Comparative effectiveness research gets grants

Pitt’s Schools of the Health Sciences and the UPMC Center for High-Value Health Care have received two of 25 new awards from the Patient-Centered Outcomes Research Institute (PCORI) to conduct comparative effectiveness research projects. Two School of Medicine faculty members will serve as collaborators on a project given a third PCORI award.

PCORI is a public-private partnership, established as part of federal health-care reform, that promotes comparative effectiveness research to provide patients and their families the best prevention, treatment and care information. PCORI is committing $40.7 million to 25 projects across the country.

Michael Schneider, a physical therapy faculty member in the School of Health and Rehabilitation Sciences, received one of the PCORI awards for the study of non-surgical treatment methods for patients with lumbar spinal stenosis. His research will involve seniors who have pinched nerves in their lower backs, comparing the usual medical care, such as oral or injected medications, to individualized manual therapy, such as traction and exercise guided by physical therapists and chiropractors, as well as to exercise in a group setting at two senior centers in Pittsburgh.

Medicare rates show that lumbar surgery for spinal stenosis has increased 15-fold in the last decade, Schneider noted.

These surgical procedures are associated with significant health care costs, risks, complications and re-hospitalization rates, he said, but noted that evidence is lacking on the effectiveness of the various non-surgical treatments offered to patients with this condition.

Jeremy Kahn and Doug White, Pitt faculty members in critical care medicine, will serve as co-investigators on a study concerning the improvement of psychological distress among critical illness survivors and their caregivers, for which Duke University received a PCORI award.

James Schuster, chief medical officer for Community Care Behavioral Health, received a PCORI award through the UPMC Center for High-Value Health. His project will test two ways to promote the health, wellness and recovery of adults with serious mental illness. Nearly 3,000 Medicaid-enrolled adults will be targeted for participation because they are at risk for chronic medical conditions and receive care at rural community mental health centers.

This research will be conducted in collaboration with Charles F. Reynolds III, School of Medicine faculty in geriatric psychiatry, and the Columbia, Montour, Snyder and Union counties’ (Pennsylvania) mental health, mental retardation and drug and alcohol programs.

Said Schuster: “While there are proven strategies that can prevent and manage significant medical conditions that are common among adults with serious mental illness, providers need a better understanding of how to shape and deliver these interventions so that they can effectively support the outcomes that matter most to patients.”

All work, no school makes Johnny more antisocial

While some people may argue that placing high-school-age juvenile offenders in jobs is a good idea, a study shows that youths who work more than 20 hours weekly and do not attend school regularly display more antisocial behavior than do other high-school-age youth.

The study was conducted by researchers at Pitt, Temple University and the University of California-Irvine, and appears online in Child Development.

Researchers interviewed 1,350 serious juvenile offenders between the ages of 14 and 17 and tracked them for five years. Information was gathered monthly about the young persons’ employment, school attendance and incidents of antisocial behavior. Those incidents ranged from beating up someone to buying or selling something they knew was stolen. The youths included in the study were African American (41.5 percent), Hispanic (33.5 percent), non-Hispanic Caucasian (20.2 percent) and from other groups (4.8 percent).

Going to school on a regular basis without working was associated with the least antisocial behavior. Young people who worked more than 20 hours a week and went to school off and on were at the greatest risk for antisocial behavior, followed by youths who worked long hours and had stopped going to school completely, and finally youths who went to school regularly while working more than 20 hours per week. These effects occurred during adolescence; by early adulthood, working more than 20 hours per week was related to fewer instances of antisocial behavior than those found in adolescents.

Lead researcher Kathryn Monahan, a Pitt psychology faculty member, said: “Our results suggest caution in recommending employment in and of itself as a remedy for adolescents’ antisocial behavior.”

The study was supported by the Office of Juvenile Justice and Delinquency Prevention of the National Institute of Justice, the John and Catherine T. MacArthur Foundation, the William T. Grant Foundation, the William Penn Foundation, the Robert Wood Johnson Foundation, the Centers for Disease Control and Prevention, the National Institute on Drug Abuse and the Arizona Governor’s Justice Commission.

Racial factors govern bone-marrow donor-registry decisions

Race-specific factors, including religious objections and less trust that donated tissues will be allocated fairly, may help to explain why potential minority donors opt out of bone-marrow donor registries at far higher rates than whites, according to a study by School of Medicine researchers. Additionally, they found that ambivalence about donation was the strongest predictor of opting out, regardless of race.

Published in the December issue of Blood, the journal of the American Society of Hematology, the study examined factors associated with race and ethnicity that may influence a donor’s decision to commit to hematopoietic stem cell (HSC) donation or opt out of a registry after being identified as a potential match for an unrelated patient.

HSCs form blood and immune cells and are collected from bone marrow or the bloodstream to re-establish hematopoietic function in patients whose bone marrow or immune system is damaged or defective. As the need for unrelated HSC donors continues to grow to treat cancers and blood-related disorders, such as leukemia and myeloma, the research findings could help to change donor recruitment and retention strategies.

