Culture

LONDON, ON - In 2012, scientists at Lawson Health Research Institute launched the world's first clinical trial comparing robotic surgery to radiation therapy for the treatment of oropharyngeal cancer (cancer at the back of the throat). The team is now reporting findings from the seven-year study which challenges beliefs that surgery leads to better swallowing outcomes, suggesting instead that radiation results in better quality of life for patients.

For Betty Ostrander, an operating room nurse from Tillsonburg, Ontario, a throat cancer diagnosis was life-changing. Betty was 59 when she discovered a small lump on the right side of her neck. After seeking medical care and testing, she was told she had oropharyngeal cancer.

"I remember thinking 'I'm healthy, I eat right and I exercise; this can't be happening to me.' But it was, and it was scary," recalls Betty. "One of the first questions I asked was whether there were any clinical trials available."

Betty was one of 68 research participants in the ORATOR trial. The study included six centres from across Canada and Australia, including London Health Sciences Centre's (LHSC) London Regional Cancer Program. Participants were randomized to receive either precision radiation therapy, often combined with chemotherapy, or transoral robotic surgery (TORS).

TORS is a surgical method for treating throat cancer which uses a small 3D camera and miniature robotic instruments to remove tumours. LHSC was the first centre in Canada to offer TORS in 2011.

"Early studies suggested TORS might reduce the risk of swallowing problems historically associated with radiation and it therefore rose quickly in popularity," explains Dr. Anthony Nichols, Associate Scientist at Lawson and Head and Neck Cancer Surgeon at LHSC. "But there was no randomized trial to compare patients' swallowing outcomes. As the first centre in Canada to offer TORS, we decided to tackle this problem through the ORATOR trial."

The research team found no difference in survival between the two groups but, surprisingly, participants in the radiation group experienced better swallowing outcomes. A mild decline in swallowing function was observed in 40 per cent of the surgery participants compared to 26 per cent of radiation participants. All participants were able eat a full diet after treatment but 16 per cent from the surgery group said they needed to specially prepare their food.

"Our findings challenge the notion that TORS leads to better swallowing outcomes," says Dr. David Palma, Associate Scientist at Lawson and Radiation Oncologist at LHSC. "While radiation was previously associated with poor swallowing outcomes, treatments have advanced considerably and are now much more precise, which may be leading to better patient outcomes."

Patients in the surgery group were also at risk for dangerous bleeding during surgery. One year after treatment, patients in the surgery group were more likely to experience pain (22 per cent versus eight per cent in the radiation group), use painkillers (45 per cent versus 15 per cent), have issues with their teeth (12 per cent versus one per cent), and experience shoulder impairment.

The team found that patients in the radiation group experienced more short-term constipation and a temporary drop in blood counts. They also experienced an increased risk of tinnitus (ringing in the ears) and high frequency hearing loss when receiving chemotherapy, with some needing hearing aids.

"Each therapy has its different potential side effects but our findings suggest that TORS is not superior to modern radiation," says Dr. Nichols. "We hope this research can be used by patients and their oncologists to help inform treatment decisions."

Cases of oropharyngeal cancer have more than doubled since the 1990s. While throat cancer was more common in elderly patients with a history of heavy smoking or drinking, physicians have seen a dramatic rise in cases caused by human papilloma virus (HPV).

There is fortunately a high survival rate in patients with HPV-related throat cancer, leading researchers to study quality of life after treatment.

Drs. Nichols and Palma recently launched the ORATOR 2 trial which will further compare TORS against radiation and chemotherapy. The goal is to reduce the intensity of radiation and chemotherapy to improve quality of life while maintaining survival rates. The team aims to recruit 140 participants.

Results from the ORATOR trial were shared by Dr. Nichols at the American Society of Clinical Oncology's Annual Meeting on May 31, 2019. The study was funded by the Canadian Cancer Society.

Researchers measured the population stock in Saleh Bay, Indonesia of the commercially valuable leopard coral grouper (Plectropomus leopardus), a species subject to population collapse due to high fishing pressure.

The researchers used yield-per-recruit modeling to evaluate population stock and to estimate a biological reference point finding that the species is in fact over-exploited in Saleh Bay.

To reduce fishing mortality, they recommend limiting the catch size and control on spear gun fishing.

A research team estimated the natural stock of reef fishes from three regencies in the lesser Sunda-Banda Seascape in Indonesia to fill gaps in knowledge of species composition and biodiversity.

