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January 7, 2016

Research Notes

Poor, rural kids have more poisonings from medication

Children younger than 5 who live in economically disadvantaged areas had a greater risk of medication poisoning that resulted in referral to a health care facility, according to scientists at the Graduate School of Public Health and the University of California-San Diego. These areas were rural and experienced high unemployment, along with lower rates of high school graduation and lower household income.

The analysis of Pittsburgh Poison Center data, published in Clinical Toxicology, gives insight into potential geographic targets for poison prevention outreach.

Said senior author Anthony Fabio, Pitt epidemiology faculty member: “Understanding where there are geographic clusters of kids being exposed to medications that could hurt them gives us the opportunity to effectively intervene. It also could help emergency clinicians to ask the right questions and perhaps zero in on a medication exposure when a child comes in with unexplained symptoms.”

Fabio and his colleagues analyzed 26,685 Pittsburgh Poison Center records of pharmaceutical drug exposures — typically defined as ingesting a medication — in children under 5 years old from 2006 to 2010. They mapped the exposures based on whether there was simply a call to the center and advice given for treatment at home, if necessary, or if the center staff felt the exposure warranted medical evaluation and referred the child to a nearby health care facility.

By mapping the exposures in this way, the researchers revealed distinct exposure and referral locations, or geographic clusters, throughout western and central Pennsylvania. The exposure clusters generally encompass urban areas where people are perhaps more familiar with the Pittsburgh Poison Center’s hotline and, therefore, more likely to call.

The referral clusters generally are in more rural areas characterized by high unemployment. The researchers found that, in these areas, the likelihood of a child under 5 being referred to a health care facility for a medication exposure is 3.2 times greater than elsewhere.

“More study is needed to determine exactly why this is, but we believe it could be related to fewer resources for child supervision — whether at home or at day care centers in the community — increasing the likelihood of a small child finding and swallowing medication,” said Fabio.

The Pittsburgh Poison Center hotline, 1-800/222-1222, is staffed 24 hours a day and serves 44 Pennsylvania counties without charging a fee.

Said co-author Anthony F. Pizon, chief of the UPMC Division of Medical Toxicology and emergency medicine faculty member at Pitt: “We now recognize the population of children most vulnerable to potentially harmful medication exposure. Our hope is that we can better tend to the needs of these children through Poison Center outreach efforts and more effectively prevent childhood poisonings.”

The lead author on this study was Margaret B. Nguyen of Rady Children’s Hospital at the University of California-San Diego, who performed the majority of the research while at Pitt. A University of Pennsylvania researcher was a co-author.

This project was supported by the Clinical and Translational Science Institute through the National Institutes of Health (NIH).

Circadian rhythm of brain genes changes with aging

Examination of thousands of genes from nearly 150 human brains shows the circadian rhythm of gene activity changes with aging, according to a study conducted by researchers at the School of Medicine. The findings, published in the Proceedings of the National Academy of Sciences, suggest also that a novel biological clock begins ticking only in the older brain.

A 24-hour circadian rhythm controls nearly all brain and body processes, such as the sleep/wake cycle, metabolism, alertness and cognition. These daily activity patterns are regulated by certain genes that are found in almost all cells, but rarely have been studied in the human brain.

Said senior investigator Colleen McClung, psychiatry faculty member: “Studies have reported that older adults tend to perform complex cognitive tasks better in the morning and get worse through the day. We know also that the circadian rhythm changes with aging, leading to awakening earlier in the morning, fewer hours of sleep and less robust body temperature rhythms.”

In addition, the presence of gene changes or “molecular aging” in the brain previously had been shown by senior co-investigator Etienne Sibille, formerly a psychiatry faculty member and now at the University of Toronto. Both the Pitt and Toronto teams decided to look at the effects of normal aging on molecular rhythms in the human prefrontal cortex, an area of the brain involved in learning, memory and other aspects of cognitive performance.

The teams examined brain samples of 146 people with no history of mental health or neurological problems whose families had donated their remains for medical research and for whom the time of death was known. The researchers categorized the brains depending on whether they had come from a person younger than 40 or older than 60, and used a newly developed statistical technique to analyze two tissue samples from the prefrontal cortex for rhythmic activity, or expression, of thousands of genes.

Using the information they had about the time of death, they identified 235 core genes that make up the molecular clock in this part of the brain.

“As we expected, younger people had that daily rhythm in all the classic ‘clock’ genes,” McClung said. “But there was a loss of rhythm in many of these genes in older people, which might explain some of the alterations that occur in sleep, cognition and mood in later life.”

