Culture

PHILADELPHIA -- Vaccine-preventable disease (VPD) outbreaks are increasing in frequency in the United States, but this trend is also met with an uptick in legislation aimed at increasing childhood vaccination in places where those epidemics occurred, according to findings published today in JAMA Pediatrics from researchers at the Dornsife School of Public Health at Drexel University.

The Drexel team found that as VPD outbreaks increased, so did introduction of state legislation intended to restrict laws that allow for skipping childhood vaccinations. The team looked at 2010-2016 state-level data on 12 different childhood VPDs reported to health departments, including Hepatitis A and B, flu, measles, whooping cough and others. They then probed state legislature data for bills introduced the year following the start of an outbreak, between 2011-2017, that would expand or reduce the criteria required to be vaccinated for these diseases.

The study found that each state reported an average of 25 VPDs per 100,000 people per year, with substantial variability year to year. Of the 175 related bills proposed during 2011-2017, 53 percent made it easier to exempt oneself from vaccine requirements while 47 percent made it more difficult to be skip vaccination.

Although there were more anti-vaccine bills than pro-vaccine bills introduced overall during this seven-year period, grouping the bills into these two categories paints a more public health-centered picture. Researchers found that increases in VPDs were actually positively associated with increases in the number of proposed pro-vaccine bills that restrict exemptions. They did not observe any statistical association between decreases in VPDs and proposed bills that would make it easier to bypass vaccination.

Legislation to increase vaccination is particularly needed in the United States. In 2000, the Centers for Disease Control and Prevention declared measles eliminated in the United States, but announced 695 measles cases in 22 states in April 2019. Two recent outbreaks in California (2015) and New York (2019), led state legislatures to remove all nonmedical exemptions.

"Vaccines are our best public health tool for controlling many childhood diseases," said lead author Neal D. Goldstein, PhD, an assistant research professor of epidemiology and biostatistics at Drexel's Dornsife School of Public Health. "Seeing an uptick in legislation aimed at cutting vaccine exemptions following disease outbreaks suggests that media coverage may raise public awareness and advocacy and response from legislators. While it is unfortunate it took outbreaks of preventable disease to spawn legislative action, it further affirms the widespread support of this life-saving intervention."

According to the Wellcome Global Monitor 2018 report, support for vaccination varies substantially between countries, with lower income regions reporting greater confidence than higher income regions do in vaccines. This distrust of vaccines in some wealthier countries makes "herd immunity" - vaccination of the vast majority of a population to prevent individuals from contracting a disease and spreading it to others - much more difficult to achieve, particularly in small, but vocal communities who are hesitant to vaccinate.

The latest report on the consensus among the scientific community in support of vaccines is summed up in The Salzburg Statement on Vaccination Acceptance, published by some public health experts in July 2019 in the Journal of Health Communication. In the text, the authors share their "unwavering commitment to universal childhood vaccination."

In November 2018, Goldstein and colleagues published a study in the American Journal of Public Health showing that, despite increasing numbers of anti-vaccine bills being introduced in state legislatures from 2011 to 2017, pro-vaccine legislation was more likely to become law.

After countless studies on how laws affect health, the Drexel team flips that model on its head to report data about how health affects laws.

"We believe this paradigm can be applied to many other public health areas, not just vaccination," said Goldstein, who also consults for Merck Sharp & Dohme Co., but noted that the company had no role in the study or its outcome.

Progeria is a very rare disease that affects about one in 18 million children and results in premature aging and death in adolescence from complications of cardiovascular disease. In a study on mice and human cells, researchers at Sweden's Karolinska Institute and IFOM, the FIRC Institute of Molecular Oncology in Italy, have identified how antisense oligonucleotide therapies could be used as a new possible treatment option for the disease. The results are published in the journal Nature Communications.

Progeria, or Hutchinson-Gilford progeria syndrome as the disease is also called, has genetic causes and is linked to progerin, a defect form of the lamin A protein found in the cell nucleus. The mutation, which inhibits cell division, was identified in 2003 by researcher Maria Eriksson, co-author in the current study. The affected children usually die in early adolescence from complications of cardiovascular disease.

So far, more than a dozen treatments of progeria have been tested in different ways, but when it comes to clinical trials conducted in patients with progeria, the results have been disappointing.

"We have seen positive effects in the treatment of mice, but in humans the effect has been too small. We therefore need to rethink and find new ways to treat the disease," says Maria Eriksson, professor at the Department of Biosciences and Nutrition at Karolinska Institutet.

In the now published study, the researchers used cell samples from children with progeria to show an impaired function in the telomeres at the far end of the chromosomes and the accumulation of so-called telomeric non-coding RNA. By adding antisense oligonucleotides, a treatment used to inactivate harmful genes, the researchers were able to reduce the level of telomeric non-coding RNA. This led to a more normalised cell division, which would likely improve patients' conditions and extend their lifespan.

"In a gene altered mouse model of progeria treated in the same way, we saw a significant increase in both the maximum life expectancy, up 44 percent, and the average life expectancy, up 24 percent," says Agustin Sola-Carvajal, former postdoc in Eriksson's research group and co-author of the study. "These results are very promising."

