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March 16, 2017

Research Notes

Exoskeleton to help impaired patients safely walk

The promise of exoskeleton technology that would allow individuals with motor impairment to walk has been a challenge for decades. A major difficulty to overcome is that even though a patient is unable to control leg muscles, a powered exoskeleton still could cause muscle fatigue and potential injury.

However, the three-year, $400,000 award from the National Science Foundation’s (NSF) cyber-physical systems program will enable Pitt researchers to develop an ultrasound sensor system at the heart of a hybrid exoskeleton that uses both electrical nerve stimulation and external motors.

Principal investigator is Nitin Sharma, mechanical engineering and materials science faculty member in the Swanson School of Engineering. Co-PI is Kang Kim, medicine and bioengineering faculty member. The Pitt team is collaborating with researchers at George Mason University, who also received a $400,000 award for the cyber-physical systems proposal.

This latest funding furthers Sharma’s development of hybrid exoskeletons that combine functional electrical stimulation (FES), which uses low-level electrical currents to activate leg muscles, with powered exoskeletons, which use electric motors mounted on an external frame to move the wearer’s joints.

Said Sharma: “One of the most serious impediments to developing a human exoskeleton is determining how a person who has lost gait function knows whether his or her muscles are fatigued. An exoskeleton has no interface with a human neuromuscular system, and the patient doesn’t necessarily know if the leg muscles are tired, and that can lead to injury. Electromyography (EMG), the current method to measure muscle fatigue, is not reliable because there is a great deal of electrical cross-talk between muscles and so differentiating signals in the forearm or thigh is a challenge.”

To overcome the low signal-to-noise ratio of traditional EMG, Sharma partnered with Kim, whose research in ultrasound focuses on analyzing muscle fatigue.

Said Kim: “An exoskeleton biosensor needs to be noninvasive, but systems like EMG aren’t sensitive enough to distinguish signals in complex muscle groups. Ultrasound provides image-based, real-time sensing of complex physical phenomena like neuromuscular activity and fatigue. This allows Nitin’s hybrid exoskeleton to switch between joint actuators and FES, depending upon the patient’s muscle fatigue.”

In addition to mating Sharma’s hybrid exoskeleton to Kim’s ultrasound sensors, the research group will develop computational algorithms for real-time sensing of muscle function and fatigue. Human subjects using a leg-extension machine will enable detailed measurement of strain rates, transition to fatigue, and full fatigue to create a novel muscle-fatigue prediction model. Future phases will allow the researchers to develop a wearable device for patients with motor impairment.

“Right now an exoskeleton combined with ultrasound sensors is just a big machine, and you don’t want to weigh down a patient with a backpack of computer systems and batteries,” Sharma said. “The translational research with George Mason will enable us to integrate a wearable ultrasound sensor with a hybrid exoskeleton, and develop a fully functional system that will aid in rehabilitation and mobility for individuals who have suffered spinal cord injuries or strokes.”

Women less likely to be speakers at grand rounds

Women are less likely than men to be chosen as speakers during grand rounds, the academic mainstay of expert-delivered lectures used to share patient-care guidelines and cutting-edge research within clinical departments. Those findings by researchers at the School of Medicine were published in JAMA Internal Medicine.

Despite women comprising 47 percent of medical students, 46 percent of residents and 36 percent of faculty nationwide, only 26 percent of grand rounds speakers were women. Across clinical specialties, grand rounds speakers were 44 percent less likely to be women among medical students, 39 percent less likely among residents and 21 percent less likely among faculty. Additionally, speakers invited from outside institutions were less likely to be women than those invited to speak at grand rounds from among an institution’s own personnel.

Said Julie Boiko, who led the study while a student at the School of Medicine: “The people at the podiums do not resemble the people in the audience. While gender representation and equality in medicine has been an important area of student discussion in recent years, this is the first time we have data to support that there may be a gender bias in speaker selection at academic grand rounds.”

Data for the research was collected from nine major clinical specialties and 79 medical schools and academic hospitals. In total, researchers analyzed more than 200 grand rounds websites and calendar listings for speaker series, as well as more than 7,000 individual sessions for speaker gender and institutional affiliations.