Using an underwater visual census method, the team recorded a total of 176 species belonging to 19 families of economically important reef fishes.

Community structure of target fish in the three regencies is still in a relatively good condition, and there is not much difference in terms of target fish community structure between the three regencies.

Evidence that breathing in tiny particles of black carbon, typically a result of burning diesel, is linked to an increased volume of peripheral, smaller blood vessels in the lungs has been observed for the first time in new research published in the European Respiratory Journal [1].

The study adds to the evidence that exposure to diesel pollutants at what are considered relatively low levels may contribute to subtle changes in the lungs that may make people more prone to developing chronic lung disease, the third leading cause of death globally.

The researchers say the differences observed in people exposed to higher levels of black carbon were comparable in magnitude to those associated with smoking a pack of cigarettes a day for 15 years.

The project was based in the US National Heart, Lung, and Blood Institute’s Multi-Ethnic Study of Atherosclerosis (MESA) Lung and Air Pollution Studies. Lead researcher Dr Carrie Pistenmaa Aaron performed this work as an Assistant Professor at Columbia University in New York, USA. She said: “A few previous studies have suggested a link between air pollution and the pulmonary circulation, but we wanted to evaluate whether there were associations between chronic air pollution exposure and the vascular structure of the lungs. We were interested in the lung vasculature as we think it may be related to chronic lung conditions.”

The researchers analysed data for more than 3,000 people from six metropolitan areas in the USA. A team led by scientists at the University of Washington calculated participants’ long-term exposure to outdoor air pollutants using specific monitoring data from the US Environmental Protection Agency’s (EPA) monitoring database, and by analysing traffic, weather patterns and land use data.

The participants’ pulmonary blood vessels were then measured using chest CT scans between 2010-12. Each participant’s age, height, weight, sex, race and ethnicity, pack-years of cigarette smoking, exposure to secondhand smoke, medical history and other socioeconomic factors were also accounted for in the analyses, as these factors can also have an impact on lung health.

The researchers estimated that on average, study participants were exposed to annual levels of black carbon of 0.8 micrograms per cubic meter and fine particulate matter (PM2.5), another measure of air pollution that includes black carbon particles, of 11 micrograms per cubic meter.

These levels are below the current air pollution limits for PM2.5 as set by the EPA in the USA, and lower than current EU limit values for pollution. Despite this relatively low average exposure, the analyses showed that exposures to a higher level of black carbon was associated with a greater volume of blood vessels in the periphery of the lungs.

Dr Aaron explained: “Our findings suggest that long-term exposure to black carbon may impact the pulmonary circulation. No previous research has looked specifically at whether these changes in humans lead to disease, so we cannot say for certain how this may be affecting health. However, other studies of similar pulmonary vascular measures on CT and MRI in humans, in addition to a number of studies in animals, suggest that differences in the pulmonary vasculature might make people more likely to develop chronic lung disease.”

The researchers say the main contributors to black carbon levels in the cities of developed countries are diesel-fuelled vehicles, oil furnaces and coal power plants, and worldwide the major sources of black carbon are from wood burning stoves, forest fires and forest clearing.

Dr Aaron added: “There are many ways to reduce outdoor air pollution levels – they start with energy efficiency, switching to clean or renewable energy sources, and by using technology to make fossil-fuel based energy as clean as possible.”

The researchers say the study’s design may limit their conclusions, as they relied on cross-sectional observational data rather than findings from direct experiments carried out with participants. They plan to conduct further research that will look in more detail at how pulmonary blood vessels relate to chronic lung disease, and understand the biological processes involved in remodeling of the pulmonary vessels.

Professor Thierry Troosters is President Elect of the European Respiratory Society and was not involved in the research. He said: “A large proportion of the European population lives in areas with unhealthy outdoor air quality and those people are unable to avoid exposure to the harmful effects of pollution. Lots of previous research has shown that in the long term, outdoor air pollution can reduce life expectancy, affect lung development, increase asthma incidence and lead to other chronic respiratory diseases.

“This study provides interesting data on how exposure to black carbon—likely a result of burning diesel—may be damaging the lungs, and highlights further how we need strict policies for cleaner air in order to reduce the impact of pollution on health of European citizens and patients. Together with the World Health Organization, the European Respiratory Society advocates for such policies at both a European and global level.”

