Culture

Results from a pioneering clinical trials programme that delivered an experimental treatment directly to the brain offer hope that it may be possible to restore the cells damaged in Parkinson's.

The multimillion-pound study, funded by Parkinson's UK with support from The Cure Parkinson's Trust and in association with the North Bristol NHS Trust, aimed to investigate whether boosting the levels of a naturally-occurring protein, Glial Cell Line Derived Neurotrophic Factor (GDNF), can regenerate dying brain cells in people with Parkinson's and reverse their condition, which is something that no existing treatment can do.

To get GDNF to the brain cells that need it, a specially designed delivery system was developed. In total, 41 participants underwent robot-assisted surgery to have four tubes carefully placed into their brains, which allowed GDNF to be infused directly to the affected brain areas with pinpoint accuracy, via a port in the side of their head.

Six took part in the initial pilot study to assess the safety of the treatment approach. A further 35 people then participated in the nine-month double blind trial, where half were randomly assigned to receive monthly infusions of GDNF and the other half placebo infusions. After the initial nine months on GDNF or placebo, all participants had the opportunity to receive GDNF for a further nine months.

While there were some encouraging signs of improvements in those receiving GDNF, disappointingly there was no significant difference between the active treatment group and those who received placebo on any assessments of Parkinson's symptoms.

However, results from brain scans revealed extremely promising effects on damaged brain cells.

All participants had brain scans before starting the trial and after nine months to assess how well their dopamine-producing brain cells were working.

After nine months, there was no change in the scans of those who received placebo, whereas the group who received GDNF showed an improvement of 100% in a key area of the brain affected in the condition - offering hope that the treatment was starting to reawaken and restore damaged brain cells.

By 18 months, when all participants had received GDNF, both groups showed moderate to large improvements in symptoms compared to their scores before they started the study. This offers further encouragement that the treatment may have long-term beneficial effects but because everyone knew they were receiving the active treatment and there was no comparison group, these improvements need to be treated with caution.

The findings from these ground-breaking trials are published today in Brain and the Journal of Parkinson's Disease.

The trial also features in an upcoming two-part documentary series for BBC Two - The Parkinson's Drug Trial: A Miracle Cure?

Dr Alan Whone, Principal Investigator on the GDNF trial, said: "The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson's. This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson's.

"Its failure to produce the same effect on symptoms could be for a number of reasons. It may be that the effects on symptoms lag behind the improvement in the brain scans, so a longer double-blind trial may have produced a clearer effect.

"It's also possible that a higher dose of GDNF would have been more effective, or that participants at an earlier stage of the condition would have responded better.

"This is why it's essential to continue research exploring this treatment further - GDNF continues to hold potential to improve the lives of people with Parkinson's."

Dr Arthur Roach, Director of Research at Parkinson's UK, said: "While the results are not clear-cut, the study has still been a resounding success. It has advanced our understanding of the potential effects of GDNF on damaged brain cells, shown that delivering a therapy in this way is feasible and that it is possible to deliver drugs with precision to the brain.

"All the partners involved - including the scientific team, companies, charities and patients - are continuing to work together to explore possible routes to further studies. It is vital that we learn everything we can from these recent trials and we're keen to work with both the wider research community and people affected by Parkinson's so that any future trials have the very best chance of success."

Trial participant Tom Phipps, 63, from Bristol, was the first person to undergo the pioneering surgery. He said:

"Clinical trials around Parkinson's are so important because it's a condition that's not going to go away unless people do proper research. Being a scientist myself - I'm a graduate of biological sciences - I wanted to contribute.

"During the trial I noticed an improvement in my mobility and energy levels, and I was even able to reduce my medication. Since it ended, I have slowly increased my medication but I still ride my bike, dig my allotment and chair the local branch of Parkinson's UK.

"My outcome was as positive as I could have wished for, I feel the trial brought me some time and has delayed the progress of my condition.

"The best part was absolutely being part of a group of people who've got a similar goal - not only the team of consultants and nurses, but also the participants.

"You can't have expectations - you can only have hope."

Professor Steven Gill, lead neurosurgeon and designer of the device, commented: "This trial has shown that we can safely and repeatedly infuse drugs directly into patient's brains over months or years through a small implanted port that emerges through the skin behind the ear. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson's because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier.

"Even at a low dose we have seen evidence of patient improvement, which is incredibly encouraging. Now we need to move towards a definitive clinical trial using higher doses and this work urgently needs funding. I believe that this approach could be the first neuro-restorative treatment for people living with Parkinson's which is, of course, an extremely exciting prospect."

Helen Matthews, Deputy CEO at The Cure Parkinson's Trust, said: "It is fantastic to see these encouraging results. This was an extremely complex trial delivered with thanks to the dedication of the entire trial team of participants, researchers, industry and charities.

"The Cure Parkinson's Trust has been involved in and has championed the GDNF story since 2003 through the commitment and determination of the charity's late co-founder and president Tom Isaacs.

"These results, particularly the brain scans show that GDNF, delivered with Convection Enhanced Delivery, has promise as a potential treatment to slow, stop or even reverse Parkinson's. However, it is critical we now concentrate on how to best support moving GDNF forward, to understand if it can be a viable treatment to potentially regenerate dopamine cells and impact the lives of people living with Parkinson's."

Dr Erich Mohr, Chairman and CEO of MedGenesis, the biotechnology company who owns GDNF, commented: "While the results are not as clear cut as would have been desirable, when you look more closely there are exciting signs of promise for Parkinson's.

"In particular, when the scores on three of the key assessments are combined - motor response, activities of daily living and good quality "on time" - it reveals a highly significant difference between the treatment and placebo groups. We believe this experimental Parkinson's Disease Composite Response (PDCORE) may better capture the full effects of GDNF and we're working to get it scientifically validated so that it can be used in future trials."

Paul Skinner, General Manager for Neurological Products at Renishaw, the engineering company which developed and built the device, said: "It has been a privilege to work alongside the study team and with the participants in this ambitious trial.

"We are very encouraged that there were changes in the brain scans, demonstrating that GDNF is having an effect, and that the delivery system achieved precision administration of drugs into the brain.