Progerin is also found in healthy subjects and has been observed to increase with age, suggesting the results may also be important for normal aging and age-related disease.

"More research is needed to assess how the relatively low levels of progerin seen in healthy individuals contribute to ageing and age-related disease," says Eriksson. "It is interesting to note that antisense oligonucleotides are now included as drugs in advanced clinical trials, some of which are already approved by the FDA in the U.S."

SACRAMENTO, Calif.) - A study of over 6,300 Latinos of Dominican, Central American, Cuban, Mexican Puerto Rican and South American heritage estimates that nearly 10% of middle-age and older Latinos in the U.S. meet the criteria for mild cognitive impairment. MCI is a transitional stage between healthy aging and dementia characterized by a slight decline in memory and thinking skills.

The research, led by researchers at the University of California at Davis and San Diego, publishes Nov. 18 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. It is an important first step in understanding Alzheimer's and other dementias in understudied Latino populations.

"Latinos share regional forms of the Spanish language, but their cultural histories, genetic ancestries and health profiles are diverse," said Charles DeCarli, co-principal investigator of the study and director of the UC Davis Alzheimer's Disease Center. "This is the first study to estimate the overall prevalence of mild cognitive impairment among diverse populations of Latinos. It also identified factors - cardiovascular disease and depression - that can be treated to reduce the risk."

The researchers found 9.8% of participants had MCI. Older age, high cardiovascular disease risk and symptoms of depression increased with MCI prevalence. However, a major risk factor gene for developing Alzheimer's in some populations, APOE4, was not associated with increased MCI risk in the Latino groups studied. This result differs from prior studies of principally white, non-Hispanic populations.

"Our findings suggest that there are other biological factors that may contribute to MCI in Latinos," said Hector M. Gonzalez, first author and co-principal investigator of the study. He also is an associate professor of neurosciences at UC San Diego.

The researchers linked Puerto Rican heritage with the highest MCI prevalence (12.9%) and those with Cuban heritage with the lowest (8.0%). MCI prevalence for those with heritage in other parts of the world included, Central Americans (10.8%), Dominicans (9.7%), South Americans (9.6%) and Mexicans (9.5%).

While MCI rates varied by Latino backgrounds, the variation was not as wide as reported in previous studies, the researchers said.

For the study, Gonzalez and colleagues assessed detailed data on Latino health from SOL-INCA, a Study of Latinos-Investigation of Neurocognitive Aging, and its parent study, the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Funded by the National Institutes of Health, SOL-INCA contained the results of cognitive tests given in English and Spanish with follow-up testing occurring seven years later on average. HCHS/SOL focused on cardiovascular risk factors.

"With the in-depth sociocultural, behavioral, biological and genetic data collected and careful study design, we were able to generalize our findings for diverse Latino populations," said Gonzalez, principal investigator of SOL-INCA. "We believe we are at the frontier of making new discoveries and more precisely understanding Latino cognitive aging and Alzheimer's disease-related dementias.

By identifying cardiovascular disease and depression as important risk factors for MCI among Latinos, the researchers believe there is a tremendous opportunity to intervene to improve health.

"Cardiovascular disease and depression can be treated to reduce MCI risk in this large, rapidly growing, but understudied population," Gonzalez said.

In a related Perspective article published in the same issue of the journal, González and colleagues suggest using SOL-INCA as a model research framework for advancing research on Latino Alzheimer's disease and other dementias.

Latinos represent nearly one-fifth of the U.S. population. In California and Texas, they represent 40% of the population. Preventing dementia and addressing cardiovascular disease in Latinos later in life begins with understanding and modifying cardiovascular health earlier in the lifespan.

Osaka, Japan - Arthritis is a common chronic disease in which joints become inflamed, leading to stiffness and pain that can often be debilitating. Rheumatoid arthritis (RA) is an autoimmune form of the disease, arising when immune cells attack the tissue that lines the joints. There is a need for new treatment options, as current therapies only alleviate symptoms or, at best, slow the disease. Now, in a study published in Nature Immunology, researchers at Osaka University have discovered a previously unknown type of RA-causing cell within arthritic joints that could someday be a target for new treatments.

There are two major cellular culprits that contribute to RA. The first are immune cells, which release inflammatory chemicals around the tissue of affected joints. The second are osteoclasts, specialized cells that secrete acids and enzymes to break down bone. Osteoclasts normally help to remodel healthy bone, but in RA their bone-dissolving ability goes into overdrive and damages joints.

"The disease-modifying anti-rheumatic drugs available today predominantly act against the inflammatory response of immune cells," says Masaru Ishii, professor at Osaka University Graduate School of Medicine and corresponding author of the study. "Therapies targeting osteoclasts are limited, largely because we don't know enough about the osteoclasts involved in RA. We were interested in understanding whether these cells are somehow different from the osteoclasts involved in normal physiological processes."

Osteoclasts are elusive, residing along the surface of bone under layers of cartilage and tissue. This makes them difficult to isolate in the lab, even with tractable models like mice. To collect the cells, the research group had to develop a surgical technique that allowed them to extract osteoclasts from the femurs of arthritic mice. With osteoclasts securely in hand, they were then able to gather new insights into RA.