Four out of five people with a hidden brain condition that causes limb weakness or paralysis experience lasting physical difficulties.

Research to assess long-term effects of the disorder, called Functional Neurological Disorder (FND) - found 80 per cent of patients still had symptoms in their arms and legs 14 years after initial diagnosis.

Experts, who tracked outcomes of more than 100 patients, hope the study - the largest of its kind - will help doctors provide realistic prognoses in future and encourage more work on treatment.

In their initial studies 14 years ago, researchers found that FND is as common and disabling as better known conditions, such as multiple sclerosis. It has, however, suffered from stigma because it cannot be seen on conventional brain scans.

Doctors often describe it as a 'software' problem of the brain rather than a 'hardware' one - a condition related to how the brain processes information rather than a physical defect in its structure.

For the follow-up study, patients filled in questionnaires to assess their physical and psychiatric symptoms, quality of life and perception of their illness.

Their answers revealed that levels of physical disability and distress remained high, even after 14 years, leading to persistent and sometimes, disabling problems.

Doctors can sometimes be reluctant to give a diagnosis of FND for fear of making a mistake, the researchers say. But the team found mistakes are rare and this should not prevent them making a diagnosis using clinical signs, even if tests are normal.

The study was carried out by the Universities of Edinburgh and Groningen in the Netherlands and is published in the journal Brain.

Professor Jon Stone, of the University of Edinburgh's Centre for Clinical Brain Sciences, said perceptions of FND have changed dramatically over the past 20 years but that doctors are still likely to dismiss patients as 'imagining' or 'putting on' the condition.

He said: "Thankfully with better research and treatment those attitudes are changing. This study shows the importance of neurologists staying involved with the long-term management of patients to guide treatment and detect additional neurological conditions, which can rarely occur years after the start of FND.

"It should also help clinicians provide a more realistic prognosis for patients with FND when it causes limb weakness and stresses the importance of active and targeted treatment which many of these patients didn't have."

EVANSTON, Ill. -- An international team has constructed the most detailed, highest resolution simulation of a black hole to date. The simulation proves theoretical predictions about the nature of accretion disks -- the matter that orbits and eventually falls into a black hole -- that have never before been seen.

The research will publish on June 5 in the Monthly Notices of the Royal Astronomical Society.

Among the findings, the team of computational astrophysicists from Northwestern University, the University of Amsterdam and the University of Oxford found that the inner-most region of an accretion disk aligns with its black hole's equator.

This discovery solves a longstanding mystery, originally presented by Nobel Prize-winning physicist John Bardeen and astrophysicist Jacobus Petterson in 1975. At the time, Bardeen and Petterson argued that a spinning black hole would cause the inner region of a tilted accretion disk to align with its black hole's equatorial plane.

After a decades-long, global race to find the so-called Bardeen-Petterson effect, the team's simulation found that, whereas the outer region of an accretion disk remains tilted, the disk's inner region aligns with the black hole. A smooth warp connects the inner and outer regions. The team solved the mystery by thinning the accretion disk to an unprecedented degree and including the magnetized turbulence that causes the disk to accrete. Previous simulations made a substantial simplification by merely approximating the effects of the turbulence.

"This groundbreaking discovery of Bardeen-Petterson alignment brings closure to a problem that has haunted the astrophysics community for more than four decades," said Northwestern's Alexander Tchekhovskoy, who co-led the research. "These details around the black hole may seem small, but they enormously impact what happens in the galaxy as a whole. They control how fast the black holes spin and, as a result, what effect black holes have on their entire galaxies."

Tchekhovskoy is an assistant professor of physics and astronomy in Northwestern's Weinberg College of Arts and Sciences and a member of CIERA (Center for Interdisciplinary Exploration and Research in Astrophysics), an endowed research center at Northwestern focused on advancing astrophysics studies with an emphasis on interdisciplinary connections. Matthew Liska, a researcher at the University of Amsterdam's Anton Pannenkoek Institute for Astronomy, is the paper's first author.

"These simulations not only solve a 40-year-old problem, but they have demonstrated that, contrary to typical thinking, it is possible to simulate the most luminous accretion disks in full general relativity," Liska said. "This paves the way for a next generation of simulations, which I hope will solve even more important problems surrounding luminous accretion disks."