"This provides great potential for using the drug delivery system, being developed by Renishaw, for future Parkinson's studies and experimental treatments for other neurodegenerative diseases and brain tumours."

When it comes to the immune system, we usually think about lymphocytes like B and T cells or macrophages going on constant seek-and-destroy missions against invading pathogens like bacteria and viruses. But our immune system actually includes a lesser-known and less-studied first line of defense referred to as "innate immunity".

One of the main weapons of innate immunity are a family of small peptides, collectively known as "antimicrobial peptides" or AMPs for short. AMPs are produced by the host's (e.g. the human's) cells and combat invading microorganisms by breaking apart their cell membranes or by disrupting their functions.

Despite their importance, we know very little about AMPs. Some in vitro studies have shown that they can kill bacteria and fungi, but scientists have been hard pressed to study them in living organisms. One of the reasons is that there are simply too many factors involved in innate immunity, so isolating the effect of individual AMPs in a living organism is a very complex proposition.

But now we have the tools. Scientists from the lab of Bruno Lemaitre at EPFL's Global Health Institute have used CRISPR, the gene-editing technique, to delete no less than 14 AMPs from the fruit fly Drosophila. By deleting single AMP genes, various combinations of genes, or even all 14 genes, the scientists were able to remove their corresponding AMPs and observe how their absence affected the fly's resistance to different bacterial and fungal pathogens.

The results showed that, at least in Drosophila, AMPs act mainly against Gram-negative bacteria (e.g. E. coli, Enterobacter species) and certain fungi. The AMPs also work either together or by adding up their individual effects. Surprisingly, they found that certain AMPs can be incredibly specific in defending against certain infections (e.g. the AMP diptericin against the pathogen P. rettgeri). This unexpected result highlights a previously unknown level of specificity to the innate immune response.

"What's really exciting is that these results will help us understand how our own AMPs might help fight infection," says Mark Austin Hanson, the study's first author. "It could be that some people have a defective copy of a specific AMP needed to prevent a common infection - as an example, uropathogenic E. coli - and so they are at higher risk. Fighting infection is great, but learning how to prevent it in the first place is the ideal of medicine. That's what these AMPs do: they prevent infection before it ever settles in."

But the applications of studying AMPs go even further, Hanson adds. "Studying how the fly's AMPs work can also help us manage economically important insects, whether it be protecting bumblebees or preventing mosquitoes from spreading disease."

Maasai farmers do not kill lions for retribution whenever they lose sheep or cattle, new research shows.

It is widely believed that Maasai farmers kill lions after losing livestock - even if lions are not involved - but the study shows this is not the case.

Instead, researchers from the University of Exeter and the International Livestock Research Institute in Nairobi found that lion killing only increases when lions are thought to have killed livestock.

If livestock are lost to other predators, theft, drought or disease, lion killing does not increase.

Lion killing - a criminal act in Kenya that is famously part of traditional Maasai culture - is less common now than in the past, but its causes remain controversial.

"In the drylands of southern Kenya, Maasai farmers are in direct conflict with carnivores that kill their livestock," said lead author Enoch Ontiri.

"We surveyed 213 focus groups of Maasai farmers, from three geographic regions, to test theories about the retaliatory nature of lion killing.

"We found that the probability of lion killing increases when lions are identified as culprits of livestock death, but not when leopard, cheetah, hyena, dog or jackal are identified.

"These results should change the common belief that lion killing is a retributive act caused by general loss of livestock - it is a retaliatory act against the loss of livestock to lions."

The survey of Maasai communities also showed there is universal agreement that humans and lions should coexist in Kenya.

The researchers hope their evidence will help shape the governance and mitigation of human-wildlife conflict in Kenya and beyond.

"The relationship between people and wildlife is changing rapidly in Kenya," said author Professor Dave Hodgson, Director of the Centre for Ecology and Conservation at the University of Exeter.

"Lion killing is part of traditional Maasai culture but in recent years we have seen this change from an indiscriminate act that signals passage into manhood, to a direct response to the loss of livestock.

"Our study makes it very clear that lion killing is provoked only by the loss of livestock to lions.

"We believe that better protection of livestock from predators is the solution to this important source of human-wildlife conflict."

The paper forms part of Enoch Ontiri's PhD, which is funded by the Ivan Bond Scholarship.

The research is also supported by Wildlife Direct, the British Ecological Society and National Geographic's Big Cats Initiative.

The paper, published in the journal People and Nature, is entitled: "Maasai pastoralists kill lions in retaliation for depredation of livestock by lions."

Chestnut Hill, Mass. (2/26/2019) -- New research that innovatively integrates empirical and theoretical work from economics and psychology shows how rising economic inequality makes upward mobility feel less possible among disadvantaged youth, and produces negative consequences for their motivation and behavior, a finding that should influence public policy.

The research review, titled "How Economic Inequality Shapes Mobility Expectation and Behavior in Disadvantaged Youth," was recently published in the February issue of London-based Nature Human Behavior, a monthly journal of the Nature Publishing Group. It was co-authored by Boston College's Alexander S. Browman, a post-doctoral fellow in the Lynch School of Education and Human Development, along with researchers from Northwestern University, the University of Maryland and Wellesley College.

Economic research has shown that negative life outcomes such as dropping out of high school and early pregnancy are more common among disadvantaged youth living in more unequal locations, while experimental research in psychology has explored how inequality can weaken people's beliefs about socioeconomic opportunity, which can reduce the likelihood that disadvantaged youth will engage in behaviors that would improve their chances of upward mobility. By integrating these social sciences -- typically operating separately -- and the evidence that each offers, the researchers present an interdisciplinary model that provides a more complete understanding of the dynamics underlying these issues, ideally resulting in policy recommendations that would enhance the mobility prospects for youth from disadvantaged backgrounds.

"Economists, psychologists, and other social scientists have worked to understand how economic inequality influences the life outcomes of disadvantaged youth, but research in these disciplines has proceeded largely in parallel," said Browman, a fellow in the Department of Counseling, Developmental, and Educational Psychology. "Integrating these separate lines of research, we find strong evidence that one way that economic inequality can contribute to negative outcomes for disadvantaged youth is by weakening the motivating belief that achieving socioeconomic success is possible for them."

