Culture

From 2012 to 2016 the drug industry donated over £57 million to UK patient organisations, with priority given to a small number of organisations supporting commercially high profile conditions like cancer, reveals an analysis published by The BMJ today.

The researchers call for greater transparency to ensure that industry funding is not unduly influenced by commercial objectives.

Patient organisations are increasingly involved in policy and research, including decisions on public funding of medicines and treatments. Yet existing evidence suggests that many patient organisations have widespread, and often not entirely transparent, financial relationships with drug companies.

Since 2012, corporate members of the European and UK pharmaceutical industry associations have had to disclose their payments to patient organisations, creating new opportunities for analysis.

Using payment disclosure reports published on company websites, combined with patient organisation websites and charity regulator records, researchers from the University of Bath (UK) and Lund University (Sweden) set out to assess the scale of industry funding, its main providers and recipients, and the nature of funded activities.

They found that during 2012 to 2016, industry disclosed 4,572 payments worth £57.3m to 508 UK patient organisations.

While this represented only a sixth of its funding for healthcare professionals and organisations (£340.3m) in 2015 alone, patient organisations seemed increasingly important for drug companies, note the authors.

For the 21 companies that disclosed consistently over the five years, the number of payments increased slightly, from 738 to 772, but their value was 1.4 times higher (£7.6m vs £10.8m).

A few companies dominated the funding landscape, with the top ten providing more than two-thirds (69.2%) of all funding. As with payments to healthcare professionals, the largest donors were "big pharma" companies.

The top funding priority was supporting patient organisations' public involvement, including "advocacy, campaigning, and disease awareness", "communication" and "policy engagement", which together attracted £17.9m (31.2%). This was followed by support for engagement in research activities, which attracted £14m (24.6%) of funding.

In contrast, "support for patients" attracted £3.4m (5.9%) and "organisational maintenance and development" attracted just £1.6m (2.8%) of funding.

When funding was assessed by 30 condition areas, the authors found that priority was given to commercially high profile conditions, such as cancer and diabetes. For example, neoplasms (any unusual tissue growth - benign or malignant - encompassing cancerous and pre-cancerous changes) attracted £20.9m (36.4%) of all funding.

The hierarchy of funding within each condition area also reflected the industry's commercial priorities. For example, within neoplasms, multiple myeloma (blood cancer) attracted £7.5m (35.9%), followed by breast cancer (19.6%).

Diabetes received £3.7m (57.6%), the most of any endocrine, nutritional, and metabolic disease, while the bulk of funding for infectious and parasitic diseases went to HIV (37.4%) and viral hepatitis (23.6%).

Importantly, the biggest donors in these condition areas have recently launched several high priced drugs, say the authors.

The emerging picture of industry funding shows that companies might seek to use some patient organisations as "third parties" in reaching other audiences, they write.

Responding to risks posed by the concentration of industry funding requires structural solutions, such as a shared corporate funding pool detached from current commercial objectives or treatment areas or a programme of public grants, say the authors.

This "would make for a more level playing field for patient organisations that cover currently underfunded condition areas or have weak industry links," they conclude.

More immediately, low-cost solutions to increase the transparency of funding might involve introducing a single standard of reporting for all companies and creating a searchable publicly available database of payments to patient organisations, they add. These solutions could be modeled on the Disclosure UK initiative, which has covered industry payments to healthcare professionals and organisations since 2015.

New research findings published today in The Lancet Global Health show that the number of people dying with palliative care needs is set to almost double over the next four decades. By 2060, an estimated 48 million people each year (47% of all deaths globally) will die with serious health-related suffering, an 87% increase compared to 2016. 83% of these people will be in low and middle-income countries.

Serious life-threatening and life-limiting illnesses place an enormous burden on society and health systems. For the first time, researchers from King's College London have produced worldwide projections of the future need for palliative care based on serious health-related suffering, in order to help inform policies that alleviate suffering and prevent health systems weakening.

They modelled future estimates of suffering by World Bank income classification, WHO region, age, gender, and condition causing death.

The main findings included:

Serious health-related suffering will increase in all world regions, with the largest proportional rise in low-income countries (155% increase between 2016 and 2060).

In high-income countries 3 million more people will die with serious health-related suffering in 2060, an increase of 57% compared to 2016.

Globally, serious health-related suffering will increase most rapidly among older people (183% increase in those aged 70+ 2016-2060).

The increase in serious health-related suffering will be driven by rises in cancer deaths (16 million people dying each year with serious health-related suffering by 2060, 109% increase 2016-2060). The condition with the highest proportional increase will be dementia (6 million people dying each year with serious health-related suffering by 2060, 264% increase 2016-2060).

Lead author, Dr Katherine Sleeman, NIHR Clinician Scientist and Honorary Consultant in palliative medicine at the Cicely Saunders Institute at King's College London said: "Immediate global action to integrate palliative care into health systems is an ethical and economic imperative.

"Palliative care can relieve suffering for patients and families, and save money for health systems and society. To direct effective health care planning and policy development, it is essential to understand both the current and future level of palliative care need.

"Our findings call for global policies to strengthen health care systems through availability of essential drugs to relieve symptoms, staff training and public education, with a focus on the populations that will experience the fastest rise of suffering and need. We have provided the first quantification of the scale of suffering we will witness if nothing is done."