Elusive alignment

Nearly everything researchers know about black holes has been learned by studying accretion disks. Without the intensely bright ring of gas, dust and other stellar debris that swirls around black holes, astronomers would not be able to spot a black hole in order to study it. Accretion disks also control a black hole's growth and rotation speed, so understanding the nature of accretion disks is key to understanding how black holes evolve and function.

"Alignment affects how accretion disks torque their black holes," Tchekhovskoy said. "So it affects how a black hole's spin evolves over time and launches outflows that impact the evolution of their host galaxies."

From Bardeen and Petterson until present day, simulations have been too simplified to find the storied alignment. Two main issues have acted as a barrier for computational astrophysicists. For one, accretion disks come so close to the black hole that they move through warped space-time, which rushes into the black hole at immense speed. Complicating matters further, the black hole's rotation forces space-time to spin around it. Properly accounting for both of these crucial effects requires general relativity, Albert Einstein's theory that predicts how objects affect the geometry of space-time around them.

Second, astrophysicists have not had computing power to account for magnetic turbulence, or the stirring inside of the accretion disk. This stirring is what causes the disk's particles to hold together in a circular shape and what causes gas eventually to fall into the black hole.

"Imagine you have this thin disk. Then, on top of that, you have to resolve the turbulent motions inside the disk," Tchekhovskoy said. "It becomes a really difficult problem."

Without being able to resolve these features, computational scientists were unable to simulate realistic black holes.

Cracking the code

To develop a code capable of carrying out simulations of titled accretion disks around black holes, Liska and Tchekhovskoy used graphical processing units (GPUs) instead of central processing units (CPUs). Extremely efficient at manipulating computer graphics and image processing, GPUs accelerate the creation of images on a display. They are much more efficient than CPUs for computing algorithms that process large swaths of data.

Tchekhovskoy likens GPUs to 1,000 horses and CPUs to a 1,000-horsepower Ferrari.

"Let's say you need to move into a new apartment," he explained. "You will have to make a lot of trips with this powerful Ferrari because it won't fit many boxes. But if you could put one box on each horse, you could move everything in one go. That's the GPU. It has a lot of elements, each of which is slower than those in the CPU, but there are so many of them."

Liska also added a method called adaptive mesh refinement, which uses a dynamic mesh, or grid, that changes and adapts to the flow of movement throughout the simulation. It saves energy and computer power by focusing only on specific blocks in the grid where movement occurs.

The GPUs substantially accelerated the simulation, and the adaptive mesh increased resolution. These improvements allowed the team to simulate the thinnest accretion disk to date, with a height-to-radius ratio of 0.03. When the disk was simulated this thin, the researchers could see alignment occur right next to the black hole.

"The thinnest disks simulated before had a height-to-radius ratio of 0.05, and it turns out that all of the interesting things happen at 0.03," Tchekhovskoy said.

In a surprise finding, even with these incredibly thin accretion disks, the black hole still emitted powerful jets of particles and radiation.

"Nobody expected jets to be produced by these disks at such slight thicknesses," Tchekhovskoy said. "People expected that the magnetic fields that produce these jets would just rip through these really thin disks. But there they are. And that actually helps us resolve observational mysteries."

Cells are incredibly adept at creating complex molecules, like therapeutics, and can do so much better than many of our best factories.

Synthetic biologists look to re-engineer cells to make these molecules for specific needs, including pharmaceuticals and energy applications. But the trial-and-error process is difficult and time-consuming, and often competes with the cell's other goals and processes, like growth and survival.

A new method developed at Northwestern University combines two state-of-the-art research approaches to create a fast, efficient way to engineer and analyze metabolic pathways.

The approaches -- cell-free protein synthesis and self-assembled monolayer desorption ionization (SAMDI) mass spectrometry -- combine to make a new tool to help engineers better understand the pathways to create molecules.

"With these two methods, we can build thousands of potential mixtures and test them all in a single day, a much faster process that will give new insights and design rules for synthetic biologists," said Milan Mrksich, the Henry Wade Rogers Professor of Biomedical Engineering, Chemistry, and Cell and Molecular Biology at Northwestern's McCormick School of Engineering. He is also the co-director of Northwestern's Center for Synthetic Biology.

The results were published June 5 in the journal Science Advances. Michael Jewett, the Charles Deering McCormick Professor of Teaching Excellence, professor of chemical and biological engineering, and co-director of the Center for Synthetic Biology, is a co-corresponding author of the research.