When discussing the policy implications of this integrated model, the authors concur that reducing economic inequality would effectively improve high poverty youth's ability to move up the socioeconomic ladder. They also advocate for more immediate interventions that could increase the chances of upward mobility among low socioeconomic status youth by increasing their access to "mobility-promoting" opportunities such as mentoring programs. The authors also cite that interventions such as providing free or substantially subsidized college tuition to high-poverty youth have been successful at improving their life chances because they offer a tangible means to completing post-secondary programs.

"We are not implying that high-poverty students who avoid positive behavior do so simply because they have misguided beliefs about social mobility, and that all that is needed is to convince them otherwise," adds Browman. "People who believe that mobility is unrealistic likely hold those beliefs because society has not historically provided viable opportunities for or pathways to advancement. Interventions should entail real, systemic changes to educational, occupational and social environments that provide high-poverty youth with concrete and viable routes to future socioeconomic success and mobility in an increasingly unequal society."

Enzymes have clearly defined active sites to allow the substrate molecule to fit intricately. This is often coupled with an enzymatic conformational change prior to the occurrence of the catalysis reaction. For Ago, the catalysis step requires insertion of a "glutamate finger" to form the catalytic plugged-in conformation, which can be stabilized through hydrogen-bonding networks provided by two symmetric positively-charged residues.

For Ago in eukaryotes, these two symmetric positively-charged residues play the identical role that is critical for cleavage. Hence, it was long speculated that the two analogous resides in prokaryotic Ago perform the same critical role in cleavage function. Surprisingly, this study (Fig. 1) showed that in pAgo, only one (Arginine 545) of the two residues is involved in cleavage function. When the other one (Arginine 486) was substituted with other amino acids, the enzyme was still able to maintain its cleavage activity. Based on these results, the study further suggested that R486 may play other roles such as assisting the insertion of the glutamate finger. The discovery of such striking differences in the roles of these symmetric resides between eAgos and pAgos provides novel insights on how the cleavage functions evolve during the evolution journey from prokaryote to eukaryote.

To achieve these results, computational methods combining Quantum Mechanics, Molecular Mechanics, and Molecular Dynamics (QM/MM) were applied to elucidate the cleavage reaction mechanism and identify functional roles of the amino acid residues. This research was made possible by large-scale high-performance computing resources, which were computed equivalent to 10,000 CPU cores for 25 weeks on the Shaheen II Supercomputer at KAUST in collaboration with Prof. Xin GAO's group.

"This research was made possible due to current day computing capabilities and the precision that QM/MM modelling allows for," said Prof. HUANG Xuhui. "Comparing which amino acid residues play a key part in the target DNA/RNA cleavage step in pAgo and eAgo sheds light on how Ago protein evolves from prokaryotes to eukaryotes to cleave DNA/RNA. This information may be useful in ultimately modifying the Ago protein for use as an enhanced gene editing tool in the future," Prof. Huang explained.

Researchers at William & Mary's Virginia Institute of Marine Science have issued the first annual update of their sea level "report cards," marking 50 years of water-level observations from 1969 through 2018.

These web-based charts--available online at vims.edu/sealevelreportcard--project sea level out to the year 2050 based on an ongoing analysis of tide-gauge records for 32 localities along the U.S. coastline from Maine to Alaska. Release of this year's cards was delayed by the 35-day government shutdown, which precluded compilation of and access to NOAA's latest tide-gauge records.

The lead on the project, VIMS emeritus professor John Boon, says the report cards add value by providing sea-level projections that are updated more frequently than those issued by NOAA or other agencies.

Boon and colleagues also use a statistical approach that includes evidence for recent acceleration in the rate of sea-level change at many U.S. tide-gauge stations, and stress their use of relative sea-level measurements--changes in water level relative to the land surface on which people live and work. The relative sea-level rise in Virginia and other East and Gulf coast areas is due to both rising water and sinking land.

This year's report cards, updated using monthly summaries of daily tide gauge records from calendar year 2018, show that trends in sea-level change generally held steady across the 32 stations, although the processes that control sea level fluctuated slightly from region to region.

Molly Mitchell, the VIMS marine scientist who compiled and analyzed this year's tide-gauge data, highlights two features of the sea-level report cards for 2018.

First is the clear signal of September's Hurricane Florence as captured in the tide-gauge record for Wilmington, North Carolina. "Heavy rainfall in North Carolina contributed to high water levels at Wilmington throughout the fall," says Mitchell, "although this had only a minor impact on the long-term trend since it was a temporary increase." Florence dropped from 20 to more than 30 inches of rain across most of coastal North Carolina between September 14th and 18th.

Mitchell also notes a noticeable acceleration in sea-level rise at five of the eight monitored locations along the California, Oregon, and Washington coasts. "Although sea level has been rising very slowly along the West Coast, models have been predicting that it will start to rise faster," she says. "The report cards from the past two years support this idea." Scientists suggest that the speed-up is due to a shift in wind patterns associated with the Pacific Decadal Oscillation, an El Niño-like pattern of climate variability.

Sea level along the Gulf Coast at Grand Isle, Louisiana and Galveston, Texas continued to rise at high rates in 2018 (7.75 millimeters per year at Grand Isle and 6.19 mm/year at Galveston), while showing no sign of significant acceleration at either location. Should the lack of acceleration continue, projected sea level through 2050 for these locations will roughly equal that for Norfolk, Virginia (about 0.49 meters [1.6 feet] above 1992 levels), even though their rise rates are presently much greater--first and third highest of the 32 monitored locations.

A high rise rate (6.72 mm/year) is also found at Rockport, Texas south of Galveston but here the measured acceleration through 2018 is the highest of any location at 0.240 mm/year2, making its year 2050 projection correspondingly high at 0.78 meter (2.6 feet) above 1992 levels. Mitchell and Boon attribute the locally high rise rates and sharp contrast in acceleration among these Gulf Coast stations to their location within a sedimentary basin with a complex history of water and hydrocarbon extraction. Pumping of groundwater and oil can cause land subsidence, which contributes to relative sea-level rise.