"We tracked precisely how arthritis-inducing osteoclasts develop from their undifferentiated precursor cells," explains Tetsuo Hasegawa, lead author of the study. "While normal osteoclasts are derived from stem cells in the bone marrow, we found that osteoclasts involved in RA come from blood-borne precursors. The circulating precursors enter the joint and differentiate into a unique sub-type of osteoclasts, which are larger and have distinct markers that aren't seen in other osteoclasts."

The newly discovered cells, dubbed "AtoMs" (Arthritis-associated osteoclastogenic Macrophages), have properties that could be exploitable in the search for new treatments. In one example highlighted by the study, the researchers found that AtoMs have high levels of a protein (called FoxM1) known to make cells invade nearby tissue. They speculated that by getting rid of this hallmark protein—splitting the AtoM, if you will—they could perhaps quell its arthritic tendencies. This is indeed what they found: when FoxM1 was chemically or genetically disrupted in AtoMs, arthritic mice showed reduced bone destructions in their joints.

"Our findings suggest that osteoclasts involved in RA have distinct properties that make them amenable to therapeutic targeting," says co-author Masaru Ishii. "While there is still a lot to learn about this class of cells, we believe the discovery could open the door to new avenues of treatment."

CHAMPAIGN, Ill. -- A new web tool speeds the discovery of drugs to kill Gram-negative bacteria, which are responsible for the overwhelming majority of antibiotic-resistant infections and deaths. The tool also offers insights into discrete chemical changes that can convert drugs that kill other bacteria into drugs to fight Gram-negative infections. The team proved the system works by modifying a Gram-positive drug and testing it against three different Gram-negative bacterial culprits in mouse sepsis. The drug was successful against each.

The researchers report their findings in the journal Nature Microbiology.

"It's really hard to find new antibiotics for Gram-negative pathogens, because these bacteria have an extra membrane, an outer membrane, that's very good at keeping antibiotics out," said University of Illinois chemistry professor Paul Hergenrother, who led the research.

The challenge is so profound that no new classes of drugs to fight Gram-negative bacteria have been approved by the Food and Drug Administration in 50 years, Hergenrother said.

"A few years ago, we discovered the molecular features that allowed an antibiotic compound to surpass this barrier," he said. "Now, we've developed a tool to help others do this as well."

The new app, called eNTRyway, can quickly evaluate potential drug compounds to determine if they have the molecular characteristics that will enable them to cross the membrane and accumulate inside Gram-negative bacteria.

Developed by graduate student Bryon Drown, the app also can point to ways of modifying existing drugs - for example, those known to work against Gram-positive bacteria - to convert them into potent killers of Gram-negative pathogens.

As a demonstration of this latter capability, postdoctoral researcher and study co-lead author Erica Parker used the tool to identify a drug already in use against Gram-positive infections that - with a basic chemical modification - could potentially be converted to fight Gram-negative bacteria. By adding a positively charged chemical group known as an amine to the drug, Parker created a compound that, further tests revealed, accumulated in Gram-negative bacteria and was effective against several types of Gram-negative infections in mice.

The process of identifying the compound and modifying it took only a few weeks, Hergenrother said.

"Keep in mind that before this, over 100 derivatives of this same compound had been made. We found them in patents and papers," he said. "And none of these other derivatives had notable Gram-negative activity."

Hergenrother and his colleagues have so far identified more than 60 antibiotics that are effective only against Gram-positive bacteria but can be converted into drugs to fight Gram-negative infections. These compounds kill bacteria in a variety of different ways. The newly created drug, known as Debio-1452-NH3, interferes with fatty acid synthesis in bacterial - but not mammalian - cells.

Hergenrother said the new tool will speed the process of drug discovery to fight the burgeoning problem of antibiotic-resistant infections.

"We can use this tool to rapidly identify compounds that accumulate in Gram-negative bacteria," he said.

Shrouded in mystery since their discovery, the phenomenon of black holes continues to be one of the most mind-boggling enigmas in our universe.

In recent years, many researchers have made strides in understanding black holes using observational astronomy and an emerging field known as gravitational wave astronomy, first hypothesized by Albert Einstein, which directly measures the gravitational waves emitted by black holes.

Through these findings on black hole gravitational waves, which were first observed in 2015 by the Laser Interferometer Gravitational-Wave Observatories (LIGO) in Louisiana and Washington, researchers have learned exciting details about these invisible objects and developed theories and projections on everything from their sizes to their physical properties.

Still, limitations in LIGO and other observation technologies have kept scientists from grasping a more complete picture of black holes, and one of the largest gaps in knowledge concerns a certain type of black hole: those of intermediate-mass, or black holes that fall somewhere between supermassive (at least a million times greater than our sun) and stellar (think: smaller, though still 5 to 50 times greater than the mass of our sun).

That could soon change thanks to new research out of Vanderbilt on what's next for gravitational wave astronomy. The study, led by Vanderbilt astrophysicist Karan Jani and featured today as a letter in Nature Astronomy, presents a compelling roadmap for capturing 4- to 10-year snapshots of intermediate-mass black hole activity.

"Like a symphony orchestra emits sound across an array of frequencies, the gravitational waves emitted by black holes occur at different frequencies and times," said Jani. "Some of these frequencies are extremely high-bandwidth, while some are low-bandwidth, and our goal in the next era of gravitational wave astronomy is to capture multiband observations of both of these frequencies in order to 'hear the entire song,' as it were, when it comes to black holes."