Co-author Professor Richard Harding Herbert Dunhill Professor of Palliative Care & Rehabilitation at King's College London said: "Palliative care and the relief of suffering have been described as some of the most neglected dimensions of global health today. It is estimated that just 14% of the people who need palliative care globally receive it, most of whom are in high income countries.

"The increase in palliative care need that we have identified will place an enormous burden on already weak health systems, particularly in low and middle-income countries. There is growing evidence that investment in palliative care services can support patients and families, as well as take pressure off hospital services by keeping people pain-free at home for as long as they wish. Society has a duty to provide care for all to the last moments of life."

Getting more exercise than normal - or being more sedentary than usual - for one day may be enough to affect sleep later that night, according to a new study led by Penn State.

In a one-week micro-longitudinal study, the researchers found that when teenagers got more physical activity than they usually did, they got to sleep earlier, slept longer and slept better that night.

Specifically, the team found that for every extra hour of moderate-to-vigorous physical activity, the teens fell asleep 18 minutes earlier, slept 10 minutes longer and had about one percent greater sleep maintenance efficiency that night.

"Adolescence is a critical period to obtain adequate sleep, as sleep can affect cognitive and classroom performance, stress, and eating behaviors," said Lindsay Master, data scientist at Penn State. "Our research suggests that encouraging adolescents to spend more time exercising during the day may help their sleep health later that night."

In contrast, the researchers also found that being sedentary more during the day was associated with worse sleep health. When participants were sedentary for more minutes during the day, they fell asleep and woke up later but slept for a shorter amount of time overall.

Orfeu Buxton, professor of biobehavioral health at Penn State, said the findings -- published today (May 22) in Scientific Reports -- help illuminate the complex relationship between physical activity and sleep.

"You can think of these relationships between physical activity and sleep almost like a teeter totter," Buxton said. "When you're getting more steps, essentially, your sleep begins earlier, expands in duration, and is more efficient. Whereas if you're spending more time sedentary, it's like sitting on your sleep health: sleep length and quality goes down."

While previous research suggests that adolescents need eight to ten hours of sleep a night, recent estimates suggest that as many as 73 percent of adolescents are getting less than eight.

Previous research has also found that people who are generally more physically active tend to sleep longer and have better sleep quality. But the researchers said less has been known about whether day-to-day changes in physical activity and sedentary behavior affected sleep length and quality.

For this study, the researchers used data from 417 participants in the Fragile Families and Child Wellbeing study, a national cohort from 20 United States cities. When the participants were 15 years old, they wore accelerometers on their wrists and hips to measure sleep and physical activity for one week.

"One of the strengths of this study was using the devices to get precise measurements about sleep and activity instead of asking participants about their own behavior, which can sometimes be skewed," Master said. "The hip device measured activity during the day, and the wrist device measured what time the participants fell asleep and woke up, and also how efficiently they slept, which means how often they were sleeping versus tossing and turning."

In addition to finding links between how physical activity affects sleep later that night, the researchers also found connections between sleep and activity the following day. They found that when participants slept longer and woke up later, they engaged in less moderate-to-vigorous physical activity and sedentary behavior the next day.

"This finding might be related to a lack of time and opportunity the following day," Master said. "We can't know for sure, but it's possible that if you're sleeping later into the day, you won't have as much time to spend exercising or even being sedentary."

Buxton said improving health is something that can, and should, take place over time.

"Becoming our best selves means being more like our best selves more often," Buxton said. "We were able to show that the beneficial effects of exercise and sleep go together, and that health risk behaviors like sedentary time affect sleep that same night. So if we can encourage people to engage in more physical activity and better sleep health behaviors on a more regular basis, it could improve their health over time."

In the future, the researchers will continue to follow up with the participants to see how health and health risk behaviors continue to interact, and how sleep health influences thriving in early adulthood.

DALLAS, May 22, 2019 -- Veterans who have post-traumatic stress disorder (PTSD) and/or depression were more likely to use cardiac rehabilitation services after an episode of ischemic heart disease than those who didn't have PTSD or depression, according to new research in Journal of the American Heart Association, the Open Access Journal of the American Heart Association/American Stroke Association.

"Prior research has shown that patients with mental health conditions may have a greater risk for cardiovascular diseases, mainly because they are more likely to engage in unhealthy activities such as smoking, lack of exercise, poor diet and not taking medications as prescribed," said Nirupama Krishnamurthi, M.B.B.S., M.P.H, the study's lead author and a postdoctoral researcher in the Department of Medicine at the University of California San Francisco. "While cardiac rehab aims to decrease a patient's risk for cardiovascular events, previous studies have suggested mental health challenges such as depression may create barriers that hinder a patients' benefit from this service."

Using electronic health records from the national Veterans Administration Corporate Data Warehouse, researchers identified 86,537 patients (average age 67, mostly white non-Hispanic men) who had been hospitalized for heart attack or coronary revascularization at any of the Veterans Health Administration's 152 hospitals between 2010 and 2014.

Researchers found:

Of the 86,537 patients hospitalized for ischemic heart disease, 24% had PTSD and/or depression.