The value of an annual, localized report card

Because long-term changes in sea level are typically on the order of a few millimeters per year, researchers have traditionally felt little need to issue frequent forecasts of sea-level changes. Moreover, many sea-level projections are global in scope, with a forecast horizon of 2100--far enough off to allow for readily discernible linear change. Thus the United Nation's oft-reported projection of 44 to 74 centimeters (1.4 to 2.4 feet) of absolute sea-level rise by the end of the century.

The VIMS team has purposefully taken a more localized and timely approach, one designed to add maximum value for coastal residents, businesses, and governments.

Says Boon, "Our report cards show what sea level has been doing recently, what's happening now at your locality. Numerous studies show that local rates of sea-level rise and acceleration differ substantially from the global rates published by the IPCC and NOAA--a key result because local rates of relative sea-level rise give a direct indication of the extent to which homes, buildings, and roads are at risk of flooding."

The team's decision to use a subset of available tide-gauge data runs counter to the traditional approach taken by NOAA, the agency that operates the nation's official network of tidal stations. "NOAA should be commended for their care in ensuring the continuity, consistency, and availability of the nation's long-term tidal datasets," says Boon. "But at the same time, a longer record isn't always better, especially when there's evidence of recent non-linear changes in the rate of sea-level rise like we see along the U.S. East Coast."

An earlier analysis by Boon showed that this acceleration began in 1987, at the center of a 36-year sliding window beginning in 1969--thus setting the start date for the VIMS report cards. This is decades after many U.S. tide-gauge stations began operation but within a span where many more stations now have complete or nearly complete records. Given recent evidence of ongoing warming, it makes sense in a nation-wide, comparative study of sea-level change to analyze only those observations made over the same period of time.

Mitchell explains further, "If you cross a threshold in terms of something like sea-level rise, what came before--say a tide-gauge record that began in 1900--is biased in terms of seeing where you're going. We think the ice sheets are melting faster today than they ever have, and if that's true then the previous 90 years of data won't accurately predict the future."

The difference between the linear rates used in NOAA's sea-level forecasts and the non-linear, accelerating rates used in VIMS' report cards can lead to sharply different forecasts of our sea-level future. Extending NOAA's linear sea-level projections to mid-century for the tide gauge in Norfolk, Virginia indicates that sea level here will be 0.3 meters (11.8 inches) higher by 2050, while the VIMS forecast--using a non-linear, accelerating rate--is 0.49 meters, or 19.3 inches. That extra 20 centimeters (8 inches) of sea-level rise would have major implications for the low-lying region.

The VIMS team moreover cautions that sea level is likely to experience short-term variations in the future just as it does today. Thus, coastal residents and planners in Virginia and other areas likely to experience significant sea-level increases by 2050 must also account for storm surges and other transient forces raising sea level even higher than the projected mean rise value. The 95% confidence bands placed about the projected quadratic curve in VIMS' sea-level report cards are a further reminder that average sea level in any given month can deviate from the projected annual mean by as much as 20 centimeters (8 inches).

ATHENS, Ohio (Feb. 25, 2019) - The damage done to America's health by the opioid epidemic is well-recognized and enormous, with drug overdose death rates helping to drive down U.S. life expectancy in recent years. Yet as the problem has worsened, American hospitals collectively have seen a loss of programs dealing with substance abuse.

That's the finding of a new paper written by faculty in Ohio University's Heritage College of Osteopathic Medicine and College of Health Sciences and Professions, and published in the journal Health Services Research. Its authors are Cory Cronin, Ph.D., CHSP assistant professor of social and public health; Berkeley Franz, Ph.D., Heritage College assistant professor of social medicine; Daniel Skinner, Ph.D., Heritage College assistant professor of health policy; and Zelalem Haile, Ph.D., M.P.H., Heritage College assistant professor of epidemiology.

The study analyzed data for 3,365 acute-care hospitals across the country, from the 2010 and 2015 installments of the American Hospital Association Annual Survey. In the time between the two surveys, it found, these hospitals showed a net loss of in-patient and out-patient opioid-related programs, even as overdose deaths continued to climb.

While some hospitals added programs during this period, a greater number discontinued them. In 2010, a total of 334 hospitals surveyed offered in-patient services and 588 offered out-patient services, but by 2015 these numbers had dropped to 327 and 577, respectively.

"Hospitals are actually backing away from these services even while we have this discussion of an epidemic and the need for services for that," noted author Cronin. That could spell problems for patients with drug dependency, Franz added.

"Hospitals play a critical role in the substance abuse services they provide and also in their ability to connect patients with local treatment and harm reduction services," she said. "We need to better understand how to support hospitals, especially in rural areas, to participate in the local opioid service infrastructure."

Why are hospitals shedding opioid programs? The paper reviews some of the more important factors that may influence a decision on whether to add, drop or continue such programs. Factors that make a hospital more likely to offer them include having more beds (larger size); being nonprofit or having a religious affiliation; being in a county with higher household income; and being in a county designated Appalachian. Hospitals are less likely to provide such substance-abuse services when their home county contains a psychiatric facility.

Hospital size, the study says, may affect a hospital's perception of its ability to afford an opioid program, while the effect of county income levels could reflect that "hospitals are more likely to offer these services if they are more confident in their patients' ability to pay."

Nonprofit public ownership and/or religious affiliation, the study says, may make hospitals "more likely to consider themselves safety net providers," and thus more willing to address the opioid crisis. "It is also likely that they are simply better situated to carry out the kind of collaborative team-based work that this treatment requires," it adds.

That having a psychiatric facility in its county makes a hospital less likely to offer opioid services, the study argues, may indicate that "if other local entities exist, hospitals may not see offering substance abuse disorder services as their responsibility beyond stabilizing acutely ill patients in the emergency room." And the fact that Appalachian counties are less likely to have such psychiatric facilities may account for hospitals in those counties being more apt to offer drug programs.

The paper calls for more research on how delivery models and payment incentives might encourage more hospitals to proactively address the opioid crisis and partner with other community-based organizations. It notes that federal law already requires nonprofit hospitals to develop programming to address needs identified through Community Health Needs Assessments, but that associated regulations are vague and often lack oversight. Reforming this process to provide more guidance and enforcement could encourage more hospital opioid programming, it suggests.