Jani, a self-proclaimed "black hole hunter" who Forbes named to its 2017 30 Under 30 list in Science, was part of the team that detected the very first gravitational waves. He joined Vanderbilt as a GRAVITY postdoctoral fellow in 2019.

Along with collaborators at Georgia Institute of Technology, California Institute of Technology and the Jet Propulsion Laboratory at NASA, the new paper, "Detectability of Intermediate-Mass Black Holes in Multiband Gravitational Wave Astronomy," looks at the future of LIGO detectors alongside the proposed Laser Interferometer Space Antenna (LISA) space-mission, which would help humans get a step closer to understanding what happens in and around black holes.

"The possibility that intermediate mass black holes exist but are currently hidden from our view is both tantalizing and frustrating," said Deidre Shoemaker, co-author of the paper and professor in Georgia Tech's School of Physics. "Fortunately, there is hope as these black holes are ideal sources for future multiband gravitational wave astronomy."

LISA, a mission jointly led by the European Space Agency and NASA and planned for launch in the year 2034, would improve detection sensitivity for low-frequency gravitational waves. As the first dedicated space-based gravitational wave detector, LISA would provide a critical measurement of a previously unattainable frequency and enable the more complete observation of intermediate-mass black holes. In 2018, Vanderbilt physics and astronomy professor Kelly Holley-Bockelmann was appointed by NASA as the inaugural chair of the LISA Study Team.

"Inside black holes, all known understanding of our universe breaks down," added Jani. "With the high frequency already being captured by LIGO detectors and the low frequency from future detectors and the LISA mission, we can bring these data points together to help fill in many gaps in our understanding of black holes."

As the extinction crisis escalates, and protest movements grow, some are calling for hugely ambitious conservation targets. Among the most prominent is sparing 50% of the Earth's surface for nature.

'Half Earth' and similar proposals have gained traction with conservationists and policy makers. However, little work has gone into identifying the social and economic implications for people.

Now, researchers have produced the first attempt to assess how many and who would be affected if half the planet was 'saved' in a way that secures the diversity of the world's habitats.

A team of scientists analysed global datasets to determine where conservation status could be added to provide 50% protection to every "ecoregion": large areas of distinct habitats such as Central African mangroves and Baltic mixed forests.

Even avoiding where possible "human footprints" such as cities and farmland, their findings suggest a "conservative" estimate for those directly affected by Half Earth would be over one billion people, primarily in middle-income countries.

Many wealthy and densely populated nations in the Global North would also need to see major expansions of land with conservation status to reach 50% - this could even include parts of London, for example.

The study's authors, led by University of Cambridge researchers, say that while radical action is urgently required for the future of life on Earth, issues of environmental justice and human wellbeing should be at the forefront of the conservation movement.

"People are the cause of the extinction crisis, but they are also the solution," said Dr Judith Schleicher, who led the new study, published today in the journal Nature Sustainability. "Social issues must play a more prominent role if we want to deliver effective conservation that works for both the biosphere and the people who inhabit it."

Towards the end of next year, the leaders of most of the world's nations will aim to agree global targets for the future of conservation at the Convention on Biological Diversity in Beijing.

"Goals that emerge from the Convention on Biological Diversity could define conservation for a generation," said Schleicher, who conducted the research while at the University of Cambridge's Conservation Research Institute and its Department of Geography.

"We need to be ambitious given the environmental crises. But it is vital that social and economic implications at local levels are considered if the drivers of biodiversity loss are to be tackled. The lives of many people and the existence of diverse species hang in the balance."

The idea of a 'Half Earth' for nature was popularised by famed biologist E.O. Wilson in his 2017 book of the same name. More recently, a 'Global Deal for Nature' - aiming for 30% protection by 2030 and 50% by 2050 - has been endorsed by a number of leading environmental organisations. However, these proposals have been ambiguous about "exact forms and location", say Schleicher and colleagues.

Based on their analyses, researchers cautiously estimate that an additional 760 million people would find themselves living in areas with new conservation status: a fourfold increase of the 247 million who currently reside inside protected areas.

The team call for proponents of Half Earth, and all supporters of area-based conservation, to "recognise and take seriously" the human consequences - both negative and positive - of their proposals.

"Living in areas rich in natural habitat can boost mental health and wellbeing. In some cases, protected areas can provide new jobs and income through ecotourism and sustainable production," said Schleicher.

"However, at the other extreme, certain forms of 'fortress' conservation can see people displaced from their ancestral home and denied access to resources they rely on for their survival."

While conservation coverage has been increasing, species numbers continue to plummet - suggesting a "disconnect" between international targets and implementation at local and regional levels, argue the team.

"Conservation needs strong action to protect life on earth, but this must be done in a way that takes account of people and their needs," said co-author Dr Chris Sandbrook from Cambridge's Department of Geography.

"Failing to consider social issues will lead to conservation policy that is harmful to human wellbeing and less likely to be implemented in the first place."