Creating enzymes through cell-free synthesis

Cells develop complex molecules through enzymes, the protein that is used to convert one molecule to another. Through a series of these conversions, a metabolite becomes a complex molecule, one that often is associated with societal benefit.

For engineers to mimic this process, they need to identify which enzymes are required to give them the desired molecule. Once they understand that metabolic pathway, they can engineer a cell -- often a bacteria cell -- to make the enzymes to create the target molecule. For example, Coenzyme A (CoA) is a central molecule in metabolism, and synthetic biologists have used its dependent pathways to engineer antimalarial drugs, brewer's yeast, and advanced biofuels.

But finding these pathways is a trial-and-error process that can take days of effort to both engineer and then test the outcome. To get past this, Jewett's lab has developed a process of cell-free protein synthesis that creates just the enzymes needed to make the target product molecules, but without having to use the whole cell itself. Here, the lab created enzymes, which allows them to mix and match potential enzymes in reaction tubes without having their ultimate goals compete with a cell's other goals, like maintaining its metabolism.

"Cell-free protein synthesis is really an exciting technology," Jewett said. "The cocktail-based approach for constructing biosynthetic functions using cell-free systems we describe here is achieving an unprecedented freedom of design to expand the capabilities of natural biocatalysts."

Analyzing quickly with SAMDI

Once these solutions are created, testing their success requires at least a half hour per sample. Because there are so many possible solutions, that manual process is not efficient enough to search for the optimal outcomes.

That's where Mrksich's SAMDI mass spectrometry comes in. The technology measures biochemical reactions extremely quickly and cheaply. "We can easily test 10,000 reaction mixtures in a single day to determine which molecules were synthesized and how much of each is present in the reaction mixtures," Mrksich said.

Additionally, the method allows them to observe all the molecules present in the reaction, which means they can find molecules that they weren't necessarily searching for in the first place. "That's pretty exciting," Mrksich said. "It's a powerful scientific tool that teaches us about how these reactions are balanced and trade off each other in the cell."

Creating factories with cells

To prove this method, the researchers synthesized hydroxymethylglutaryl-CoA (HMG-CoA), a common metabolite used in the synthesis of many complex molecules, including a class of important molecules known as isoprenoids (including steroids and cancer drugs), and mapped more than 800 unique reaction conditions.

"Today, a typical synthetic biology project might explore dozens of variants of a pathway," Jewett said. "With our method, we show it's possible to test hundreds to thousands of pathway variations. This is important because it will enable new types of data driven design to facilitate pathway optimization."

Because the SAMDI method creates so many data points for each test, the researchers hope to employ more machine learning and artificial intelligence methods going forward to help them analyze and make sense of all the data.

The ultimate goal is to have enough of an understanding to harness the power of a cell to create next-generation pharmaceuticals and sustainable chemicals for energy. Just as rapid increases in the performance of computational devices -- described by Moore's law -- has had a profound impact on the entire computation and consumer electronics industry, "this approach represents the next step in engineering that will have an analogous impact on synthetic biology for all of its applications," Jewett said.

"Imagine replacing entire factories with a barrel of bacteria," Mrksich said. "Those bacteria cells can be engineered to produce our target molecules, without the high temperatures and unsafe solvents and chemicals that are normally required.. It's an attractive route to manufacturing chemicals, and with this new process, we've significantly improved the efficiency with which the pathways can be discovered and optimized."

More than nine million Americans know the scary feeling: sudden, severe shoulder pain and the sensation that their arm feels stuck, unable to move. "Frozen shoulder" is a common condition that happens when the connective tissues around the shoulder joint become thickened and stiff, often a result of trauma, extended use, immobilization, surgical procedures, or inflammation.

It affects more women than men, and typically strikes people between the ages of 40 and 60. Steroid shots or pain medications can sometimes manage symptoms of frozen shoulder, but there's no easy cure. As a last resort, invasive surgery can sometimes restore range of motion and relieve pain.

Researchers from Boston University and Beth Israel Deaconess Medical Center (BIDMC) found that giving relaxin in the form of several injections directly to the shoulder joint, could restore full range of motion. The results of their study were published in the Proceedings of the National Academies of Sciences.