As follow-up to this study, researchers plan to identify specific factors associated with having greater gender balance on grand rounds speaker rosters.

Said Alyce Anderson, coauthor of the study and an MD/PhD candidate in the School of Medicine: “We were surprised by the consistency of this underrepresentation across most specialties and the discovery that speakers invited from outside a given institution are less likely to be women than speakers invited from within the institution. With this data, speaker planning committees, departments and institutions can strive for gender representation that approximates that of individual clinical specialties’ faculty and/or trainees. Such efforts may have a positive effect on retaining women in the academic medical workforce.”

Rachael Gordon, an MD/PhD student in the School of Medicine, was a co-author on the study.

Boiko now is a resident physician in the Department of Pediatrics at the University of California-San Francisco.

New center to study diseases linked to misshapen proteins

Through a comprehensive understanding of how to fix protein architecture when it goes awry, Center for Protein Conformational Diseases researchers will be positioned to improve prognoses for millions of people with debilitating diseases.

The new center, set to launch in April, is one of only two in the United States.

The center will bring together faculty members across 15 academic departments as well as nine other Pitt centers and researchers from Duquesne University to hunt for breakthroughs in protein breakdown.

Said center director Jeffrey Brodsky, a molecular biologist and Department of Biological Sciences faculty member: “The center was a way to codify the research relationships we’ve already been having for many years.”

Brodsky likens the protein problems to the real estate market. Consider a neighborhood of houses spanning all styles: Victorian, Georgian, classical, modern. All are distinct and comfortably lived in. But then a few families move away, and their homes are left vacant. Over time, the vacant houses become derelict, and the neighborhood’s property values depreciate.

So, too, in the ecosystem of the human body, Brodsky said. Approximately 23,000 proteins, each with its own structure and function, are responsible for keeping us healthy by sustaining our systems. Biochemical maintenance crews, which include a family of proteins appropriately known as “molecular chaperones,” help keep a neighborhood watch. “If a specific protein becomes misshapen, basically a cellular bulldozer wipes out that house,” he explained. “Typically that’s a good thing, so that cellular property values don’t fall.”

But as we age “the cellular bulldozer driver starts to take longer holidays,” Brodsky added. Misshapen proteins accumulate and stop performing their essential functions. The result is any number of ailments, ranging from cystic fibrosis, Alzheimer’s disease and Parkinson’s disease to some types of kidney and liver disease and certain cancers.
“Ultimately, if we survive other bad things that can happen earlier in life,” Brodsky said, “eventually we will die from one of these diseases.”

3 engineering faculty win CAREER awards

For the first time, three researchers from one department were recognized simultaneously with the NSF’s most significant award in support of junior faculty. John Keith, Giannis (Yanni) Mpourmpakis and Christopher Wilmer, all chemical and petroleum engineering faculty members in the Swanson school, received individual NSF CAREER awards, which the NSF says were created to “recognize faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organizations.”

Each received $500,000 in funding for the five-year awards.

• Keith, inaugural R.K. Mellon Faculty Fellow in Energy, won for “SusChEM: Unlocking Local Solvation Environments for Energetically Efficient Hydrogenations With Quantum Chemistry.” This project will address the production of carbon-neutral liquid fuels via electrocatalytic reduction of carbon dioxide (CO2) to methanol. Its focus will integrate high-level electronic structure theory, molecular dynamics and machine learning to understand how interactions between solvent molecules, salts and co-solutes regulate CO2 reduction from greenhouse gas into fuels. Keith’s graduate and undergraduate students will develop educational modules to engage students in Pittsburgh Public Schools about opportunities in STEM fields, with an emphasis on renewable energy and computational chemistry.

• Mpourmpakis won for “Designing Synthesizable, Ligand-Protected Bimetallic Nanoparticles and Modernizing Engineering Curriculum Through Computational Nanoscience.” Although scientists can chemically synthesize metal nanoparticles (NPs) of different shapes and sizes, understanding of NP growth mechanisms affecting their final morphology and associated properties is limited. With the potential for NPs to impact fields from energy to medicine and the environment, determining with computer simulations the NP growth mechanisms and morphologies that can be synthesized in the lab is critical to advance NP application. Because this is a relatively new field, traditional core courses in science and engineering lack examples from the nanotechnology arena. In addition to improving the research, the award will enable Mpourmpakis and his students to modernize the traditional course of chemical thermodynamics by introducing animation material based on cutting-edge nanotechnology examples and developing a nanoscale-inspired interactive computer game.