Conservation is not just a problem for people of the Global South. Recent reports on UK wildlife revealed devastating declines in iconic species. Yet the study reveals that achieving 50% ecoregion coverage could even see parts of central London become protected. "It highlights the absurdity of hitting arbitrary targets," Sandbrook said.

New research has identified the genetic basis of resistance to ash dieback in UK trees, opening up new avenues for conservation.

Researchers from Queen Mary University of London and the Royal Botanic Gardens, Kew sequenced the DNA from over 1,250 ash trees to find inherited genes associated with ash dieback resistance.

The study, published in leading journal Nature Ecology & Evolution, showed that resistance is controlled by multiple genes, offering hope that surviving trees could be used to restore diseased woodlands, either by natural regeneration or selective breeding.

Professor Richard Nichols, author of the study from Queen Mary University of London, said:

"We found that the genetics behind ash dieback resistance resembled other characteristics like human height, where the trait is controlled by many different genes working together, rather than one specific gene."

"Now we have established which genes are important for resistance we can predict which trees will survive ash dieback. This will help identify susceptible trees that need to be removed from woodlands, and provide the foundations for breeding more resistant trees in future."

Samples were collected from ash trees in a Forest Research mass screening trial, which comprises 150,000 trees planted across 14 sites in South East England.

The researchers screened for resistance genes using a rapid, cost-effective approach, where the DNA of multiple trees was combined into separate pools for diseased and unaffected trees.

Many of the genes found to be associated with ash dieback resistance were similar to those previously shown to be involved in disease or pathogen responses in other species.

Ash dieback is a major threat to the UK landscape, and it is predicted it will kill over half of ash trees across the UK.*

The disease, caused by the invasive alien fungus Hymenoscyphus fraxineus, has spread throughout Europe's ash populations, and was first recorded in the UK in 2012. It is estimated to cost the British economy £7.6 billion over the next 10 years.**

Professor Richard Buggs, Senior Research Leader in Plant Health at the Royal Botanic Gardens, Kew and lead author of the paper, says:

"There is no cure for ash dieback and it threatens to kill over half of the 90 million ash trees in the UK. This will have huge impacts on the British landscape. Our new findings of the genetic basis of natural resistance found in a small minority of British ash trees help us to predict how ash populations will evolve under ash dieback. While many ash trees will die, our findings are encouraging from a long-term perspective and reassure us that ash woodlands will one day flourish again."

Synthetic protocells can be made to move toward and away from chemical signals, an important step for the development of new drug-delivery systems that could target specific locations in the body. By coating the surface of the protocells with enzymes--proteins that catalyze chemical reactions--a team of researchers at Penn State was able to control the direction of the protocell's movement in a chemical gradient in a microfluidic device. A paper describing the research appears November 18, 2019 in the journal Nature Nanotechnology.

"The futuristic vision is to have drugs delivered by tiny 'bots' that can transport the drug to the specific location where it is needed," said Ayusman Sen, the Verne M. Willaman Professor of Chemistry at Penn State and the leader of the research team. "Currently, if you take an antibiotic for an infection in your leg, it diffuses throughout your entire body. So, you have to take a higher dose in order to get enough of the antibiotic to your leg where it is needed. If we can control the directional movement of a drug-delivery system, we not only reduce the amount of the drug required but also can increase its speed of delivery."

One way to address controlling direction is for the drug-delivery system to recognize and move towards specific chemical signals emanating from the infection site, a phenomenon called chemotaxis. Many organisms use chemotaxis as a survival strategy, to find food or escape toxins. Previous work had shown that enzymes undergo chemotactic movement because the reactions they catalyze produce energy that can be harnessed. However, most of that work had focused on positive chemotaxis, movement towards a chemical. Until now, little work had been done looking at negative chemotaxis. "Tunable" chemotaxis--the ability to control movement direction, towards and away from different chemical signals--had never been demonstrated.

The researchers make uniformly sized protocells, tiny sacs called liposomes that have the same components that make up natural cells. They can then attach different enzymes to the outer surface of these protocells. The enzymes they used for this study were catalase, urease, and ATPase. These enzymes convert specific reactants to products; catalase for example converts hydrogen peroxide into water and oxygen.

"We place the enzyme-coated liposomes in a microfluidic device that maintains a gradient of either the enzyme's reactant or its products," said Ambika Somasundar, a graduate student at Penn State and the first author of the paper. "We can then measure the movement of the liposomes towards or away from specific chemicals."

In their experiments, catalase-coated protocells moved toward their reactant, while urease-coated protocells moved away from their reactant. ATPase-coated protocells moved both toward and away from the reactant, depending on the concentration.

"To effectively deliver drugs, you need two things: the ability to carry the drug and the ability to precisely control movement," said Sen. "The interior of the protocells that we use can be filled with a payload and we are now getting closer to finely controlling their movement."

In addition to Sen and Somasundar, the research team at Penn State includes Subhadip Ghosh, Farzad Mohajerani, Lynnicia N. Massenburg, Tinglu Yang, Paul S. Cremer, and Darrell Velegol. The research was funded by the U.S. National Science Foundation's Center for Chemomechanical Assembly.

PHILADELPHIA -- Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov. 16, at the American Heart Association's Scientific Sessions 2019.

High levels of LDL cholesterol -- which builds up in the walls of the arteries, making them hard and narrow, thereby leading to blockages -- causes increased risk of heart attacks and strokes.