BUFFALO, N.Y. -- The federal government considers many factors when dividing money nationwide to prevent structure fires. The key driver, however, is economic losses -- for example, the greater the cost of fire within a state, the more aid that state is likely to receive.

A new model developed by University at Buffalo engineers emphasizes an additional factor: the losses associated with human fatalities and injuries. That tweak throws the current system off-track, suggesting that some states receive an outsized share of fire protection money, while others are shortchanged.

"Computer models can always be improved. We hope this will be a new tool that helps emergency planners save more lives," says the study's lead author Jun Zhuang, PhD, professor in the Department of Industrial and Systems in Engineering in the School of Engineering and Applied Sciences at the University at Buffalo.

The model, described in a study published Jan. 16 in the journal Risk Analysis, is applicable to structural fires -- those involving residential, commercial and industrial buildings. It is not intended for prevention efforts involving wildfires, vehicle fires and other outdoor fires.

The use of models to calculate costs associated with fires dates back nearly 100 years. Over the years, these models have grown more sophisticated, especially with advancements in computing and risk analysis.

An example of this is a 2017 report written by Zhuang and issued by the National Fire Protection Association. It identified the total cost of structural fires in the United States in 2014 at $328.5 billion.

In the Risk Analysis study, Zhuang and co-authors Vineet M. Payyappalli (PhD candidate in Zhuang's lab) and Adam Behrendt (a UB alumnus who studied under Zhuang) created fire risk scores for all 50 states using data from 2005-15. These scores indicate how likely someone is to be affected by a structure fire given the state they live in.

States with highest risk scores were Alaska, Montana, North Dakota, South Dakota, Vermont and Wyoming, according to the model. States with the lowest risk scores were Arizona, California, Florida, Illinois, North Carolina, New York, Pennsylvania and Texas.

The researchers also tracked how much money the federal government spent on the Assistance to Firefighters Grant (AFG) program in 2014.

They then ran the new model, which suggested that Alabama, Ohio, Pennsylvania and other states received more aid than they should have. Conversely, states such as Florida and Texas received less aid than what the model allots for.

The new model has limitations. For example, California and Texas are outliers because of their populations and gross domestic product. Also, calculations could change based on how human lives and injuries are valued.

Additionally, AFG allocations only account for less than 1 percent of state and local government expenditures. Finally, losses reported in the National Fire Incident Reporting System, under which the fire risk scores were calculated, cover only 75 percent of all fire incidents nationwide.

The team plans to further refine the model, consider other factors and update statistics to provide an even more robust tool for emergency planners.

"The model can be used for decision making not just at state-level. It can be used for counties, even ZIP codes," says Zhuang. "The more information fire protection officials have, the more informed decisions they can make, and the more lives they can help save."

Researchers at Karolinska Institutet in Sweden have discovered a new and rare skeletal disease. In a study published in the journal Nature Medicine they describe the molecular mechanism of the disease, in which small RNA molecules play a role that has never before been observed in a congenital human disease. The results are important for affected patients but can also help scientists to understand other rare diagnoses.

The newly identified skeletal disease was first observed in a parent and a child from a Swedish family.

"They came to my clinic," says the study's lead author Giedre Grigelioniene, physician and associate professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. "They'd received a different diagnosis previously, but it didn't fit with what we were seeing in the X-rays. I was convinced that we were looking at a new diagnosis that had not been described before."

A long, arduous process then began to examine the finding further. The results of these efforts are now published in a study in Nature Medicine, in which Giedre Grigelioniene and her colleagues describe the new skeletal disease - a type of skeletal dysplasia - and its mechanism.

Together with Fulya Taylan, assistant professor at the same department at Karolinska Institutet, the disease causing mutation in a gene called MIR140 was identified. The gene does not give rise to a protein but to a so-called micro-RNA (miR-140), a small RNA molecule that regulates other genes.

Working alongside with Tatsuya Kobayashi, associate professor at Massachusetts General Hospital, Harvard Medical School in Boston, USA, the researchers produced a mouse model of the disease, using the CRISPR-Cas9 "molecular scissors" technique to create a strain carrying the identified mutation. They subsequently observed that the animals' skeletons displayed the same aberrations as the three patients in the study.

The researchers also show that the identified mutation leads to an abnormal expression of several important genes in the cartilaginous growth plates and the ends of the long tubular bones. These studies were done in collaboration with Hiroshi Suzuki, researcher at the Massachusetts Institute of Technology in the lab of Phillip Sharp, Nobel laureate in medicine. Some genes that are normally suppressed by miR-140 are expressed, while others are down-regulated.

"This causes a change in skeletal growth, deformed joints and the delayed maturation of cartilage cells in the patients, who have short stature, small hands and feet and joint pain," says Dr Grigelioniene.

The identified mutation knocks out a normal function of the micro-RNA, which is replaced by a different function. The mechanism is called neomorphic and has never before been described involving small RNAs in human congenital disease. A similar mechanism in cancer cells was described last year in a paper in Nature Genetics by researchers who were also involved in the present study.

According to Dr Grigelioniene, the results now published are important both for patients with the disease and for scientists interested in how small regulatory RNA molecules are involved in the development of human congenital disease.

"We plan to examine whether similar mechanisms with mutations in small RNA genes are involved in the development of other rare congenital disorders," she says. "As for patients who already have this disease, the results mean that they can choose to use prenatal fetal diagnostic, in order not to pass the disease on to their children".

SAN FRANCISCO, C.A. - Until now it has been believed that in order for a tick to trigger an allergic immune response to alpha-gal in humans, the tick would need to have recently fed on the alpha-gal-rich blood of a mammal. New research from the UNC School of Medicine presented at the American Academy of Allergy, Asthma and Immunology (AAAAI) annual conference in San Francisco shows that may not be so.

Alpha-gal is a sugar found in most mammal blood, except humans. When humans develop an allergic immune response to it, this response can lead to a red meat allergy called alpha-gal syndrome (AGS).

"Our original hypothesis was that humans developed the allergy after being exposed to alpha-gal through a tick that had fed on a deer, dog or other small mammal that has alpha-gal," said Dr. Scott Commins, associate professor of medicine and pediatrics at UNC School of Medicine. "This new data suggests that ticks can induce this immune response without requiring the mammal blood meal, which likely means the risk of each bite potentially leading to the allergy is higher than we anticipated."