To their surprise, the team also found a set of genes that gained rhythmicity in older individuals.

This information ultimately could be useful in the development of treatments for cognitive and sleep problems that can occur with aging, as well as a possible treatment for sundowning, a condition in which older individuals with dementia become agitated, confused and anxious late in the day.

Next the researchers will explore the function of the brain’s circadian-rhythm genes in lab and animal models, as well as see if they are altered in people who have psychiatric or neurological illnesses.

Pitt co-investigators included Cho-Yi Chen, Ryan W. Logan, Tianzhou Ma, David A. Lewis and George C. Tseng.
This work was supported by the National Institute of Mental Health, part of NIH.

New genetic clues to macular degeneration

The public health school recruited hundreds of local participants and analyzed data for an international study that has significantly expanded the number of genetic factors known to play a role in age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older.

Supported by the National Eye Institute (NEI), the research findings may help improve understanding of the biological processes that lead to AMD and identify new therapeutic targets for potential drug development and predictive genetic tests. The results were published in Nature Genetics.

Said co-author Daniel Weeks, faculty member in human genetics and biostatistics: “This work opens the doors to potential new treatments for a devastating disease.”

AMD is a progressive disease that causes the death of the retinal photoreceptors, the light-sensitive cells at the back of the eye. The most severe damage occurs in the macula, a small area of the retina that is needed for sharp, central vision necessary for reading, driving and other daily tasks. There currently are no Food and Drug Administration-approved treatments for the more common form of advanced AMD, called geographic atrophy or “dry” AMD.

AMD is caused by a combination of genetic, environmental and lifestyle risk factors. For example, smoking increases the risk of the disease, while eating leafy greens and fish may reduce the risk. Up to this point, researchers had identified 21 regions of the genome, called loci, that influence the risk of AMD. The new research brings the number to 34 loci.

The International AMD Genomics Consortium, which includes 26 centers worldwide, collected and analyzed the genetic data from 43,566 people of predominantly European ancestry to systematically identify common and rare variations, called variants, in genetic coding associated with AMD. Pitt contributed data from 839 people recruited in the Pittsburgh region by former Pitt faculty member Michael Gorin, now with the University of California-Los Angeles.

As a result, the research team has discovered a total of 52 genetic variants that are associated with AMD, providing a foundation for further genetic studies of the disease. The next step is to investigate what the variants are doing to the genes and how they affect gene function — whether that be turning the genes on or off, interacting with other genes to spur a chain reaction leading to AMD, or some other action.

For the first time, the researchers also identified a variant specific to the neovascular, or “wet,” form of AMD, which may point to reasons why therapy for this form of the disease is effective for some people, but not everyone.

In addition to NEI grants, this research was supported by the National Human Genome Research Institute, the National Institute on Aging and the National Center for Advancing Translational Sciences.

Oxidation research earns two NSF grants

Judith Chun-Hsu Yang, faculty member in chemical and petroleum engineering at the Swanson School of Engineering, received two grants from the National Science Foundation (NSF) for research that will challenge classical theories of oxidation. By using electron microscopy capable of observing changes in real time, Yang will analyze the effects of oxidation on copper and the nano-structure of other metals used in a variety of industries.

Both projects take advantage of a new environmental transmission electron microscope that arrived at Pitt in August.

The first project, “DMREF: Collaborative Research: Toolkit to Characterize and Design Bifunctional Nanoparticle Catalysts,” will receive $1.2 million over three years, with $270,000 coming to Pitt. Yang will serve as co-principal investigator on the collaborative grant with the University of Texas-Austin and Yeshiva University. Using both in situ and scanning transmission electron microscopy, the researchers will look for optimal, cost-efficient combinations of metals that achieve desired reactions and catalyst formulations for industry.

Said Yang: “Industry tests catalysts empirically, trying many different combinations of metals and seeing what works. Ideally, we want to be able to use theory and computational studies to predict new catalyst structures more efficiently.”

The second grant of $300,357 will fund the project “Dynamic Atomic-scale Metal Oxidation to Correlate with Multi-scale Simulations.” Yang will work with Wissam Saidi, a mechanical and material science faculty member. The study will analyze the nanoscale stages of oxidation in metal oxides to reform outdated theories that explain environmental stability in engineered materials. Recent studies of the oxidation of copper at Pitt have revealed flaws in the common assumption that oxide formation is uniform.