Those with PTSD and/or depression had higher cardiac rehab participation rates than those without PTSD or depression (11% vs. 8%).

In comparison to patients without PTSD or depression, the adjusted odds of participation were 24% greater in patients with depression alone, 38% greater in patients with PTSD alone, and 57% greater in patients with both PTSD and depression.

Previous studies found that patients with mental health disorders were less likely to use rehabilitation, but these studies had smaller sample sizes and included only patients who were referred by their doctor, rather than all eligible patients. In the current study, researchers were unable to determine the reason patients with mental health conditions were more likely to use cardiac rehabilitation services because of the limited information available in electronic health records.

"Our study shows that mental health disorders may not be barriers to preventive cardiovascular efforts," said Krishnamurthi, who conducts her research at the San Francisco Veterans Affairs Medical Center. "In fact, we think that having a mental health condition may actually increase patient engagement in care."

Scientists of the National Center for Cardiovascular Research (CNIC) led by Rui Benedito have developed a new genetic tool (iSuRe-Cre) that provides certainty in Cre-inducible genetic modifications, a key technique for understanding gene function.

Most analysis of gene function in biomedical research relies on the use of Cre-lox technology. Since its introduction in 1994, this technology has revolutionized biomedical science because it allows scientists to eliminate or activate the function of any gene in any cell type in the mouse. Using this technology, it has been possible to investigate the precise role of almost any mouse gene, in any cell type, and at a defined time-point, all of which are crucial requirements for understanding the function of genes during organ development, physiology, and disease.

Cre-Lox technology allows the regulation of gene expression at any time or in any cell type thanks to the ability of the Cre recombinase protein to recognize and recombine lox sites introduced at specific locations in the mouse genome, leading to the deletion of the genes being studied.

Despite the major impact of Cre-loxP technology on biomedical research, numerous studies have demonstrated the need for caution in its use. The main problem is that often the Cre activity level is insufficient to fully recombine and eliminate expression of the target gene, generating uncertainty about whether the desired genetic modification has been achieved.

Because the Cre-loxP recombination event is invisible, genetic and fluorescent reporters have been developed to track Cre activity, so that cells reaching a certain threshold of Cre activity are labeled. These reporters have become established as essential genetic tools for monitoring any conditional genetic study. However, as study author Macarena Fernández-Chacón points out, many studies have shown that Cre-induced reporter expression can occur even though other genes with loxP sites are not completely eliminated.

To overcome this technical hurdle, the CNIC team have developed an innovative method based on a new allele called iSuRe-Cre. iSuRe-Cre is compatible with all existing Cre/CreERT2/lox alleles and guarantees high Cre activity in the cells that express the fluorescent reporter. This ultimately increases the efficiency and reliability of the analysis of Cre-dependent gene function. Moreover, the use of the new iSuRe-Cre mice permits the induction of multiple genetic deletions in the same cell. This important property allows the study of functional genetic interactions or epistasis, or in other words, how the function of one or more genes depends on the function of another.

Macarena Fernández-Chacón says that "the use of this new genetic tool will significantly change research projects that depend on the Cre-lox system, because now we can see and be confident about the location of cells that have one or more genes eliminated." Lead investigator Rui Benedito adds that the new genetic tool will be of great interest in biomedical research "because it significantly increases the ease, efficiency, and reliability of genetic modification in the mouse, the most widely used animal model in research." The new study is published in Nature Communications.

Researchers from Gero, Skolkovo Institute of Science and Technology (Skoltech), Moscow Institute of Physics and Technology (MIPT), and University of Arkansas for Medical Sciences (UAMS) collaborated to derive a transcriptomic signature of aging, which they confirmed using large transcriptomic databases. They discovered that aging in nematodes is partially programmed and can be therapeutically reversed by a number of FDA-approved drugs. The study is published in Scientific Reports.

C.elegans, a nonparasitic roundworm, is one of the most intensively studied animals on Earth. Its genome was the first to be sequenced among multicellular organisms; each and every one of its almost thousand cells has been characterized by biologists (1). These nematodes normally have a short lifespan of 15-25 days, which makes them a convenient model organism for aging studies. However, their lifespan can be extended almost ten-fold by introducing a mutation to a single gene (2). Details remained unanswered, as to how such a dramatic intervention affects gene expression and aging to achieve this extension, and whether it can be mimicked therapeutically, ideally with the drugs already approved for human use.

To answer this question, an international team of researchers led by Peter Fedichev, a founder of the longevity biotech startup Gero, required gene-activity data from nematodes with a wide variety of lifespans, at many ages across their lifespans. The UAMS researchers created the necessary strains (mutant worms in a constant, normal background) as well as normal, wild-type worms after suppression of selected target genes, and assessed their expression profiles at a range of adult ages. The Gero/Skoltech/MIPT scientists then leveraged machine learning techniques to analyze these experimental results and to compare them with earlier data available from public resources. The cost of the resulting dataset, named "MetaWorm", is approaching $10 million and is a perfect example of scientific "data recycling". Through analysis of the unique "MetaWorm" dataset, they confirmed and extended the pattern of transcriptomic shifts that accompany nematode aging.