To reach these findings, researchers stripped white blood cells of their Immunoglobulin E (IgE), antibodies produced by the immune system during an allergic reaction. The stripped white blood cells were then primed with plasma from individuals with AGS and without AGS. Then, researchers added to the cells tick salivary gland extract from four species of ticks - Lone Star, Deer, Gulf Coast and American Dog. Some of the ticks had recently fed on blood containing alpha-gal, and some had not.

As researchers expected, saliva from the Lone Star and Deer ticks that recently fed on blood caused a reaction. However, saliva from those same types of tick that had not recently fed on blood also caused a reaction. Saliva from a Lone Star tick that had not recently fed caused reactivity 40 times higher compared to the control. Neither type of saliva from the Gulf Coast nor the American Dog ticks caused a reaction.

Because samples of both blood-fed and non-blood-fed tick saliva in these experiments exhibited a range of reactivity, Commins says, "These results suggest that more tick bites than we initially suspected could pose a risk for developing red meat allergy."

There is no treatment for AGS, other than avoiding foods and products that cause a reaction. Commins urges everyone to take precautions to prevent tick bites.

Whether healthy or diseased, human cells exhibit behaviors and processes that are largely dictated by growth factor molecules, which bind to receptors on the cells. For example, growth factors tell the cells to divide, move, and when to die--a process known as apoptosis.

When growth factor levels are too high or too low, or when cells respond irregularly to their directions, many diseases can result, including cancer. "It is believed that cells respond to growth factors at extreme levels of sensitivity," said University of Illinois at Urbana-Champaign Bioengineering Associate Professor Andrew Smith. "For example, a single molecule will result in a major change in cell behavior."

In a recent paper published in Nature Communications, Smith reported the invention of a new technology platform that digitally counts, for the first time ever, the amount of growth factor entering an individual cell. Prior to this, researchers inferred growth factor binding based on how the receiving cells responded when the growth factor molecules were introduced.

"We showed the first direct cause-and-effect relationships of growth factors in single cells," he said. "We expect the outcomes to lead to a new understanding of cell signaling, how cells respond to drugs, and why cell populations become resistant to drugs, particularly toward improved treatments for cancer."

Smith's technology platform tags each growth factor with a single engineered (10 nanometer) infrared fluorescent quantum dot, which can then be viewed using a three-dimensional microscope. In their study, they counted how many epidermal growth factor (EGF) molecules bound to human triple-negative breast cancer cells that were pre-patterned on island-like surfaces.

EGF molecules typically signal cell division and lead to tissue growth. Numerous cancers have mutations in their EGF receptors.

"We used quantum dots as the fluorescent probe because they emit a lot more light compared to other conventional fluorescent probes such as organic dyes, and we can tune their wavelengths by changing their chemical composition," said Bioengineering doctoral student Phuong Le, the lead author of the paper. "In our study, we demonstrated that quantum dots emitting light in the near-infrared wavelength allowed the most accurate counting of growth factors binding to cells."

According to Le, the team also treated the breast cancer cells with quantum dot-tagged EGF in the absence and presence of pharmaceutical drugs that inhibit EGF signaling in cells. "We found that the amount of EGF binding is inversely proportional to drug efficacy," Le said. "This finding is significant as it means that signaling molecules present in the cancer cells' tumor--a place where signaling molecules are often misregulated--can enhance the cancer cells' resistance to pharmaceutical agents."

When dog-parents spend extra time scratching their dogs' bellies, take their dogs out for long walks and games of fetch, or even when they feel constant frustration over their dogs' naughty chewing habits, they are gradually shaping their dogs' personalities. Dogs, like people, have moods and personality traits that shape how they react in certain situations. New findings from Michigan State University went where few researchers have gone before to reveal that, also like humans, dogs' personalities likely change over time.

"When humans go through big changes in life, their personality traits can change. We found that this also happens with dogs - and to a surprisingly large degree," said William Chopik, professor of psychology and lead author. "We expected the dogs' personalities to be fairly stable because they don't have wild lifestyle changes humans do, but they actually change a lot. We uncovered similarities to their owners, the optimal time for training and even a time in their lives that they can get more aggressive toward other animals."

Additionally, Chopik found that dogs' personalities can predict many important life outcomes. For example, canines' personalities will influence how close they feel to their owners, biting behavior and even chronic illness.

The research, published in Journal of Research in Personality, is one of the first - and is the largest - studies of its kind to examine changes in dogs' personalities. Chopik surveyed owners of more than 1,600 dogs, including 50 different breeds. Dogs ranged from just a few weeks old to 15 years, and were split closely between male and female. The extensive survey had owners evaluate their dog's personalities and answered questions about the dog's behavioral history. The owners also answered a survey about their own personalities.

"We found correlations in three main areas: age and personality, in human-to-dog personality similarities and in the influence a dog's personality has on the quality of its relationship with its owner," Chopik said. "Older dogs are much harder to train; we found that the 'sweet spot' for teaching a dog obedience is around the age of six, when it outgrows its excitable puppy stage but before its too set in its ways."

One trait that rarely changes in age with dogs, Chopik said, was fear and anxiety.

Honing in on the saying, "dogs resemble their owners," Chopik's research showed dogs and owners share specific personality traits. Extroverted humans rated their dogs as more excitable and active, while owners high in negative emotions rated their dogs as more fearful, active and less responsive to training. Owners who rated themselves as agreeable rated their dogs as less fearful and less aggressive to people and animals.

The owners who felt happiest about their relationships with their dogs reported active and excitable dogs, as well as dogs who were most responsive to training. Aggression and anxiety didn't matter as much in having a happy relationship, Chopik said.

"There are a lot of things we can do with dogs - like obedience classes and training - that we can't do with people," he said. "Exposure to obedience classes was associated with more positive personality traits across the dog's lifespan. This gives us exciting opportunities to examine why personality changes in all sorts of animals."

Chopik's findings prove how much power humans have over influencing a dog's personality. He explained that many of the reasons a dog's personality changes are a result of the "nature versus nurture" theory associated with humans' personalities.