“We would like to reach a fundamental understanding of how to design materials that can appropriately react with the environment,” said Yang. “Structural changes resulting from exposure to gas and heat are well known, but classic oxidation analysis mostly measures the weight change of the material. We can use an environmental transmission electron microscope during dynamic experiments to observe structural changes that occur during oxidation.”

Predicting topological phases of quantum atomic matter

Wensheng Vincent Liu has received a five-year $1.42 million grant from the Air Force Office of Scientific Research to predict and understand topological phases of quantum atomic matter — a cold ensemble of interacting atoms — under novel conditions, well beyond the standard regimes. Liu is a physics and astronomy faculty member in the Dietrich School of Arts and Sciences.

While the research is theoretical in nature, the findings are expected to motivate and guide ongoing and future experiments in atomic, molecular and optical physics, as well as provide the models for engineering novel electronic materials of the desired quantum properties in condensed matter physics. The acquired new knowledge has the potential to find applications in the future generation of precision quantum-based devices and possibly topological quantum computers and communication technology.

Trapping ultracold atoms in optical lattices has come a long way, Liu notes. A popular trend has been to use atoms to emulate condensed matter physics of electrons in solid-state materials. But, Liu says, “this project will venture into some unconventional directions that will enable us to study exciting, unique aspects of no prior analogue in solids, hence beyond the standard quantum regime. A whole new world of exotic states is expected to appear.”

Research has flourished at the interdisciplinary frontier of the fields of condensed matter physics and atomic-molecular-optical (AMO) physics. This interface area now is widely known as cold atom physics. Physicists have developed advanced experimental techniques to trap atoms and cool them down to below a few hundred degrees of nano-Kelvin. This represents the coldest temperature regime that scientists have ever achieved. Each of these alkali-metal atoms typically is several thousand times more massive than an electron. Unlike electrons, the massive atoms do not exhibit appreciable quantum effects at room temperature, not even at the liquid nitrogen temperature. They behave fully quantum once cooled to ultralow temperature.

The world of quantum particles behaves entirely differently than the classical world. One simple consequence is that each atom at such a low temperature acts as both a wave and particle at the same time, Liu says. For the wave part, they can form interference and organize together like an atom laser. “Atom laser” is a coherent matter wave, one of the most remarkable effects achieved and demonstrated in recent years in the lab of this field.

Atoms also interact with light, and physicists have found ways to use laser beams to form light crystals to trap and manipulate the atoms. These now are widely called “optical lattices.” When trapping thousands and millions of such atoms in optical lattices in the lab, one creates interacting quantum atomic matter. A number of other interesting many-body quantum phenomena are discovered or predicted. The optical lattices turn out to be one of the most flexible physical systems. It shows unprecedented tunability through manipulating the configurations of laser beams.  The research so far appears to have just scratched the surface of a field of seemingly infinite potential and possibilities.

New model of collaborative cancer research

A new system that facilitates data and biospecimen sharing among cancer centers may speed cancer research findings from the laboratory to patient care, according to a study led by School of Medicine researchers. The study was published in Cancer Research.

Researchers from UPMC CancerCenter and its partner, the University of Pittsburgh Cancer Institute, along with Georgia Regents University Cancer Center, Roswell Park Cancer Institute and the Abramson Cancer Center of the University of Pennsylvania, developed the TIES Cancer Research Network (TCRN). The researchers propose that the TCRN, a federated network that uses advanced text processing of medical reports, is a useful model to promote translational research across all cancer centers.

As the need for personalized therapies and precision medicine grows, the development of more sophisticated systems to facilitate the sharing of data and even tissue samples across centers is essential.

Said lead researcher Rebecca Jacobson, biomedical informatics faculty member and chief information officer for the Institute for Personalized Medicine: “With the TCRN, we can study rare diseases and rare behaviors of common diseases much more effectively. Investigators may not have enough cases at a single institution to support a compelling study, but they can now aggregate and access data and biomaterials across multiple institutions.”

Traditionally, cancer researchers from various institutions have collaborated through centralized networks, in which one institution accepts all of the relevant data and materials and makes it available to the others. Each individual study requires its own technology infrastructure and agreements to operate. As an alternative, the researchers set out to create one infrastructure that could be used for many studies, across many institutions, without moving any of the data.

“The centralized model cannot scale to a national network,” Jacobson said. “Every new study or new institution means more work for the central data broker, and institutions don’t want to cede their authority to manage their own data. This new network model provides the technology, legal agreements and standards needed to easily use de-identified data and tissue specimens across institutions. You can think about it like a superhighway for data and biomaterial sharing, helping researchers get there much, much faster.”