"Our main concern was that aging in an extremely long-living worm might be totally different from that of normal, wild-type nematodes. In that case, the radical extension of lifespan would require complex interventions, and studies of animals with drastically slowed aging would not help us in our search for a truly effective anti-aging therapy", explains Peter Fedichev, the principal investigator of the Gero/Skoltech/MIPT group.

It turned out that on the molecular level, the process of aging in nematodes always unfolds in the same way, and all the observed differences in lifespan appear to reflect changes in the rate of aging. The researchers proposed that similar effects should be achievable without genetic interventions. To test the hypothesis, the researchers employed the Connectivity Map (CMAP) created by scientists at the Broad Institute of MIT and Harvard. CMAP contains information about the effect of almost all available FDA-approved drugs on gene activity in human cells. The researchers looked for drugs that alter human gene expression in a way opposing the age-related changes observed for corresponding genes in nematodes.

From the 1309 drugs in the CMAP database, the researchers chose 10 candidates that appear to act on genes in the desired direction. Six of these drugs had been previously documented anti-aging potential, while 4 of the shortlisted drugs had never been studied before in that context. The experiment demonstrated that all these drugs slow down aging in nematodes, albeit to different degrees. The most efficient compound extended the nematode lifespan by 30%.

"This study resulted in several practical implications for aging research and the growing longevity industry. Firstly, we demonstrated that aging in nematodes is partially programmed and can be modified therapeutically. This might well hold true for other multicellular organisms, humans included. Secondly, we proposed a new method of searching life-extending compounds. The usual procedure involves laborious screening of large libraries of potential drugs. Unfortunately, even successful hits sometimes get missed by chance or due to non-optimal dosage. Our method allows for a targeted search of the compounds with the required activity, including FDA-approved drugs. The latter compounds have the advantage that they have already passed all the necessary clinical trials and can be used off-label as anti-aging drugs," commented Andrei Tarkhov, Gero research scientist and a PhD candidate at Skolkovo Institute of Science and Technology.

Robert Shmookler Reis, leader of the UAMS team, emphasized how extraordinary these results were. "Previous studies of pharmacologically active compounds (3) had found less than 1 out of 20 that were able to extend C. elegans lifespan, in striking contrast to our observation of life extension by 4 out of 4 drugs for which there were no previous aging data, selected only for transcriptomic signatures opposing those observed for aging of nematodes. This is remarkably compelling evidence that the expression profile of aging must be conserved from nematodes to humans, and is likely to be fundamental to all animals."

During the height of the Civil War, the Confederate Surgeon General commissioned a guide to traditional plant remedies of the South, as battlefield physicians faced high rates of infections among the wounded and shortages of conventional medicines. A new study of three of the plants from this guide -- the white oak, the tulip poplar and the devil's walking stick -- finds that they have antiseptic properties.

Scientific Reports is publishing the results of the study led by scientists at Emory University. The results show that extracts from the plants have antimicrobial activity against one or more of a trio of dangerous species of multi-drug-resistant bacteria associated with wound infections: Acinetobacter baumannii, Staphylococcus aureus and Klebsiella pneumoniae.

"Our findings suggest that the use of these topical therapies may have saved some limbs, and maybe even lives, during the Civil War," says Cassandra Quave, senior author of the paper and assistant professor at Emory's Center for the Study of Human Health and the School of Medicine's Department of Dermatology.

Quave is an ethnobotanist, studying how people use plants in traditional healing practices, to uncover promising candidates for new drugs. "Ethnobotany is essentially the science of survival -- how people get by when limited to what's available in their immediate environment," she says. "The Civil War guide to plant remedies is a great example of that."

"Our research might one day benefit modern wound care, if we can identify which compounds are responsible for the antimicrobial activity," adds Micah Dettweiler, the first author of the paper.

If the active ingredients are identified, "it is my hope that we can then [further] test these molecules in our world-renowned models of bacterial infection," says co-author Daniel Zurawski, chief of pathogenesis and virulence for the Wound Infections Department at the Walter Reed Army Institute of Research.

"I've always been a Civil War buff," Zurawski adds. "I am also a firm believer in learning everything we can garner from the past so we can benefit now from the knowledge and wisdom of our ancestors."

Additional co-authors on the paper include Ryan Reddinger, from the Walter Reed Army Institute of Research; James Lyles, from the Quave lab; and Kate Nelson, from Emory School of Medicine's Department of Dermatology.

Dettweiler was still an Emory undergraduate when he heard about the Civil War plant guide and decided to research it for his honors thesis. He has since graduated with a degree in biology and now works as a research specialist in the Quave lab.

"I was surprised to learn that far more Civil War soldiers died from disease than in battle," he says. "I was also surprised at how common amputation was as a medical treatment for an infected wound."

About one in 13 surviving Civil War soldiers went home with one or more missing limbs, according to the American Battlefield Trust.

At the time of the Civil War, from 1861 to 1865, germ theory was in its developmental stages and only gradually beginning to gain acceptance. Formal medical training for physicians was also in its infancy. An antiseptic was simply defined as a tonic used to prevent "mortification of the flesh." Iodine and bromine were sometimes used to treat infections, according to the National Museum of Civil War Medicine, although the reason for their effectiveness was unknown.