Next, Chopik's will research will examine how the environment owners provide their dogs might change the dogs' behavior.

"Say you adopt a dog from a shelter. Some traits are likely tied to biology and resistant to change, but you then put it in a new environment where it's loved, walked and entertained often. The dog then might become a little more relaxed and sociable," Chopik said. "Now that we know dogs' personalities can change, next we want to make strong connection to understand why dogs act - and change - the way they do."

Neighbourhood income and education level is associated with risk of disability progression in patients with multiple sclerosis, suggests new research from the University of British Columbia.

UBC researchers, along with colleagues in Wales, compared population health data across several measures of socioeconomic status, and found that lower neighbourhood-level income and educational attainment was associated with an increased likelihood of reaching key physical disability milestones, such as difficulties with walking.

The findings--published online today in Neurology®, the medical journal of the American Academy of Neurology--paint a clearer picture of the way that wealth and education might affect patients with MS.

"This study is the first of its kind," says the study's senior author Helen Tremlett, professor in the division of neurology at UBC and the Canada Research Chair in neuroepidemiology and multiple sclerosis. "Previous studies have looked at the relationship between socioeconomic status and risk of developing MS. Here, we were able to show a relationship between socioeconomic status and subsequent risk of disability progression."

MS is a chronic inflammatory disease that occurs when the body's immune system attacks myelin, the fatty material that insulates neurons to enable rapid transmission of electrical signals. When myelin or neurons are damaged, communication between the brain and other parts of the body is disrupted leading to impaired ability including vision problems, muscle weakness, difficulty with balance and coordination, and cognitive decline. Most people who live with MS will experience some form of reduced ability.

As the Welsh and Canadian systems for tracking population health data are similar, the team was able to access comparable information for the two groups of patients. For the Canadian patients, the team determined socioeconomic status based on census data, which links postal codes with neighbourhood-level income. Clinical information from a provincial MS database was linked with population-based provincial health administrative data. The Welsh patients were assessed by linking similar datasets, including National Health Service information, postal code-related income data and educational attainment.

A key component of this study was that the data on socioeconomic status were captured before MS onset, therefore predating any possible effect of the disease itself on socioeconomic status.

The researchers did not look at specific factors that might explain the relationship between lower socioeconomic status and higher risk of disability progression, but they suggest that modifiable lifestyle factors, such as diet and exercise, could be involved.

"If that is the case, the risk may be amenable to change," says Tremlett. "One of the next steps is to understand why this relationship exists."

North Vancouver resident Marilyn Lenzen, who was diagnosed with MS nearly two decades ago, says she wasn't surprised to learn that researchers have now established a clear link between socioeconomic status and disability progression in patients with MS.

"I'm glad to see that there is now research that backs up what I and many in the MS community have been experiencing for years," says Lenzen. "Someone who has the financial means to buy healthier food or afford to participate in yoga, pilates or specialized exercise to rebuild their strength after a relapse doesn't experience the same progression of disabling symptoms as others who can't afford to access the same healthy lifestyle choices."

After her diagnosis, Lenzen, now 59, could no longer keep up with the long hours and extensive travel required by her corporate job. When she gave up her job, however, she also lost her extended health benefits and experienced a significant decline in household income.

"When I was first diagnosed, I remember having to crawl on my knees up the stairs to get to bed every night," she recalls. "But I was determined to exercise and to keep my muscles strong. I took up cycling and with the assistance of an e-bike, cycled 3,000 kilometres last year.

"I do still have occasional relapses but the relapses are not as bad and I have the strength in my body to rebuild again. I wish that everyone with MS, regardless of their socioeconomic status, has the same lifestyle opportunities to slow the progression of their disease."

The researchers hope that future MS studies will consider the socioeconomic status of participants, especially if multiple study sites are involved and findings are compared across regions, as their socioeconomic status could be an important factor in disability progression.

Fact: About 66 million years ago, at the end of the Cretaceous period, 75 percent of plant and animal species went extinct, including the dinosaurs (except those that evolved into birds).

Fact: About 66 million years ago, an enormous asteroid or comet hit the Earth near what is now Chicxulub, Mexico, throwing rock, dust and water vapor into the atmosphere.

Fact: About 66 million years ago, a massive volcano erupted lavas in India that are now called the Deccan Traps, burying much of the subcontinent under more than 11,000 feet of basalt (lava rock) and pouring poisonous gases into the atmosphere.

Princeton geoscientists Blair Schoene and Gerta Keller led an international team of researchers who have assembled the first high-resolution timeline for the eruptions in India's Deccan Traps. Their research appears in the Feb. 22 issue of the journal Science.

"Everyone has heard that the dinosaurs died from an asteroid hitting the Earth," said Schoene, an associate professor of geosciences. "What many people don't realize is that there have been many other mass extinctions in the last 500 million years, and many of them coincide with large volcanic outpourings" from the massive volcanoes known as flood basalts or large igneous provinces.

Keller, a professor of geosciences, has argued for decades that the eruption of the Deccan Traps caused the dinosaur mass extinction. In 2013, she, Schoene, and his students began trying to find the ages of the thick layers of lava, which were known to be about the right age but had never been precisely dated.

Schoene uses several techniques for geochronology, the science of assigning ages to rocks. The most famous geochronology technique, usually called "carbon dating," uses the decay rate of radioactive carbon-14 to find fossils ages. That works for plants or animals that are a few thousand years old, making it useful for archaeology but not for 66-million-year-old basalt. For rocks from around the time of the mass extinction, geoscientists have a few choices of naturally radioactive materials. Uranium-lead geochronology yields very precise ages, but minerals containing uranium rarely occur in basalt, the rock that makes up the massive lava flows; uranium-bearing zircon is more often found in explosive eruptions from Mount St. Helens-type volcanoes, which have a more silica-rich chemistry.

The researchers were aware that the odds were stacked against them. "I don't think that any of us anticipated that our first trip to the Deccan Traps would lead to the type of dataset that we were able to produce," said Mike Eddy of the Class of 2011, now a postdoctoral research associate in geosciences and a co-author on the Science paper.