Jacobson’s team previously developed the Text Information Extraction System (TIES), a state-of-the-art language processing system that serves as the underlying technology for TCRN.

This project is supported by the National Cancer Institute.

Hybrid material has potential for 4-D printed adaptive devices

Combining photo-responsive fibers with thermo-responsive gels, researchers at the Swanson school and Clemson University have modeled a new hybrid material that could reconfigure itself multiple times into different shapes when exposed to light and heat, allowing for the creation of devices that not only adapt to their environment, but also display distinctly different behavior in the presence of different stimuli.

Computational modeling developed by Anna C. Balazs, chemical and petroleum engineering faculty member, and a Clemson colleague predicted these composites would be both highly reconfigurable and mechanically strong, signaling a potential for biomimetic four-dimensional printing. Their research, “Stimuli-Responsive Behavior of Composites Integrating Thermo-Responsive Gels with Photoresponsive Fibers,” was published in Materials Horizons.

“In 4-D printing, time is the fourth dimension that characterizes the structure of the material; namely, these materials can change shape even after they have been printed. The ability of a material to morph into a new shape alleviates the need to build a new part for every new application, and hence, can lead to significant cost savings,” Balazs explained. “The challenge that researchers have faced is creating a material that is both strong and malleable and displays different behavior when exposed to more than one stimulus.”

The study resolved this issue by embedding light-responsive fibers, which are coated with spirobenzopyran (SP) chromophores, into a temperature-sensitive gel. This new material displays distinctly different behavior in the presence of light and heat.

The researchers note that by localizing the SP functionality specifically on the fibers, the composites can encompass “hidden” patterns that are only uncovered in the presence of light, allowing the material to be tailored in ways that would not be possible by simply heating the sample. This biomimetic, stimuli-responsive motion could allow for joints that bend and unbend with light and become an essential component for new adaptive devices, such as flexible robots.

“Robots are wonderful tools, but when you need something to examine a delicate structure, such as inside the human body, you want a ‘squishy’ robot rather than the typical devices we think of with interlocking gears and sharp edges,” Balazs said. “This composite material could pave the way for soft, reconfigurable devices that display programmed functions when exposed to different environmental cues.”

As Balazs points out, “The real significance of the work is that we designed a single composite that yields access to a range of dynamic responses and structures. On a conceptual level, our results provide guidelines for combining different types of stimuli-responsive components to create adaptive materials that can be controllably and repeatedly actuated to display new dynamic behavior and large-scale motion.”

Future research will focus on tailoring the arrangements of the partially embedded fibers to create hand-like structures that could serve as a type of gripper.

If the shoe fits…

According to the Centers for Disease Control and Prevention, workplace slips, trips and falls cost the U.S. economy $180 billion each year and represent the majority of nonfatal injury costs. While injury prevention strategies can save lives and reduce costs, one factor rarely taken into consideration is footwear.
Researchers at the Swanson school are exploring techniques to better predict the wear rate of shoes in order to improve shoe design and replacement policies to reduce slip and fall accidents.

The proposal, “Impact of Worn Shoes on Slipping,” was the recipient of a four-year, $1.5 million grant from the National Institute of Occupational Safety and Health. Principal investigator is Kurt E. Beschorner, bioengineering faculty member, with co-investigators Joel M. Haight, faculty member in industrial engineering and director of the safety engineering program, and Mark S. Redfern, William Kepler Whiteford Professor of Bioengineering.

Said Beschorner: “Our primary mode of transportation is walking, and every time you move your feet you risk a slip or a trip that can lead to a fall. What we want to address is the preventative side to falling. We have preventative screenings for many health issues such as cancer. Yet relatively few studies have been done to reduce fall prevention by improving the slip resistance of shoes.”

Beschorner compared the research to advances in tire technology and tread wear. Like the grip between a car’s tires and the road, the friction between the sole of a shoe and a walking surface maintains a person’s grip to the floor. Shoes that are heavily worn have a reduced coefficient of friction (COF) and are associated with increased risk of slipping. When worn, treads can no longer channel fluids from beneath the shoe. The fluid then becomes pressurized and the COF decreases, thereby increasing the chance of a fall.

The researchers note that knowledge gaps exist regarding the factors that contribute to shoe wear rate and the wear thresholds at which the COF begins to decrease. This gap inhibits design and selection of more effective wear-resistant shoes and preventative programs that replace shoes before they become too worn. To identify the underlying causes of shoe wear and the tread thresholds where shoes become unsafe, new technology developed by the research team will simulate wear using a robotic slip-tester and measure shoe tread hydroplaning using a fluid pressure measurement system. The research also will develop computational models that can be used to predict shoe wear for new shoe sole designs.