When Beth Israel Deaconess Medical Center orthopedic surgeon Edward Rodriguez had a startling realization--some of his patients experienced lasting relief from their frozen shoulders after becoming pregnant--he hoped it could lead to a better noninvasive therapy and turned for help to Boston University scientist Mark Grinstaff, a College of Engineering Distinguished Professor of Translational Research, and his research group. The Grinstaff Group, a lab bridging BU's College of Engineering and College of Arts & Sciences, is doing research at the intersection of biomedical engineering, chemistry, and materials science engineering.

Guided by Rodriguez's hunch that biochemical changes related to pregnancy could be responsible for melting away a frozen shoulder, the team of researchers, including Boston University graduate student Will Blessing from Grinstaff's team, dove headfirst into reading everything known about pregnancy hormones.

The team's interest was piqued by a natural hormone called "relaxin," which pretty much does what its name indicates. It helps tissues stretch, an important capability for a woman's body to adjust to pregnancy and prepare for childbirth. Relaxin is present in all men and women at a low baseline level, but when a woman becomes pregnant, her body begins producing relaxin to a much higher degree.

"In everyone, relaxin helps maintain the structure of tissue so that it can function properly and not be absolutely rigid," says Blessing, who is earning a PhD in chemistry at BU. "Pregnancy kicks it into overdrive because it helps prime the uterus for childbirth and loosens up and dilates blood vessels to account for carrying blood for an extra person, without increasing the burden on the mother's heart."

Blessing, Grinstaff, and research collaborators at BIDMC, led by Ara Nazarian, tested the effects of administering relaxin to rats with stiff shoulder joints.

"It's an especially cool finding because the answer was in front of our eyes the whole time--relaxin is found in all of us naturally," Blessing says.

He credits Rodriguez for noticing a link between pregnancy and improved frozen shoulder over the course of routine checkups with his patients. Instead of just chalking it up to being a fluke, Blessing says, Rodriguez realized it could be a clinically significant observation.

For the millions of people currently coping with frozen shoulder, or any other frozen joint, the discovery brings hope that a cure is within sight. Known medically as arthrofibrosis, frozen joints affect more than five percent of the general population. For a good sense of just how common the condition is, just look to people who have undergone ACL reconstruction surgery. A third of them will go on to develop arthrofibrosis in their affected knee.

Depending on joint location and how stiff it becomes, people with a frozen joint can experience reduced quality of life and be limited in performing even the most basic activities of daily living and self-care. It can also impact their ability to work and to drive a car. If a patient doesn't respond to currently available steroid and pain management treatments, their disability can be considered permanent.

"While more research is needed, repurposing this pregnancy hormone as a treatment for arthrofibrosis could provide an unprecedented opportunity," said Nazarian, one of the study's co-corresponding authors, in a BIDMC press release.

Although their research is preliminary, Blessing is hopeful they can advance their findings so that it can help people with frozen joints go about their everyday routines more easily, no longer restricted by an elbow or shoulder that won't move as they need it to. "Someday, this might actually reverse the disease," he says.

In a Journal of Internal Medicine study that followed older adults with prediabetes for 12 years, most remained stable or reverted to normal blood sugar levels, and only one-third developed diabetes or died.

Among 918 individuals aged 60 years and older with prediabetes, 204 (22%) reverted to normal blood sugar levels, 119 (13%) developed diabetes, and 215 (23%) died. Lower systolic blood pressure, absence of heart diseases, and weight loss were linked with a higher likelihood of reverting from prediabetes to normal blood sugar levels, while obesity accelerated its progression to diabetes.

"Despite numerous studies focusing on prediabetes in the younger population, this is the first study describing the natural history of prediabetes in the older population," said lead author Ying Shang, of the Karolinska Institutet in Sweden. "The results of our study suggest that even in old age, reverting back from prediabetes to a normal blood sugar level is possible with effective weight management and blood pressure control."

A European Journal of Cancer Care study found that listening to music at home reduced the severity of symptoms, pain intensity, and fatigue experienced by patients with breast cancer.

For the study, 60 participants listened to music in five 30-minute sessions per week. After 6, 12, and 24 weeks, the music therapy reduced symptom severity, pain intensity, and overall fatigue. Furthermore, it instantaneously reduced physical and mental fatigue.

"Using music can support patients' physical and psychological well-being," said senior author Kuei-Ru Chou, PhD, RN, of Taipei Medical University, in Taiwan. The authors recommend that home-based music interventions be administered to patients with breast cancer to reduce their negative thoughts associated with cancer.