"Maintaining low LDL over a sustained period is essential to reduce the risk of heart attacks and stroke," says R. Scott Wright, M.D., a Mayo Clinic cardiologist and principal investigator of ORION-10 trial.

ORION-10, a phase 3 placebo-controlled, double-blind, randomized study at 145 U.S. sites, enrolled 1,561 participants with established atherosclerotic cardiovascular disease (disease where plaque builds up in the arteries) and elevated LDL (greater than 70 milligrams per deciliters), despite maximum tolerated oral statin therapies. Participants received inclisiran or placebo by subcutaneous injections at baseline, and then at three months and every six months thereafter.

Inclisiran, developed by The Medicines Company, is a siRNA (small interfering RNA) drug and the only cholesterol-lowering medication in its class. The medication mimics a gene variant and prevents production of the protein PCSK9, which in turn lowers LDL.

Results showed that inclisiran dosed initially, and then again at three months and every six months thereafter, resulted in placebo-adjusted LDL reductions of 58% at day 510 and demonstrated time-averaged, placebo-adjusted LDL reductions of 56% from days 90 through 540.

"The data show that inclisiran dosed twice-yearly achieved durable and potent LDL reductions with an excellent safety profile, and no treatment-related liver or kidney side effects," Dr. Wright says. "Twice-yearly administration by a health care professional coincides with typical patient visits, which can help with medication adherence."

PHILADELPHIA -- Communities in the United States that experienced the most economic distress in the wake of the Great Recession saw a significant increase in death rates from heart disease and strokes among middle-aged people, according to a new multi-institution study led by researchers at Penn Medicine. While the death rates remained nearly unchanged in counties with the least economic distress (62.6 deaths per 100,000 residents in 2010; 61.5 in 2015), areas experiencing worsening economic trends--such as high unemployment, lower median incomes and lack of affordable housing--saw a sharp increase, from 122 deaths per 100,000 residents in 2010 to 127.6 deaths in 2015.

Authors say the findings, which will be presented on Monday, Nov. 18, at the American Heart Association's 2019 Scientific Sessions in Philadelphia, underscore how economic disparities contribute directly to health disparities.

"Our study shows that large economic trends--whether it's a significant reduction in employment or a recession--have a real impact on communities and on the cardiovascular health of people living in those communities," said the study's lead author Sameed Khatana, MD, a Cardiovascular Medicine fellow at Penn Medicine. "It's important that policymakers, physicians and even patients are aware of this increase in mortality rates. Interventions, such as policies like a health insurance expansion, may help slow this trend or even reverse it."

After more than 50 years of steep declines, cardiovascular death rates in the United States have been nearly stagnant since 2011--with rates even rising in some groups of middle-aged adults, according to data from the Centers for Disease Control and Prevention (CDC). Although it's known that the United States has experienced an uneven recovery following the Great Recession, it hasn't been clear whether economic factors contribute to the varying--and, in some cases, heightened--heart disease death rates in communities nationwide.

The team, which includes researchers from Beth Israel Deaconess Medical Center and Harvard T.H. Chan School of Public Health, examined county-level cardiovascular mortality rates, spanning 2010 to 20105, for adults aged 25 to 64. They also pulled county-level values for the Distressed Communities Index, which combines seven markers of economic activity, such as income, access to housing, and educational attainment. In order to identify links between cardiovascular mortality and economic distress, the team then developed a linear regression model that included a variety of factors, such as county-level health insurance coverage, the prevalence of obesity and diabetes and density of primary care providers.

They found counties with the highest Distressed Communities Index rating at baseline also had the highest baseline cardiovascular mortality and saw largest increases in deaths from 2010 to 2015. Additionally, the counties that had worsening economic distress experienced a significantly greater increase in heart disease deaths compared to counties with the lowest ratings, independent of baseline economic distress.

"We found that it's not a uniform increase--communities experiencing the most economic difficulties are the ones that are hardest-hit by heart disease deaths," Khatana said.

National Institutes of Health researchers found that a single, low-dose ketamine infusion was relatively free of side effects for patients with treatment-resistant depression. Elia Acevedo-Diaz, M.D., Carlos Zarate, M.D., and colleagues at the NIH's National Institute of Mental Health (NIMH) report their findings in the Journal of Affective Disorders.

Studies have shown that a single, subanesthetic-dose (a lower dose than would cause anesthesia) ketamine infusion can often rapidly relieve depressive symptoms within hours in people who have not responded to conventional antidepressants, which typically take weeks or months to work. However, widespread off-label use of intravenous subanesthetic-dose ketamine for treatment-resistant depression has raised concerns about side effects, especially given its history as a drug of abuse.

"The most common short-term side effect was feeling strange or loopy," said Acevedo-Diaz, of the Section on the Neurobiology and Treatment of Mood Disorders, part of the NIMH Intramural Research Program (IRP) in Bethesda, Maryland. "Most side effects peaked within an hour of ketamine administration and were gone within two hours. We did not see any serious, drug-related adverse events or increased ketamine cravings with a single-administration."