• Wilmer won for “Fundamental Limits of Physical Adsorption in Porous Materials.” The development of new porous materials is critical to improving important gas storage and separations applications, and will have a positive impact on reducing greenhouse gases. This includes the deployment of methane and/or hydrogen gases as alternative fuels, development of new filters for removing trace gaseous contaminants from air, and separation of carbon dioxide from flue gas to mitigate greenhouse emissions from the burning of fossil fuels. Wilmer’s grant will enable his lab to use computational methods to probe the limits of material performance for physical adsorption to porous materials. Although past computational screening has suggested physical limits of adsorption capacity for metal-organic frameworks, this project will explore the novel use of so-called “pseudomaterials,” which represent all potential atomistic arrangements of matter in a porous material. As part of community outreach, Wilmer’s research group will develop educational movies on the fundamental science of gas adsorption, including those relevant to carbon capture to mitigate climate change.

Why violent music appeals to teens

Back view of a young man with headphones posing in the city streAs a teenager listening to his favorite “emo” CD, Joshua Groffman always skipped one track. Repelled by the overt violent imagery, he couldn’t help but wonder, “Am I sick if I listen to this?”

Now as music faculty member at Pitt-Bradford, he is revisiting this genre to understand its appeal to teens and preteens, presenting “‘I Know What You Feel Like’: Harming Ourselves and Others in the Emo Genre” at the International Association for the Study of Popular Music annual U.S. conference.

Emo grew out of the punk movement and became popular in the 1990s. While emo has punk traits such as “extreme distortion and blistering tempi,” Groffman explained, one of its defining traits is the “aggressively thin, nasally timbre that is purposely immature.”

“Emo really is rooted in teenagers singing to teenagers,” he said of the vocal style.

Aside from musical traits, the subject matter of the genre is entrenched in the agony of adolescence. Lyrics are almost entirely self-referential, without consideration of politics, the culture at large or even non-teenagers.

Sometimes that expression takes the extreme form of violent imagery. The graphic intensity of some of the images — exposed viscera and blood, for example — “become a stand-in for the intensity of youthful feeling, the indignities of growing up.”

While Groffman argues that the brutality is metaphoric, he also acknowledges that it can still be troubling, particularly in the post-Columbine era.

Telephone care can ease anxiety

Nervous businesswoman bites fingernails during telephone conversA telephone-delivered collaborative care program for treating panic and generalized anxiety disorders in primary care is significantly more effective than doctors’ usual care at improving health-related quality of life, anxiety and mood symptoms, according to a study by researchers at the School of Medicine. These findings from the Reduce Limitations from Anxiety (RELAX) trial, funded by the National Institutes of Health (NIH), were published in the Journal of General Internal Medicine.

Researchers enrolled 329 patients 18-64 years old who were referred by their primary care physicians from six UPMC-affiliated practice locations. Approximately 250 patients were rated “highly anxious” and randomized to either the telephone-delivered intervention or to their primary care physician’s usual care. The other 79 patients with “moderate” levels of anxiety symptoms were assigned to a “watchful waiting” group and later randomized if their anxiety symptoms worsened.

A study care manager regularly called patients in the intervention group to provide basic psycho-education; encourage healthy habits (sleep, exercise, avoid excess alcohol); assess treatment preferences for anti-anxiety medications; monitor response to treatment; and inform their primary care physicians of their care preference and progress.

At 12-months’ follow-up, anxiety symptoms remitted in 53 percent of intervention patients versus only 32 percent of patients who continued to receive their primary care physicians’ usual care, and the intervention also produced similar significant improvements in health-related quality of life, panic and mood symptoms. These benefits persisted for another year after the intervention ended. African Americans and men reported the greatest levels of improvement, and the 79 patients who reported moderate levels of anxiety at baseline generally did well over the course of follow-up, whether they were later randomized to the study intervention or not.