There is concern about the misuse of the sedative anti-anxiety medication alprazolam (Xanax®) because of the "high" it can create. A new British Journal of Clinical Pharmacology study found that non-medical use of alprazolam in the United Kingdom is a significant issue, and it appears to be more prevalent in younger adults.

The study examined results from a survey that included 10,019 adults in the United Kingdom. The estimated national prevalence of lifetime non-medical use of alprazolam was 0.32%, and 1.30% for diazepam (valium), another anti-anxiety medication. The prevalence of non-medical use in the last 90 days was significantly different when split by age category for alprazolam, but not for diazepam, with alprazolam non-medical use being more common among younger adults.

The authors noted that most individuals taking alprazolam for non-medical reasons are doing so without a prescription and therefore are unlikely to obtain medical advice before use.

"Further research is urgently needed to further explore the motivations for and appeal of alprazolam for non-medical use among young adults," they wrote. "This will enable appropriate public health interventions to prevent short-term toxicity and long-term dependence among young adults who are regularly using alprazolam."

A new study has uncovered an increased risk of behavioral problems in children of mothers with epilepsy who took common antiepileptic drugs during pregnancy.

In the Epilepsia study, behavioral questionnaires were completed for 181 children aged 6 to 7 years, and for most children both parents completed behavioral questionnaires.

Based on parental ratings, valproate- exposed children were most affected, but parents of carbamezepine-, lamotrigine-, and levetiracetam-exposed children also reported behavioral problems.

"It is important to monitor children of mothers with epilepsy and also consider other possible contributing factors, such as family factors. These may provide starting points for interventions to help parents cope with or even decrease child behavioral problems," said lead author Yfke Huber-Mollema, MsC, of the Stichting Epilepsy Instellingen Nederland (SEIN) and the University of Amsterdam.

Research linking economic conditions and health often does not consider children's mental health problems. In a new Health Economics study, investigators found that U.S. children's mental health worsened as the economy weakened. The use of special education services for emotional problems also rose when economic conditions worsened.

The study, which drew on data from the 2001-2013 National Health Interview Survey, found that the effects of economic conditions on children's mental health were comparable regardless of whether investigators measured economic conditions via unemployment rates or housing price indices. In addition, the effects were seen across sexes and ages (4-11 and 12-17 years of age).

"Along with providing new insight into the determinants of child mental health, our results have implications for policy responses to poor economic conditions. We confirm that the consequences of a bad economy extend beyond labor market participants," the authors wrote. "These spillover effects to child mental health suggest that policy responses to weak economic conditions may have larger effects than anticipated. Interventions like extending unemployment benefits to cushion the loss of income, for example, may have benefits for child health that get overlooked."

To treat large gaps in long bones, like the femur, which result from bone tumor removal or a shattering trauma, researchers at Penn Medicine and the University of Illinois at Chicago developed a process that partially recreates the bone growth process that occurs before birth. A bone defect of more than two centimeters is considered substantial, and current successful healing rates stand at 50 percent or less, with failure often resulting in amputation. The team hopes that their method, which they've developed in rodent models to mimic the process of rapid fetal bone growth, can substantially improve success rates. Their findings are published in Science Translational Medicine.

"When bones are originally formed in the embryo, they're first generated from cartilage, like a template," said senior author Joel Boerckel, PhD, an assistant professor of Orthopaedic Surgery and Bioengineering at the University of Pennsylvania. "In order to regenerate bone within defects that otherwise won't heal in grown people, we are seeking to recreate the embryonic bone development process."

To do that, the researchers' process begins with the delivery of specially engineered stem cells (called a condensation of mesenchymal cells) to the rodents' bone defect, which sparks endochondral ossification, the specific term for embryonic bone development.

But, the researchers note that a baby's movement in the womb is also an important factor in the process to develop new bone quickly. Therefore, the second step taken by the team to mimic bone development involved special orthopaedic plates that can be adjusted to vary the mechanical forces placed on the regenerating limbs. This allowed for some movement in the defect area that contributed to cartilage formation and blood vessel growth, key steps of endochondral ossification. Through this combination of development-like stem cell delivery and mechanical forces, bone regeneration was on par with current methods for healing defects, such as high doses of the growth factor, BMP-2, a potent protein that stimulates bone formation. However, this experimental process did not generate any of the typical adverse side effects, such as abnormal bone growth, that can result from using BMP-2.