The researchers compiled data on side effects from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls who participated in one of five placebo-controlled clinical trials conducted at the NIH Clinical Center over 13 years. While past studies have been based mostly on passive monitoring, the NIMH IRP assessment involved active and structured surveillance of emerging side effects in an inpatient setting and used both a standard rating scale and clinician interviews. In addition to dissociative (disconnected, unreal) symptoms, the NIMH IRP assessment examined other potential side effects - including headaches, dizziness, and sleepiness. The study did not address the side effects associated with repeated infusions or long-term use.

Out of 120 possible side effects evaluated, 34 were found to be significantly associated with the treatment. Eight occurred in at least half of the participants: feeling strange, weird, or bizarre; feeling spacey; feeling woozy/loopy; dissociation; floating; visual distortions; difficulty speaking; and numbness. None persisted for more than four hours. No drug-related serious adverse events, cravings, propensity for recreational use, or significant cognitive or memory deficits were seen during a three-month follow-up.

To overcome the limitations associated with side effects and intravenous delivery, ongoing research efforts seek to develop a more practical rapid-acting antidepressant that works in the brain similarly to ketamine. These NIMH researchers, in collaboration with the National Institute on Aging, and the National Center for Advancing Translational Science, are planning a clinical trial of a ketamine metabolite that showed promise as a potentially more specific-acting treatment in pre-clinical studies. Meanwhile, the U.S. Food and Drug Administration earlier this year approved an intranasal form of ketamine called esketamine, which can be administered to adults with treatment-resistant depression in a certified doctor's office or clinic.

Hyoliths are extinct invertebrates with calcareous shells that were common constituents of the Cambrian fauna and formed a minor component of benthic faunas throughout the Palaeozoic until their demise in the end-Permian mass extinction. The biological affinity of hyoliths has long been controversial and the group has been compared with a number of animal phyla, most frequently the Mollusca or the Sipuncula, although other researchers have considered hyoliths as a separate "extinct phylum". However, recent discoveries of a tentaculate feeding apparatus ('lophophore') and fleshy apical extensions from the shell ('pedicle'), have resulted in hyoliths being placed within the lophophorates with a close relationship to the brachiopods.

A new article by Zhifei Zhang and his research group at Northwest University, China, together with Dr. Christian Skovsted from the Swedish Museum of Natural History have questioned this phylogenetic placement, after analyzing hundreds of hyolith fossils from the lower Cambrian (520 million years ago) Chengjiang Biota of South China (Liu et al.). In their material from South China, the first credible soft parts of an orthothecid hyolith other than the gut has been preserved in the species Triplicatella opimus.

The soft part morphology of Triplicatella opimus confirms the presence of a tentaculate feeding organ in orthothecids, demonstrating that both recognized orders of hyoliths possessed a tentaculate feeding organ. The tuft-like arrangement of the tentacles of T. opimus differs from that of hyolithids suggesting a different function of the feeding organ between orthothecid (collecting food directly from the substrate) and hyolithid hyoliths (filter feeding strategy).

A comparative study was undertaken by Liu et al., investigating the structure of the feeding organ between hyoliths and other recognized fossil and modern lophophore-bearing animals. This analysis indicated that the structure lacked many morphological features that are distinctive of a lophophore and consequently it is likely that the feeding organ of hyoliths is not a lophophore. The tuft-like morphology of the feeding apparatus of Triplicatella from South China additionally suggests that the organ was adapted to feeding on nutrients directly from the substrate rather than filter feeding as seen in younger hyolith specimens. Liu et al. further suggest filter feeding in hyoliths may have been a secondary adaption, evolving later with the appearance of helens, a mineralized structure used to lift the body of the hyoliths above the seafloor.

Recently, scientists illustrated apical structures from a species of hyolith from the Cambrian of South China, claiming that they represent an attachment structure similar to the brachiopod pedicle. A detailed analysis of the apical structures by Liu et al. have demonstrated that these structures represent crushed portions of the shell and are not in any way comparable to the brachiopod pedicle. The identical morphology of apical structures could also be observed in hyolith specimens from a nearly contemporaneous fauna (Shipai Biota) that allows for a better understanding of how this part of the shell is preserved. The similarity in ornament between the apical structure and the rest of the shell and the similarity in preservation indicates that the purported pedicle in orthothecid hyoliths represents a partly crushed apical shell section and is not a biological analogue to the complex organ that constitutes a brachiopod pedicle.

In their article for NSR, Liu et al. consider that this new evidence suggests that hyoliths did not possess a lophophore or a pedicle similar to those of brachiopods. Liu et al. instead argue that hyoliths likely occupied a more basal position in the Lophophorata, a conclusion which is strengthened by recently published data on hyolith shell structures.

Northwestern Medicine scientists have discovered a new phenomenon in the brain that could explain the development of early stages of neurodegeneration seen in diseases such as ALS, which affects voluntary muscle movement such as walking and talking.

The discovery was so novel, the scientists needed to coin a new term to describe it: mitoautophagy, a collection of self-destructive mitochondria in diseased upper motor neurons of the brain that begin to disintegrate from within at a very early age. Upper motor neurons in the brain are responsible for initiating muscle movement and relaxation and are one of the first to break down in neurodegenerative diseases.

The study was published in the journal Frontiers in Cellular Neuroscience.