Other conventional medicines available at the time included quinine, for treating malaria, and morphine and chloroform, to block pain.

Military field hospitals within the Confederacy, however, did not have reliable access to these medicines due to a blockade -- the Union Navy closely monitored the major ports of the South to prevent the Confederacy from trading.

Seeking alternatives, the Confederacy commissioned Francis Porcher, a botanist and surgeon from South Carolina, to compile a book of medicinal plants of the Southern states, including plant remedies used by Native Americans and enslaved Africans. "Resources of the Southern Fields and Forests," published in 1863, was a major compendium of uses for different plants, including a description of 37 species for treating gangrene and other infections. Samuel Moore, the Confederate Surgeon General, drew from Porcher's work to produce a document called "Standard supply table of the indigenous remedies for field service and the sick in general hospitals."

For the current study, the researchers focused on three plant species Porcher cited for antiseptic use that grow in Lullwater Preserve on the Emory campus. They included two common hardwood trees -- the white oak (Quercus alba) and the tulip poplar (Liriodendron tulipifera) -- as well as a thorny, woody shrub commonly known as the devil's walking stick (Aralia spinosa).

Samples of these three plants were gathered from campus specimens, based on Porcher's specifications. Extracts were taken from white oak bark and galls; tulip poplar leaves, root inner bark and branch bark; and the devil's walking stick leaves. The extracts were then tested on three species of multi-drug-resistant bacteria commonly found in wound infections.

Aceinetobacter baumannii -- better known as "Iraqibacter" due to its association with wounded combat troops returning from the Iraq War -- exhibits extensive resistance to most first-line antibiotics. "It's emerging as a major threat for soldiers recovering from battle wounds and for hospitals in general," Quave says.

Staphylococcus aureus is considered the most dangerous of many common staph bacteria and can spread from skin infections or medical devices through the bloodstream and infect distant organs. Klebsiella pneumoniae is another leading cause of hospital infection and can result in life-threatening cases of pneumonia and septic shock.

Laboratory tests showed that extracts from the white oak and tulip poplar inhibited the growth of S. aureus, while the white oak extracts also inhibited the growth of A. baumannii and K. pneumoniae. Extracts from both of these plants also inhibited S. aureus from forming biofilms, which can act like a shield against antibiotics.

Extracts from the devil's walking stick inhibited both biofilm formation and quorum sensing in S. aureus. Quorum sensing is a signaling system that staph bacteria use to manufacture toxins and ramp up virulence. Blocking this system essentially "disarms" the bacteria.

Traditional plant remedies are often dismissed if they don't actively attack and kill pathogens, Quave notes, adding: "There are many more ways to help cure infections, and we need to focus on them in the era of drug-resistant bacteria."

"Plants have a great wealth of chemical diversity, which is one more reason to protect natural environments," Dettweiler says. He plans to go to graduate school with a focus on researching plants for either medical or agricultural purposes. "I'm interested in plants because, even though they don't move from place to place, they are extremely powerful and important."

The first ever study to assess secondary school choices made across all households in England has shown that the system is unfair to households in areas where they are given fewer options on the application form, with these parents having to make "less ambitious" choices.

Whilst it was shown that most parents actively use the school choice system and 85% of households receive their first-choice school, the system's constraints still restrict education equality across England with parents who are allowed six options - compared to the more regular three - being afforded less caution in their choices.

This new research, which has published in the Oxford Review of Education, looked at a two large data sets making up more than 526,000 pupils in England.

It found:

contrary to a widely held belief, only a minority of parents (39%) choose their local school as their first option

27% of parents make the maximum number of choices permitted and so having more options may be beneficial.

Almost twice as many choices are made in local authorities (LAs) where more choices are allowed.

Conducted by a team from the Universities of Cambridge and Bristol, the study also investigated the extent to which parents actively use the school choice system and how use of this system varies across households and neighbourhoods.

Black or Asian families (or families of children with English as an Additional Language, EAL) make more use of the school choice system (41% of White British households only make one choice, compared to 17% of Asian households and 12% of Black households); prefer higher performing schools; and are far less likely to apply for their local school (only 27% of EAL students compared to 42% of non EAL pupils).

Despite making more choices, EAL students have a lower chance (73% relative to 88% for non EAL students) of receiving an offer from their first-choice school, perhaps because they were more ambitious in their choices

There was almost no difference in the number of choices made by more and less affluent families. However, households in more affluent neighbourhoods were more likely to choose their closest school, perhaps reflecting the higher quality of their nearest school.

In addition, the study, which looked at data from the 2014/15 academic year, found:

35% of households make only one school choice

those that make one choice, only 55% nominate their closest school

97% of households that make only one choice receive an offer from this school

For those making the maximum number of choices, 77% received an offer from their first-choice school.

Professor Vignoles at the Faculty of Education, University of Cambridge believes that the current system is causing a situation where families are being made to make cautious decisions about their school choice.

She said: "There appears to be a degree of caution being exhibited whereby parents are more likely to put down the school that they have the greatest chance of their child being admitted to (often their nearest) when they are only permitted three choices.