While plates are currently used to fix serious defects, they keep the joints completely stiff and don't allow for mechanical loading. In this study, the researchers compared stiff plates to those that were "unlocked" to allow limited movement. While bone volume increased in bones that were always kept in the stiff plates, the plates that were unlocked generated far more bone growth as time went on.

"Very little has been known about how the mechanical environment in bone defects affects the capacity of transplanted cells to contribute to the regeneration of the defects," said senior author Eben Alsberg, PhD, the Richard and Loan Hill Professor of Bioengineering and Orthopaedics at the University of Illinois at Chicago. "In this work, we've shown how critically important mechanical forces are in this process when implanting stem cell condensation constructs."

Not only did the researchers look at plates that were unlocked, they also studied the differences that occurred when plates were unlocked. One set was unlocked about four weeks after they were put in place, while the others were unlocked immediately. At 12 weeks after the plates were put in place, the bone growth for plates unlocked a month in was triple that of the plates that remained stiff the entire time. For plates unlocked immediately, the bone growth was doubled what resulted from using stiff plates.

"While this work is in its early stages, it is possible that these finding could influence how non-healing bone defects are treated with respect to both fixation and other transplanted therapeutic strategies," said Alsberg.

Moving forward, the researchers feel that further preclinical studies will be required to determine how these this process and the findings therein can be used in clinic. Additionally, the long-term goal is to not only map development and regeneration processes for bones themselves, but other tissues where the potential for regeneration is limited, such as in cartilage for patients with osteoarthritis.

"Devices and techniques we develop out of this research could also influence the way we implement physical therapy after injury," Boerckel explained. "Our findings support the emerging paradigm of 'regenerative rehabilitation,' a concept that marries principles from physical therapy and regenerative medicine. Our goals are to understand how mechanical stimuli influence cell behavior to better impact patient outcomes without additional drugs or devices."

Like fishermen, Rice University bioengineers are angling for their daily catch. But their bait, biomolecules in a hydrogel scaffold, lures microscopic stem cells instead of fish.

These, they say, will seed the growth of new tissue to heal wounds.

The team led by Brown School of Engineering bioengineer Antonios Mikos and graduate student Jason Guo have developed modular, injectable hydrogels enhanced by bioactive molecules anchored in the chemical crosslinkers that give the gels structure.

Hydrogels for healing have until now been biologically inert and require growth factors and other biocompatible molecules to be added to the mix. The new process makes these essential molecules part of the hydrogel itself, specifically the crosslinkers that allow the material to keep its structure when swollen with water.

Their work, reported in Science Advances, is intended to help repair bone, cartilage and other tissues able to regenerate themselves.

Best of all, the Rice lab's customized, active hydrogels can be mixed at room temperature for immediate application, Mikos said.

"This is important not only for the ease of preparation and synthesis, but also because these molecules may lose their biological activity when they're heated," he said. "This is the biggest problem with the development of biomaterials that rely on high temperatures or the use of organic solvents."

Experiments with cartilage and bone biomolecules showed how crosslinkers made of a soluble polymer can bond small peptides or large molecules, like tissue-specific extracellular matrix components, simply by mixing them together in water with a catalyst. As the injected gel swells to fill the space left by a tissue defect, the embedded molecules can interact with the body's mesenchymal stem cells, drawing them in to seed new growth. As native tissue populates the area, the hydrogel can degrade and eventually disappear.

"With our previous hydrogels, we typically needed to have a secondary system to deliver the biomolecules to effectively produce tissue repair," Guo said. "In this case, our big advantage is that we directly incorporate those biomolecules for the specific tissue right into the crosslinker itself. Then once we inject the hydrogel, the biomolecules are right where they need to be."

To make the reaction work, the researchers depended on a variant of click chemistry, which facilitates the assembly of molecular modules. Click chemistry catalysts don't usually work in water. But with the helpful guidance of Rice chemist and co-author Paul Engel, they settled on a biocompatible and soluble ruthenium-based catalyst.

"There's one specific ruthenium-based catalyst we can use," Guo said. "Others are often cytotoxic, or they're inactive under aqueous conditions, or they might not work with the specific kind of alkyne on the polymer.

"This particular catalyst works under all those conditions - namely, conditions that are very mild, aqueous and favorable to biomolecules," he said. "But it had not been used for biomolecules yet."