Bruce Rollman

Bruce Rollman

Said Bruce L. Rollman, medicine faculty member and director of the Center for Behavioral Health and Smart Technology: “While dozens of clinical trials have demonstrated the effectiveness of collaborative care for treating depression in primary care, comparatively few have addressed anxiety, despite their similar prevalence and adverse impact on health-related quality of life and excess utilization of health services. Effective collaborative care for anxiety can be provided via telephone by college-educated, non-mental health care managers who follow an evidence-based treatment algorithm and work under the direction of a primary care physician.”

Others from Pitt involved in the study were Bea Herbeck Belnap, Sati Mazumdar, Kaleab Abebe and Jordan F. Karp. Colleagues from Washington University School of Medicine and Weill Cornell Medical College also contributed.

Childhood abuse, misbehavior among adolescents linked

An important learning process is impaired in adolescents who were abused as children, a psychology researcher has found, and this impairment contributes to misbehavior patterns later in life.

Associative learning — the process by which an individual subconsciously links experiences and stimuli — partially explains how people generally react to various real-world situations. Jamie L. Hanson’s study in the Journal of Child Psychology and Psychiatry detailed the connection between impaired associative learning capacities and instances of early childhood abuse.

Said Hanson, a psychology faculty member in the Dietrich School of Arts and Sciences with a secondary appointment in the Learning Research and Development Center: “We primarily found that a poorer sense of associative learning negatively influences a child’s behavior patterns during complex and fast-changing situations. Having this knowledge is important for child psychologists, social workers, public policy officials and other professionals who are actively working to develop interventions. We have long known that there is a link between behavioral issues in adolescents and various forms of early life adversities. Yet, the connection isn’t always clear or straightforward. This study provides further insight into one of the many factors of how this complicated relationship comes to exist.”

To uncover these relationships, researchers asked 81 adolescents ages 12-17 to play computer games where the child had to figure out which set of visual cues was associated with a reward. Forty-one participants had endured physical abuse at a young age, while the remaining 40 served as a comparison group. The most important aspect of the test, said Hanson, was that the cues were probabilistic, meaning children did not always receive positive feedback.

“The participants who had been exposed to early childhood abuse were less able than their peers to correctly learn which stimuli were likely to result in reward, even after repeated feedback,” said Hanson. “In life we are often given mixed or little to no feedback from our significant others, bosses, parents and other important people in our lives. We have to be able to figure out what might be the best thing to do next.”

Hanson and his colleagues also observed that mistreated children generally were less adept at differentiating which behaviors would lead to the best results for them personally when interacting with others. Additionally, abused children displayed more pessimism about the likelihood of positive outcomes compared to those who hadn’t been abused. Taken as a whole, these findings clarify the relationship between physical abuse and the aggressive and disruptive behaviors that often plague abused children well into the later stages of childhood.

Researchers from the University of Wisconsin-Madison, the University of Illinois-Urbana/Champaign and the Max Planck Institute for Human Development in Berlin, Germany, also contributed to the study.

Advance probed in viral load measuring

U.S. beaches and waterways often are closed when tests indicate an increase in E. coli, usually after heavy rains overwhelm sewer systems. However, the concentration of these common bacteria is not a reliable indicator of viruses in the water, which present a greater danger of causing illness in humans. Through a five-year, $500,000 CAREER Award from NSF, researchers at the Swanson school will be developing new DNA sequencing methods to directly measure viral loads in water and better indicate potential threats to human health.

“Quantitative Viral Metagenomics for Water Quality Assessment,” funded through NSF’s Division of Chemical, Bioengineering, Environmental and Transport Systems, is being led by Kyle J. Bibby, civil and environmental engineering faculty member.

Bibby’s expertise in genomics tools to study, understand and solve environmental challenges influenced this latest research, which will capitalize on new genetic sequencing tools used in medicine.

Said Bibby: “Viruses can persist in water longer than E. coli, and are an important component of disease caused by contaminated water. Although viruses don’t often appear in greater concentrations than bacteria, they still present a danger especially when waterways are contaminated by human waste.”