"Due to the limit in the number of options allowed, first choice schools may be 'safe' rather than 'ambitious'. The data show that the quality of parents' first choice school is higher in LAs where more choices are permitted, suggesting that where more choices are allowed, parents are more ambitious.

"On average we found parents and pupils usually attempt to try to study at the highest attaining school, rather than the one which is closest."

Importantly, although most households receive an offer from their first-choice school (85%) this is probably masking a wider issue, co-author, Professor Simon Burgess from the University of Bristol added: "Households seem to make pragmatic choices based on the probability of admission at each school. 85% may therefore be viewed negatively as reflecting parents being very cautious in their choices.

"A successful system with active and ambitious choices by parents would result in a lower percentage of parents getting their first choice.

"Allocating places to popular over-subscribed schools by proximity means that some households have negligible chance of admission to the best schools and it seems that many therefore do not bother applying. This is what needs to change to increase fairness in the English system."

Co-author Ellen Greaves, from the University of Bristol, added: "The school a pupil attends can affect their attainment and enjoyment of school, ultimately affecting their life chances. Understanding the functioning of the school choice system and how pupils are allocated to schools is therefore critical if we are to understand and improve educational equality and social mobility.

"Our data suggests that many parents are making active choices for schools and appear to value academic attainment. While many households clearly engage with the school choice process, choice is curtailed for others by the limited number of choices permitted, these households may decide that making an 'ambitious' choice would be wasteful."

The planned next stage of the research is to determine the relative importance of parental choice and constraints in school allocation.

People who suffer a stroke caused by bleeding in the brain - known as brain haemorrhage - can take common medicines without raising their risk of another stroke, a major clinical trial has found.

Researchers say the findings are reassuring for the thousands of people who take the medicines to reduce their risk of heart attack and another common type of stroke caused by blood clots in the brain.

These everyday treatments - known as antiplatelet medicines - work by slowing or stopping blood from clotting. They are often prescribed to older people because they can lower risk of heart attack and stroke caused by a blood clot.

Doctors had thought the medicines - which include aspirin and clopidogrel - might make people with stroke due to brain haemorrhage more likely to suffer another bleed in the brain.

Researchers led by the University of Edinburgh tracked outcomes from 537 people from across the UK who had suffered a brain haemorrhage while they were taking medicines to stop blood clotting.

Patients were randomly assigned to either start taking antiplatelet treatment or avoid it for up to five years.

The team found that people who took antiplatelet medicines experienced fewer recurrences of brain haemorrhage compared with those who did not take these treatments. Some 12 people suffered a brain bleed while taking the medication compared with 23 people who did not.

This may suggest the treatments reduce rather than increase risk of further bleeding in the brain, the researchers say, but further studies are needed to confirm this.

Around half of the participants underwent an additional brain scan using MRI at the beginning of the study. These scans are often used by doctors to check for the presence of tiny blood deposits in the brain, known as microbleeds, which can be a warning sign of future strokes.

The researchers found treatment with antiplatelet medication was not more hazardous for people who already had microbleeds in their brain.

Experts say this provides further reassurance that brain haemorrhage survivors can safely continue to take antiplatelet medicines to reduce their risk of future heart attacks or strokes.

It also suggests that patients do not need to undergo an MRI scan before starting treatment. This is important because older people are often unable to have an MRI.

The study - called RESTART - is published in The Lancet and The Lancet Neurology. It was funded by the British Heart Foundation. Findings are being presented at the European Stroke Organisation Conference in Milan.

Professor Rustam Salman, of the University of Edinburgh's Centre for Clinical Brain Sciences, said: "The results of the RESTART trial are reassuring for survivors of brain haemorrhage who need to take antiplatelet medicines to prevent heart attacks and strokes. I am keen to investigate the possibility that these medicines might halve the risk of brain haemorrhage happening again."

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation (BHF), said: "Around a third of people who suffer a brain haemorrhage, also known as haemorrhagic stroke, do so when they are taking an antiplatelet medicine such as aspirin to reduce the risk of a heart attack or an ischaemic stroke. We now have a strong indication they can carry on taking these potentially life-saving medicines after the brain haemorrhage without increasing the risk of another one, which is crucial new information for both patients and doctors.

"Although some developments have been made, the options at our disposal for treating and preventing strokes are still far too limited. Around 36,000 people die each year in the UK after having a stroke, most commonly an ischaemic stroke. Every advance from important research such as this takes us a step closer to better stroke prevention and management."

Overall active surveillance rates are up, though the increase is significantly smaller for black patients

Black men may be deterred by both socioeconomic factors and providers' hesitation given concern for underlying aggressive disease

BOSTON - At a time when a growing number of men with prostate cancer considered "low risk" are opting for active surveillance or watchful waiting rather than immediate treatment with surgery or radiation, a new study reveals that black men are less likely than white men to adopt an active surveillance strategy for their disease.

This difference, reported in a letter to The New England Journal of Medicine¸ appears to be due in part to socioeconomic and insurance factors, according to Brandon Mahal, MD, from the department of radiation oncology at Dana-Farber/Brigham and Women's Cancer Center, and last author of the report. For example, he suggested, poorer or less well-insured black men might experience more barriers to the follow-up care - periodic exams, blood tests, and repeat biopsies - involved in active surveillance, resulting in a decision by providers and/or patients to opt for immediate definitive treatment.