The phenomenon is observed mainly in one of the most common pathologies observed in neurodegenerative diseases, TDP-43 pathology, which is seen in more than 90% of ALS cases. When a pathology is present in the body, it indicates that something is wrong or functioning abnormally.

"I think we have found the culprit that primes neurons to become vulnerable to future degeneration: suicidal mitochondria," said senior study author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. "The mitochondria basically eat themselves up very early in the disease. This occurs selectively in the neurons that will soon degenerate in patient's brains."

"This type of degeneration begins much earlier than previously thought," said study lead author Mukesh Gautam, the A Long Swim Ellen Blakeman fellow at Northwestern.

Using a process called immuno-coupled electron microscopy, the scientists investigated the cellular events that go wrong inside the neurons that become vulnerable to disease. After analyzing more than 200 neurons, they observed the self-destruction of mitochondria only in the diseased neurons, and especially within the context of TDP-43 pathology.

Mitochondria are powerhouses of the cell that create and maintain energy in the cells. In the diseased upper motor neurons, mitochondria self-destruct first by elongating, then forming a ring-like structure, until they finally disintegrate from the inside out.

It is a type of degeneration never been seen before, and it is different from previously described stages of mitochondrial degeneration.

The study analyzed mitochondria in the upper motor neurons of three different mouse models of ALS at only 15 days old - equivalent to a toddler in humans. While the study was in mice, Ozdinler and her team showed many times before that the upper neurons even in different species are almost identical at a cellular level, especially within the context of TDP-43 pathology.

These self-destructive mitochondria could become a future target for drug therapies to treat ALS and other neurodegenerative diseases in which a person's movement is affected, Ozdinler said. They are currently working with drug companies to see if drugs used for human patients with mitochondrial disease could in fact improve the health of diseased motor neurons.

"Many of the drugs currently on the market that target the health and the integrity of mitochondria may well be repurposed and considered for neurodegenerative diseases in the future," Ozdinler said. "Maybe we don't need to reinvent the wheel to cure ALS and other neurodegenerative diseases.

"To overcome neurodegeneration, we need to improve the health and the stability of mitochondria. If we improve the health of the mitochondria early, we may even eliminate protein aggregate formation, a pathology broadly observed in many diseases."

When we search for information on the Internet, buy online or use social networks we often see ads relating to our likes or profile. The fact is not everyone knows how online advertising works and what data companies are using to create personalized ads to show us. Dr. Nikolaos Laoutaris, Research Professor at IMDEA Networks, has published new research results on the detection of behavioural targeting in online advertising.

The relevancy of this study, according to Laoutaris, is that researchers can "test whether an advertisement is targeted or not, and if so, towards which demographic groups; it's fundamental for being able to check (proactively or reactively) the application of new data protection laws that, among others, put restrictions on targeted advertising".

The General Data Protection Regulation (GDPR), which came into force on the 25th of May, 2018, was adopted precisely by the European Union to return control of personal data to the individual and to unify the regulatory framework for multinationals. "GDPR defines several sensitive categories such as health, religion, political beliefs, sexual orientation all of which require special type of consent that has usually not been granted when targeted advertising happens", states, Dr. Nikolaos Laoutaris. For this reason, it's very important to identify targeted ads in order to protect specific demographic groups, like minors.

Earlier work of the IMDEA Networks Research Professor has found correlations between specific targets and some topics. For instance, it's the case of people who suffer from cancer, Alzheimer or sexually transmitted diseases.

How can users and Data Protection Authorities (DPA's) test ad targeting? There are two ways: detection via content-based analysis and count-based detection & crowdsourcing. Following these methodologies, it's possible to know if ads have been targeted to those groups protected by GDPR and FTC's Child Online Privacy Protection Act (COPPA). "By doing so they offer a valuable tool for Data Protection Authorities and can even help the advertising sector itself validate its own self-regulation programs like AdChoices [...] It is really difficult to see how these laws will be applied if there are no easy methods for detecting violators", highlights, Dr. Laoutaris.

The first method basically looks at the browsing history of a user and tries to understand the types of website he visits. Then looks for correlations between these websites and the advertisements offered. Laoutaris explains that to do that "the method needs to understand and characterise the type of content of web-sites and ads and, hence, the name content-based analysis". The second method and the latest one is, in the words of the researcher, even more powerful. Why? Because it's using frequency-based analysis so as to detect targeting. To use it, it's just needed a free to use tool called eyeWndr, which only cares to see if a particular advertisement "follows" a user across websites more than other ads. "This alone proves to be enough for distinguishing targeted from non-targeted ads", says, Laoutaris. The App is very simple to use, because it marks with a colour circle the ad and clicking above it the user can see a score: if it's high does means that ad it's targeted. The results of this study will be presented in ACM CoNEXT Conference to be held in Orlando, Florida, this December. An early version of this paper can be found here.

Going beyond online advertising, Dr. Laoutaris has presented, in a seminar celebrated at IMDEA Networks within the Science Week of Madrid, an earlier work on detecting online price discrimination as well as his community building efforts in setting up and growing the Data Transparency Lab. He found out that depending on the country you are connected you have to pay a different price for the same product. On the other hand, the researcher has talked about why it's important making online services pay users for their data.