According to Bibby, conventional methods used to detect viral pathogens in the environment are limited because of viral diversity. However, advances in medicine, specifically in DNA sequencing, have increased the ability to detect even the slightest viral load. Bibby’s group, which previously studied the persistence of the Ebola virus in the environment and has worked to develop novel indicators of viral contamination, will use quantitative viral metagenomics for viral water quality assessment.

“There’s actually very little known about viral pathogen diversity and dynamics in wastewater-impacted systems because, in the past, viruses were difficult to detect,” Bibby said. “New DNA sequencing methods and methods to concentrate the virus and analyze the data rapidly and accurately are necessary for this method [to be] applicable and economical. In addition, we need to demonstrate the efficiency and accuracy across several sources in the U.S.”

The CAREER Award includes an outreach component that allows Bibby to engage with students at the Pittsburgh Public Schools’ Science & Technology Academy (SciTech) next to the Swanson school, leading to development of a hands-on educational module for high school students to characterize microbial water quality. Bibby also will use the research to expand the H2Oh! interactive exhibit he developed with the Carnegie Science Center, enabling children to better understand the impact of water quality on everyday life.

“Applying quantitative viral metagenomics to these DNA/RNA sequencing techniques has the potential to advance water quality monitoring not only in developing countries, but also in U.S. municipal systems that currently rely on fecal indicator bacteria such as E. coli to determine water quality. In the future, viral pathogen detection would be greatly beneficial in many other settings, such as sudden viral outbreaks, food production safety and viral epidemiology.”

Schizophrenia and rheumatoid arthritis causal link studied

An in-depth computational analysis of genetic variants implicated in both schizophrenia and rheumatoid arthritis by School of Medicine researchers points to eight genes that may explain why susceptibility to one of the disorders could place individuals at lower risk for the other, according to the results of a study published in npj Schizophrenia.

Said Madhavi Ganapathiraju, biomedical informatics faculty member in the school and senior author of the study: “There is a wealth of genomic data on both schizophrenia and rheumatoid arthritis. Analyzing it jointly with known protein interaction information could provide invaluable clues to the relationship between the diseases and also shed light on their shared roots.”

While schizophrenia is a psychiatric disorder of unknown origin and rheumatoid arthritis is an autoimmune disease of the joints that occurs as a result of the body’s immune system attacking its own cells, both disorders are thought to be influenced by multiple genetic risk factors modified by the environment.

Said co-senior author Vishwajit Nimgaonkar, faculty member in psychiatry in the School of Medicine and human genetics in the Graduate School of Public Health: “Several previous research studies have hinted at a potential inverse relationship in the prevalence and risk for the two disorders, so we wondered if individual genetic variants may exist that could have opposing effects on the risk of schizophrenia and rheumatoid arthritis.”

The researchers first analyzed two large databases of genetic variants significantly associated with either schizophrenia or rheumatoid arthritis. They identified 18 unique variants, also known as single nucleotide polymorphisms (SNPs) that were located in the HLA region of the genome that harbors genes associated with immune function. The variants appeared to confer different risk for schizophrenia or rheumatoid arthritis. As the SNPs were located near eight known genes in this region, the authors suggested those genes might lead to dysfunction in both schizophrenia and rheumatoid arthritis. Proteins encoded by two of these eight genes, HLA-B and HLA-C, are present in both brain and immune cells.

Analysis of proteins that interact with these eight genes using a computational model developed last year by Ganapathiraju’s team called high-precision protein interaction prediction found more than 25 signaling pathways with proteins common to both rheumatoid arthritis and schizophrenia signaling. Moreover, several of these pathways were associated with immune system function and inflammation.

The findings are encouraging because they support associations of the HLA gene region and immune function with schizophrenia and rheumatoid arthritis that were known over four decades ago, said Ganapathiraju.

Increasing evidence also suggests that a dysfunctional immune system could play a role in the development of schizophrenia.

“We believe that the research community studying these two disorders will find our results extremely helpful,” Nimgaonkar said.