But the study, which looked at trends between 2010 and 2015, found that even after socioeconomic factors were accounted for, African American men were 16 percent less likely to adopt active surveillance or watchful waiting for "low risk" prostate cancer. A possible explanation, said Mahal, is that providers may be concerned that low risk prostate cancer in black men may be more aggressive than in white men; in fact, he said several studies have suggested that black men with low-risk disease might have poorer outcomes compared to non-African American men. "Given the under-representation of black patients in clinical trials and concern about underlying aggressive disease, expert panels advise caution when applying conservative management to black patients," said the report. That awareness could drive more black men toward immediate surgery or radiation therapy, noted Mahal.

The disparity "really demonstrates that there's a need for further study into low-risk disease in African American men so that we can better treat these men with low-risk disease," Mahal said.

Low-risk prostate cancer is defined as being clinical stage T1 to T2a (early stage disease); a Gleason score of 6 or less (on a scale of 2 to 10) and a prostate-specific antigen (PSA) level of less than 10 ng per milliliter.

The researchers' analysis used data from the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting Database, which included 50,302 patients of whom 7,517 (14.9%) were black and 42,785 (85.1%) were nonblack. From 2010 through 2015, the use of radical prostatectomy (surgery to remove the prostate gland) and definitive radiotherapy decreased from 41.4% and 46.0% to 28.8% and 34.8% respectively among black men. The decrease was from 48.5% (prostatectomy) and 36.7% (radiotherapy) to 31.8% and 24.9% among nonblack men.

In the same period, the use of active surveillance or watchful waiting almost tripled, increasing from 12.6% to 36.4% among black men and from 14.8% to 43.3% among nonblack men - the latter group adopting surveillance at a greater rate.

"This is the first study that has truly been able to examine how the factors of race and socioeconomic status impact the use of active surveillance for prostate cancer in the United States," said Santino S. Butler, first author of the report. "Black men are underrepresented in clinical trials that have evaluated active surveillance. These findings demonstrate the need for clinical trials to better guide management for black men with low-risk prostate cancer."

Specifically, said Mahal, to investigate whether active surveillance is a safe option for black men with low-risk disease, "we need clinical trials of African American men with low-risk prostate cancer where we evaluate their tumors for aggressive markers and also evaluate their outcomes with active surveillance. These studies would settle debates about the aggressiveness of low-risk prostate cancer in African American men and would help guide management decisions, which are now being made based on limited data."

They've never seen animals like hippos and sharks but adults born blind have rich insight into what they look like, a new Johns Hopkins University study found.

"First-person experience isn't the only way to develop a rich understanding of the world around us," says Judy Kim, a doctoral candidate at Johns Hopkins and corresponding author of the study published May 21 in Proceedings of the National Academy of Sciences.

"Essentially, the question is, how do we know what we know?"

While some previous research has shown that blind people do have knowledge of things like light and color, researchers still have little understanding of what blind people know about appearance and how such information is learned. Some studies suggest that people born blind remember verbal facts, like 'flamingos are pink,' so the research team wanted to investigate further.

"People often have the intuition that we can't know what we can't see," says Kim.

The researchers presented 20 blind and 20 sighted adults with animal names and asked participants to: order animals by size (smallest to largest) and height (shortest to tallest); sort animals into groups based on shape, skin texture and color; pick which animal out of a group is unlike the others in shape, and choose from various texture options ("Does a hippo have feathers, fur, skin or scales?").

Overall, blind and sighted participants organized animals in similar ways and agreed on which physical features were most likely to be observed within animal groups. For example, blind and sighted participants judged that dolphins are similar in shape to sharks and sloths are similar in texture to grizzlies. 15 out of 20 blind and 19 out of 20 sighted participants judged elephants to be bigger than rhinos. But the groups also showed some differences.

Contrary to the idea that blind people learn about animal appearance from sighted people's descriptions of what animals look like, blind and sighted participants disagreed most about the dimension that was easiest for sighted people to describe in words: animal color. Sighted participants created groups for white, pink, black, black and white, brown and grey animals, and they easily labeled these groups according to their primary colors. By contrast, sighted people had a hard time verbally describing their shape groupings; they used many words and did not agree with each other. Nevertheless, blind people created similar shape groups to the sighted but did not make consistent color groups.

The researchers found that to deduce what animals looked like, blind people relied on similar biological classifications that scientists use to group species. This strategy works very well for shape and texture: birds, for example, have feathers and a characteristic winged shape. Such inference works less well for color because many very different animals are white (e.g., swans, polar bears and sheep).

The main conclusion is that blind people develop rich and accurate ideas about appearance based on inference.

"It's sometimes assumed that the senses and direct experience are the best way to learn about the world. What the findings show is that linguistic communication can give us rich and accurate knowledge, even knowledge that at first glance seems 'visual.'" says Marina Bedny, Assistant Professor of Psychological and Brain Sciences at Johns Hopkins and another author on the paper.

"Neither sighted nor blind people living in urban environments really need to know about wild animals. But we are fascinated by them. Knowing about lions and elephants is part of our culture and blind people who are members of the same culture infer animal appearance from linguistic communication."