Beschorner said: “We’ve developed novel technology to test shoe tread drainage to more precisely measure how shoe wear is impacting slipperiness. We will examine shoe wear and determine specific limits to wear, so that people know when to replace worn shoes. Then we will determine the critical factors that impact how quickly shoes wear, which can help manufacturers build a more durable shoe.”

Excess CO2 from atmosphere: A new fuel?

A team of chemical engineers in the Swanson school recently identified the two main factors for determining the optimal catalyst for turning atmospheric carbon dioxide (CO2) into liquid fuel. The results of the study, which appeared in ACS Catalysis, will streamline the search for an inexpensive yet highly effective new catalyst.

Imagine a power plant that takes the excess CO2 put in the atmosphere by burning fossil fuels and converts it back into fuel. Now imagine that power plant uses only a little water and the energy in sunlight to operate. The power plant wouldn’t burn fossil fuels and would actually reduce the amount of CO2 in the atmosphere during the manufacturing process. For millions of years, actual plants have been using water, sunlight and CO2 to create sugars that allow them to grow. Scientists around the globe now are adopting their energy-producing behavior.

Said Karl Johnson, William Kepler Whiteford Professor in the Department of Chemical and Petroleum Engineering and principal investigator of the study: “We’re trying to speed up the natural carbon cycle and make it more efficient. You don’t have to waste energy on all the extra baggage it takes to grow plants, and the result is a man-made carbon cycle that produces liquid fuel.”

There’s one catch. CO2 is a very stable molecule, and enormous amounts of energy are required to get it to react. One common way to make use of excess CO2 involves removing an oxygen atom and combining the remaining CO with H2 to create methanol. However, during this process parts of the conversion reactor need to heat as high as 1000 degrees Celsius, which can be difficult to sustain, especially when the only energy source is the sun.

A catalyst can get the CO2 to react at much lower temperatures. Some researchers have been experimenting with different materials that can get the CO2 to split, even at room temperature. But these, and most, reactive catalysts already identified are too expensive to mass-produce, and fossil fuels still offer a cheap source of energy. The low price and abundance of fossil fuels prevents a lot of companies from investing in the expensive trial-and-error process of researching new catalysts.

The study, “Screening Lewis Pair Moieties for Catalytic Hydrogenation of CO2 in Functionalized UiO-66,” provides researchers with a good idea of how they should start looking for an optimal catalyst. Johnson and co-author Jingyun Ye, a post-doctoral engineering researcher, examined a series of eight different functional groups of Lewis acid and base pairs (or Lewis pairs), which are highly reactive compounds often used as catalysts. They found that the two factors qualifying a material as a good catalyst are its hydrogen adsorption energy and the Lewis pair’s hardness — a measurement of the difference between its ionization potential and electron affinity.

Johnson plans to work with experimentalists to screen for catalysts more effectively and, ideally, bring researchers closer to creating power plants that create liquid fuel while reducing atmospheric CO2.

Doctors’ body language may show racial bias

Physicians give less compassionate nonverbal cues when treating seriously ill black patients compared with their white counterparts, a small School of Medicine trial revealed. The study examined these interactions in a time-pressured, end-of-life situation.

The finding, published in The Journal of Pain and Symptom Management, could be one reason blacks are far more likely to request extraordinary life-sustaining measures and report worse communication with their physicians.

Said senior author Amber Barnato, faculty member in clinical and translational medicine in the school:
“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues such as eye contact, body positioning and touch. Poor nonverbal communication — something the physician may not even be aware he or she is doing — could explain why many black patients perceive discrimination in the health care setting.”

Barnato and her team recruited 33 hospital-based attending emergency medicine physicians, hospitalists and intensivists from Allegheny County and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member. The actors depicted comparable medical conditions — plummeting vital signs related to either metastatic gastric or pancreatic cancer — and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the team could not derive any statistically significant conclusions about whether the physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7 percent lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” said Barnato.

She explained that something as simple as a physician staying near the door and holding a binder in front of them could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust that the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill. However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust — or mistrust — and physicians need to ensure that their body language isn’t contributing to that decision. To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Additional Pitt authors on this research were Andrea M. Elliott, Craig A. Mescher and Deepika Mohan. A colleague from Purdue University also contributed.

This research was funded by the American Cancer Society and the National Cancer Institute.

—Compiled by Marty Levine


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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