The authors note that the study only focused on SNPs in known gene regions, and other mechanisms apart from the ones they described also may contribute to the diseases. However, the study has significantly narrowed the list of potential genes for examining the schizophrenia/rheumatoid arthritis relationship. Studying the functional relevance of the gene candidates in cells and tissues will provide insights into the two disorders, according to the researchers.

Other Pitt study authors were Tulsi A. Malavia, Srilakshmi Chaparala, Joel Wood, Kodavalli Chowdari, Konasale M. Prasad and Lora McClain. A colleague from Cincinnati Children’s Hospital also contributed.

The research was funded by NIH.

Social media use connected to social isolation

The more young adults use social media, the more likely they are to feel socially isolated, according to a national analysis led by School of Medicine scientists. In addition to the time spent online, frequency of use was associated with increased social isolation, the scientists found.

The study, published in the American Journal of Preventive Medicine, suggests that use of social media does not present a panacea to help reduce perceived social isolation — when a person lacks a sense of social belonging, true engagement with others and fulfilling relationships.

In the past, social isolation has been independently associated with an increased risk for mortality.

Brian Primack

Brian Primack

Said lead author Brian A. Primack, director of the Center for Research on Media, Technology and Health and assistant vice chancellor for health and society in the Schools of the Health Sciences: “This is an important issue to study because mental health problems and social isolation are at epidemic levels among young adults. We are inherently social creatures, but modern life tends to compartmentalize us instead of bringing us together. While it may seem that social media presents opportunities to fill that social void, I think this study suggests that it may not be the solution people were hoping for.”

In 2014, Primack and his colleagues sampled 1,787 U.S. adults ages 19-32, using questionnaires to determine time and frequency of social media use by asking about the 11 most popular social media platforms at the time: Facebook, YouTube, Twitter, Google Plus, Instagram, Snapchat, Reddit, Tumblr, Pinterest, Vine and LinkedIn.

The scientists measured participants’ perceived social isolation using a validated assessment tool called the Patient-Reported Outcomes Measurement Information System.
Even when the researchers controlled for a variety of social and demographic factors, participants who used social media more than two hours a day had twice the odds for perceived social isolation than their peers who spent less than a half-hour on social media each day. And participants who visited various social media platforms 58 or more times per week had about triple the odds of perceived social isolation of those who visited fewer than nine times per week.

Said senior author Elizabeth Miller, pediatrics faculty member and chief of the Division of Adolescent and Young Adult Medicine at Children’s Hospital: “We do not yet know which came first — the social media use or the perceived social isolation. It’s possible that young adults who initially felt socially isolated turned to social media. Or it could be that their increased use of social media somehow led to feeling isolated from the real world. It also could be a combination of both. But even if the social isolation came first, it did not seem to be alleviated by spending time online, even in purportedly social situations.”

The researchers have several theories for how increased use of social media could fuel feelings of social isolation, including:

• Social media use displaces more authentic social experiences because the more time a person spends online, the less time there is for real-world interactions.

• Certain characteristics of social media facilitate feelings of being excluded, such as when one sees photos of friends having fun at an event to which they were not invited.

• Exposure to highly idealized representations of peers’ lives on social media sites may elicit feelings of envy and the distorted belief that others lead happier and more successful lives.

Primack, a family medicine physician, and Miller, a pediatrician, both encourage doctors to ask patients about their social media use and counsel them in reducing that use if it seems linked to symptoms of social isolation.

However, they noted, much more study is needed to understand nuances around social media use.

“People interact with each other over social media in many different ways,” said Primack, also a faculty member in medicine, pediatrics and clinical and translational science. “In a large population-based study such as this, we report overall tendencies that may or may not apply to each individual. I don’t doubt that some people using certain platforms in specific ways may find comfort and social connectedness via social media relationships. However, the results of this study simply remind us that, on the whole, use of social media tends to be associated with increased social isolation and not decreased social isolation.”

Additional Pitt authors on this research were Ariel Shensa, Jaime E. Sidani, Erin O. Whaite, Liu Yi Lin, Daniel Rosen, Jason Colditz and Ana Radovic.

The study was supported by NIH.

—Compiled by Marty Levine

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