A team of international scientists--including researchers at the University of St. Andrews, Syracuse University and Royal Holloway, University of London--have demonstrated a new source of food for early life on the planet.

Life on Earth relies on the availability of critical elements such as nitrogen and phosphorus. These nutrient elements are ubiquitous to all life, as they are required for the formation of DNA, the blueprints of life, and proteins, the machinery. They are originally sourced from rocks and the atmosphere, so their availability to life has fluctuated alongside significant changes in the chemistry of Earth's surface environments over geologic time.

The research, published in Nature Geoscience, reveals how the supply of these elements directly impacted the growth of Earth's oxygen-rich atmosphere and were key to the evolution of early life on Earth.

The most dramatic change in Earth history followed the evolution of oxygenic photosynthesis, which fundamentally transformed the planet by providing a source of carbon to the biosphere and a source of oxygen to the atmosphere, the latter culminating in the Great Oxidation Event (GOE) some 2.3 billion years ago.

Despite the critical importance of nutrients to life, the availability of nitrogen and phosphorus in pre-GOE oceans is not well understood, particularly how the supply of these elements drove and/or responded to planetary oxygenation.

Using samples of exceptionally well-preserved rocks that have been associated with early evidence for oxygenic photosynthesis 2.7 billion year ago, the team of researchers examined Earth's early nitrogen cycle to decipher feedbacks associated with the initial stages of planetary oxygenation.

"There is precious little rock available from this time interval that is suitable for the type of analyses we performed. Most rocks that are this old have been deformed and heated during 2.7 billion years of plate tectonic activity, rendering the original signals of life lost," says Christopher Junium, associate professor of Earth sciences in the College of Arts and Sciences.

The rock samples showed the first direct evidence of the build-up of a large pool of ammonium in the pre-GOE oceans. This ammonium would have provided an ample source of nitrogen to fuel the early biosphere and associated oxygen production.

Research team leader Aubrey Zerkle, reader in the School of Earth and Environmental Sciences at the University of St Andrews, says: "Today we think of ammonium as the unpleasant odor in our cleaning supplies, but it would've served as an all-you-can-eat buffet for the first oxygen-generating organisms, a significant improvement on the dumpster scraps they relied on earlier in Earth's history."

As well as helping scientists better understand the role of the nitrogen cycle in global oxygenation, the new findings also provide context for other nutrient feedbacks during early planetary evolution.

"It is becoming ever more clear that the game of nutrient limitation has tipped back and forth through Earth's history as life has evolved and as conditions have changed," Junium says.

Surprisingly, evidence for significant atmospheric oxygenation does not appear until 400 million years later, meaning that some other nutrient, such as phosphorus, must have been important in setting the evolutionary pace.

Paris, France, 21 May 2019. This PCR statement on paclitaxel drug-coated balloons (DCB) use in peripheral interventions addresses the controversy raised by the meta-analysis of K. Katsanos, MD, PhD (Patras University Hospital, Rion, Greece) and colleagues, published in late 2018. The Katsanos meta-analysis prompted widespread concern in the interventional community by suggesting that treatment with paclitaxel-eluting stents or DCBs for femoropopliteal disease is associated with increased
death beyond 1 year out to 5 years compared with uncoated balloon therapy.

The statement outlines that, as for any meta-analysis, the Katsanos analysis is subject to major inherent methodological limitations that prevent reliable interpretation of the primary findings. These include the use of study-level (rather than patient-level) data, limited longterm
data and high dropout rates (>80% loss of patient data at 4-5 years), unknown repeated exposure to paclitaxel during re-interventions, lack of adjudication of causes of death, and subsequent corrections to primary source data (announced in February 2019).

The Statement acknowledges that, while the results of the meta-analysis itself were far from conclusive, further evaluation is warranted given the widespread use of paclitaxel in peripheral interventions and the implications of the reported hazard. The publication did
serve as a wakeup call and swift action on the part of the interventional community, including industry and the FDA, to convene collaborative discussions, new analyses and presentations of patient level pooled data. A planned industry-wide pooled analysis is anticipated to be
presented at an upcoming FDA panel meeting in mid-June, with rapid dissemination of preliminary findings and planned next steps to the broader physician community.

The statement emphasises that additional evidence from individual sponsor-driven patientlevel analyses of clinical trial data, as well as large-scale claims data, have failed to replicate the results of the meta-analysis with respect to an association of paclitaxel exposure with
long-term mortality. Furthermore, no safety signal has ever been shown in coronary DCB applications in the long-term.

PCR acknowledges the vital need for a carefully conducted and adjudicated industry-wide patient level pooled analysis to compare long-term safety outcomes. This analysis is planned to be presented at the upcoming FDA panel on June 19th and 20th. Finally, PCR strongly
supports resuming, under careful safety oversight, two large prospective randomised trials (BASIL 3 and SWEDPAD) that were suspended shortly after the Katsanos publication. These trials would provide the vital evidence necessary to evaluate the safety of DCB to better inform clinicians in everyday practice.

Pending the availability of more conclusive data, there is currently no strong evidence to justify changing clinical practice and clinicians should continue to use best judgment in the use of paclitaxel-based DCBs.