to medical practices.

When parents are under stress, household rules about screen time often get abandoned, new University of Guelph research finds.

A first of its kind in Canada, the study found parents of young children reporting high levels of life or parenting stress were less likely to monitor and limit their kids' screen use and more likely to use their own devices in front of their children.

Published in the Journal of Children and Media, the research comes at a time when many Canadian families are experiencing more stress than usual because of upheaval caused by COVID-19 pandemic.

The study surveyed 64 parents from 39 families of children 18 months to five years of age taking part in the Guelph Family Health Study. The parents were asked about their stress as well as whether they monitored and limited their children's screen use, and whether they used screens in front of their children.

Lead author Lisa Tang, a PhD student in the Department of Family Relations and Applied Nutrition, said previous U of G research has shown that parenting practices influence how much time children spend on screens.

"With this study, we wanted to understand the implications of parental stress on media parenting practices. We found parenting stress does indeed affect how parents manage screen time but influenced mothers and fathers differently," she said.

For example, when mothers reported a high level of general life stress, they were more likely to report they used devices in front of their children and less likely to monitor or limit their kids' screen use.

That may be because mothers anticipate conflicts with their children if they attempt to impose limits so decide it is either too hard or not worth the fight during times of stress, said Tang.

But fathers, who reported high general life stress, were more likely to limit their kids' screen use.

This could mean that stressed dads are more likely to enforce rules, said Tang. Or it could suggest that when children already have screen limits, fathers are more likely to report high general life stress because children who can't use devices might increase their demands on their parents, she added.

Mothers who reported they found parenting itself stressful were more likely to say they used devices in front of their children and were less likely to monitor or limit their children's screen use. Fathers experiencing similar stress reported no change.

"Parents do seem to say they use their screens more when they say they are under stress, perhaps as an escape," said Tang. "This is an important finding because research has shown that when parents use screens in front of their preschool-aged children, it is associated with those children having greater levels of screen time."

Prof. Jess Haines said this research is not about making parents feel guilty about screen use.

"There's nothing wrong with using screens now and again. We are all doing the best we can, especially now, and parents of children under five need to allow themselves a break. This is really about excess screen time. It's about making parents conscious of their practices and balancing active play with screen time, and modelling that behaviour," she said.

Study co-author Valerie Hruska, a doctoral candidate in U of G's Department of Human Health and Nutritional Sciences, said the study's findings are important given the potential health consequences for young children.

"Previous research has shown that high screen use is linked to health issues in children, including lower activity levels, obesity and even language delays in younger children because they engage in less back-and-forth conversation," she said.

One surprising finding involved a slightly different kind of stress called household chaos, which assesses commotion and noise in a home. The researchers expected high household chaos would be linked to high screen use but found the opposite: chaos was linked with more screen-time monitoring by both mothers and fathers.

The researchers theorize that when children put away their devices and get involved in other activities in the house, it leads to more chaos compared to quieter screen time.

"So perhaps a little chaos in the home isn't a bad thing if it means kids take a break from screens," said Hruska, adding the next goal is to help find ways for parents to limit screen times without increasing household chaos.

The COVID-19 pandemic threatens the survival of organizations nationwide that provide critical outdoor environmental and science education to K-12 students, with an alarming 63% of such groups uncertain about their ability to ever reopen their doors, according to a study released this week by the Lawrence Hall of Science at the University of California, Berkeley.

By the end of May, the study’s authors estimated, some 4 million youth had missed the opportunity to engage in these programs. This number could rise to 11 million by December 2020 if these organizations are unable to reopen. The impact in California is even higher than nationally.

The loss of outdoor education is a devastating situation with potentially catastrophic impact, said Rena Dorph, director of the Lawrence Hall of Science (LHS), a science center and leader in developing K-12 science curricula. Getting youth outside, connecting with the world around them and learning about nature have many documented academic, health and social benefits, and most of outdoor education is conducted by residential outdoor science schools, nature centers, parks and zoos, not in traditional classrooms.

“This is happening at a time when public health leaders are promoting the value of outdoor learning as safe, engaging, effective and essential,” Dorph said. “The outdoors is a resource for learning, engagement and health, and it should be available to all.”

The loss will be felt disproportionately by historically marginalized groups, particularly students of color and students from low-income families, that are most likely to lose environmental education within their local school districts.

“Years of efforts to increase access to the benefits of learning and thriving in the outdoors could be undone, even if environmental and outdoor science education programs manage to reopen,” said Craig Strang, LHS associate director. “Resource-strapped organizations tell us they will need to forego initiatives to promote equitable and inclusive workplaces, and even perhaps to halt subsidized programming, scholarships, fee waivers, transportation grants and community partnerships in favor of paying customers, which could lead, once again, to the exclusion of low-income students and students of color. There are things we can do now to prevent that.”

Outdoor instruction key part of education

The national survey of environmental and outdoor science education organizations was funded by the National Science Foundation and conducted in partnership with the California Environmental Literacy Initiative, the North American Association for Environmental Education and Ten Strands — organizations that focus on bringing environmental education to all K-12 students.

The study authors received nearly 1,000 responses from 49 states and the District of Columbia, with the majority of respondents coming from nonprofit organizations (62%) and/or public/governmental organizations (35%). Such programs serve a wide range of learners in areas including science, environmental literacy, conservation, youth development, community building, social emotional learning, career and job skill development, and environmental justice.

In the policy brief, the authors estimated that by Dec. 31, 2020:

Some 11 million kids who would have been served by 1,000 organizations will have missed environmental and outdoor science learning opportunities. About 60% of them are from communities of color or low-income communities.
The 1,000 organizations surveyed will have lost about $600 million in revenue.
About 30,000 employees will have been laid off or furloughed from these organizations.
It is highly likely that 37% of these organizations in California and 30% nationally will not reopen.
Over one-third of the outdoor education field — up to 65% — will likely have disappeared, eroding a key component of the nation’s education infrastructure.

The policy brief suggests ways to mitigate the potential losses through funding priorities and intentional coordination of efforts with local and state education agencies. The ideas include redeploying outdoor educators to work in K-12 school settings to increase the capacity of the schools to educate students, while following social distancing guidelines. Such partnership arrangements could expand the space limits of schools and help them achieve learning goals, while allowing parents to return to work and providing educational, health and social benefits to students.

The authors also suggest that financial aid be preferentially allocated to efforts in marginalized communities to prevent the loss of gains made toward broadening participation in the field and achieving greater equity, inclusion, cultural relevance and social justice.

“Outdoor science and environmental learning organizations are an essential part of the education system,” Strang said. “They offer solutions to challenges the schools are currently facing as a result of the COVID-19 pandemic and need to be considered as key partners in developing funding priorities, health policies and guidelines for opening schools and delivering educational programming. It is our hope that this policy brief will help inform these decisions, while underscoring the importance outdoor learning plays in meeting educational and societal goals.”