For the first few days, the researchers gathered samples of coarse-grained basalts, trying unsuccessfully to find uranium-bearing minerals. Then came a stroke of luck.

"During our first week in India, we found a high-silica ash bed between two basalt flows, and it got our gears turning," Eddy said. The researchers knew that silica-rich volcanic ash could easily contain the tiny zircon crystals that preserve radioactive uranium. "The real breakthrough came a day or two later, when Blair realized that the fossil soils may have also collected this type of ash in small amounts," Eddy said.

In other words, instead of focusing on the lava flows themselves, the researchers shifted their focus to the zircon crystals found in the layers of ash in soil between the lava beds. By precisely dating zircons that were deposited before and after the Deccan Traps lava flows, they could tightly constrain when the volcano must have erupted.

Over three field seasons, the researchers gathered samples from more than a hundred sites and shipped them back to the lab at Princeton. "It is always entertaining when we ship samples at the end of the trip," said Eddy. "This frequently involves a full day, starting with finding cardboard boxes that have enough structural integrity to make it back to the USA, packing said boxes, a visit to the post office to pick up the necessary forms and have the boxes inspected, a visit to a cloth shop to buy canvas, a visit to a tailor to have the boxes sewn into canvas bags, traveling around town to numerous ATMs to collect enough cash to ship the boxes internationally, and a final few hours of paperwork and stamps to get the boxes out the door. In total, the entire process can take up to 12 hours."

Of the 141 sample sites, 24 yielded uranium-bearing zircon crystals, which allowed the research team to conclude that the Deccan Traps erupted in four distinct pulses, each time belching enormous volumes of sulfur and carbon dioxide into the atmosphere. The thousands of tons of lava would have killed anything living nearby, but the gases reached around the world.

Sulfurous gases can cool the atmosphere in the short term, while carbon dioxide warms it in the long term. When volcanoes release enormous volumes of both, "these can lead to climate swings between warm and cold periods that make it really hard for life on Earth," said Schoene. To determine how big an effect it would have had, they needed to constrain the timing of the eruptions: Tons of carbon dioxide erupted in a hundred years will have very different effects than the same volume outgassed over the course of a million years.

Of the four eruption pulses, two took place before the mass extinctions, with the second beginning only tens of thousands of years before the Chicxulub impact -- a geologically short amount of time. "The first two pulses ... correspond with a period of time where climate fluctuated from cold to hot to cold again, and many scientists think this indicated an initial disruption to the climate that may have contributed to the mass extinction event," said Schoene. "Our data show that maybe the second pulse could have played an important role in the extinction itself because it happened right before it."

Keller is more definitive in her conclusions: "Deccan volcanism is the most likely cause of the dinosaur mass extinction," she said. "The Chicxulub impact may have contributed to their demise, though the timing and environmental effects of this impact still remain to be determined."

"In general, I think this paper is significant and interesting," said Pincelli Hull, an assistant professor of geology and geophysics at Yale who was not involved in this research and who has argued against the role of the volcano in the mass extinction. "The paper is a huge advance in timing the [Deccan Traps] eruptions, but how that relates to the timing of outgassing is still a major question that needs to be resolved to figure out exactly what the relevant roles of volcanism and impact were."

The researchers will continue to tease apart the effects of the one-two punch of the Deccan Traps eruptions and the planet-shaking impactor, said Eddy. "Regardless, it seems like the end-Cretaceous was a terrible time to be on Earth."

MINNEAPOLIS, MN- February 22, 2019 - Nearly 3 million Americans are living with atrial fibrillation (AFib), which is described as quivering or irregular heartbeat (arrhythmia). With increasing lifespan and increasing prevalence of risk factors such as obesity, experts believe the number of people living with AFib will increase at an exponential rate in the next decade. This has important public implications since AFib is associated with a higher risk of stroke, heart failure, cognitive decline and dementia, and death.

Lin Yee Chen, MD, MS, Associate Professor with Tenure, Cardiovascular Division, in the Department of Medicine with the University of Minnesota Medical School was part of a Writing Committee tasked with updating the 2014 guidelines for patients with AFib. The 2019 American College of Cardiology/American Heart Association/Heart Rhythm Society Guidelines for the Management of Patients with Atrial Fibrillation were just published in Circulation, the Journal of the American College of Cardiology, and Heart Rhythm as the standard for the management of Afib in the U.S.

"These guidelines are written for all physicians in all specialties," said Chen. "It doesn't matter whether the clinician is an orthopedic surgeon, gynecologist, oncologist or brain surgeon, everyone is bound to encounter AFib in their patients because it is so prevalent."

One section of the new guidelines speaks to guiding practitioners across the whole spectrum of medicine, focusing on the use of new blood thinners or anticoagulants in people with AFib. The new guidelines help determine how and when to use these new agents, including in a situation that involves surgery.

Another portion of the document addresses the management of AFib in different scenarios, such as patients who have developed heart attacks.

"AFib patients are put on blood thinners to prevent stroke. When we need to perform procedures like a coronary angioplasty to open up any blockage in the heart arteries during a heart attack in AFib patients, we will also have to prescribe other agents called antiplatelets which when used in combination with blood thinners can elevate significantly the risk of bleeding, which is a real dilemma." said Chen. "Current research is now in favor of double therapy- one antiplatelet agent and one anticoagulant, as opposed to two antiplatelets and an anticoagulant."

A final section addresses the importance of weight-loss and weight management in improving the outcomes in people with AFib. In recent years, there is increasing evidence to suggest that lifestyle modification such as weight loss and physical activity can reduce the frequency and the burden of AFib. This has been incorporated into the new guidelines.

"The University of Minnesota could potentially make some significant contributions in the field of lifestyle modification and AFib," explained Chen. "Currently, I am the Principal Investigator of an Academic Health Center Faculty Research and Development grant which funds a randomized controlled trial aimed at evaluating different exercise protocols in reducing the burden of AFib.

"Being represented on the Writing Committee is a great honor for the University of Minnesota Medical School, because ultimately, the point of our research is to influence and impact the way we practice medicine," said Chen. "I think this is testimony to the outstanding research we perform for AFib at the University of Minnesota which is recognized by the American Heart Association and the American College of Cardiology."