Said Galen Switzer, a faculty member in medicine and psychiatry and lead author of the study: “Minorities searching national donor registries for potential matches today face a two-fold disadvantage. Not only is the pool of donors matching their precise blood and tissue types substantially smaller, but there also is a significantly higher rate of attrition from these registries among certain racial and ethnic groups.”

According to data from the National Marrow Donor Program, the largest registry of unrelated HSC volunteer donors in the world, approximately 60 percent of potential minority donors who register opt out before donation, compared with 40 percent of whites. Whites have a 79 percent chance of finding a donor match, compared with 50 percent for Asian/Pacific Islanders, 44 percent for Hispanics and 33 percent for African-Americans.

To try to explain the higher attrition rate among potential minority donors, researchers interviewed a randomly selected cross-section of five racial and ethnic groups: whites, African-Americans, Hispanics, Asian/Pacific Islanders and American Indians. They interviewed 843 people who continued toward donation and 224 potential donors who opted out of the registry. Switzer and his colleagues found that four factors were particularly important in terms of their association with minority group membership and increased risk of attrition: As compared to whites, minorities reported more religious objections to donation, less trust that HSCs would be allocated equitably, more concerns about donation and a greater likelihood of having been discouraged from donating.

In contrast, minorities appeared to be less likely to opt out of the registry if they reported that being a potential donor was an important part of their identity and if others in their social group were aware that they were potential donors.

“Our findings suggest that recruitment messages delivered through mass media, strategies used at donor drives and the approach to managing individual donors at key points in the donation process can be tailored to overcome potential barriers to donation and to capitalize on factors that might lower the risk of attrition,” said Switzer.

The project was funded by a grant from the National Heart, Lung and Blood Institute.

Low vitamin D levels in early pregnancy may yield lower birth weight

Women deficient in vitamin D early in their pregnancies are more likely to deliver babies with lower birth weights, Graduate School of Public Health researchers have found.

The study, co-authored by researchers from the School of Medicine and Ohio State University, appears in the January edition of the Journal of Clinical Endocrinology & Metabolism.

Said lead author Alison Gernand of the GSPH epidemiology department: “A mother’s vitamin D level early in pregnancy may impact the growth of her baby later in pregnancy. Also, if the mother was deficient in vitamin D during the first trimester, her baby had twice the risk of suffering from growth restriction in utero.”

Gernand and her co-authors discovered that mothers with levels of vitamin D in their blood of less than 0.015 parts per million in their first 26 weeks of pregnancy delivered babies who weighed an average of 46 grams less than their peers. Only full-term babies — those delivered between 37 and 42 weeks of pregnancy — were included in the study.

In addition, women who were vitamin D deficient in the first trimester of pregnancy — 14 weeks or less — were twice as likely to have babies who fell in the lower 10th percentile for weight when compared to other full-term babies born in the same week of pregnancy, a condition known as “small for gestational age.”

Babies born small for gestational age are at five-10 times greater risk for death in their first month and have a higher risk of chronic diseases, such as heart disease, hypertension and type 2 diabetes, later in life.

Vitamin D is unique in that human bodies can make it from sunlight, though it also is in fortified foods such as dairy products and breakfast cereals, and can be taken as a supplement.

People with darker skin are more likely to be deficient in vitamin D. Researchers found that nearly half of the black women and about 5 percent of the white women in the United States are vitamin D deficient.

The study used a random sample of 2,146 pregnant women who participated in the collaborative perinatal project conducted in 12 U.S. medical centers from 1959 to 1965. The blood samples were well preserved and able to be tested for vitamin D levels.

Said senior author Lisa M. Bodnar, an epidemiology faculty member: “Although the blood samples were in remarkably good condition, it would be beneficial to repeat our study in a modern sample. Today, women smoke less, weigh more, have less sun-exposure and get more vitamin D in their foods — all things that could impact their vitamin D levels and babies’ birth weights.”

This research was supported by the National Institutes of Health (NIH).

Racial pride increases school success among black teens

African-American adolescents tend to have more success in school if their parents instill in them a sense of racial pride, reducing their vulnerability to the effects of racial discrimination from teachers and peers.

That is the conclusion of a Pitt study published in the journal Child Development. It shows that when African-American parents use racial socialization — talking to their children or engaging in activities that promote feelings of racial knowledge, pride and connection — it offsets racial discrimination’s potentially negative impact on students’ academic development.

Preparing the adolescents for possible bias also was a protective factor, though a combination of this preparation and racial socialization was found to be ideal in moderating the possible damaging effects of racial discrimination by teachers or fellow students.

Said lead author Ming-Te Wang from Pitt’s department of psychology in education in the School of Education: “Our findings challenge the notion that ‘race blindness’ is a universally ideal parenting approach, especially since previous research has shown that racially conscious parenting strategies at either extreme — either ‘race blindness’ or promoting mistrust of other races — are associated with negative outcomes for African-American youth.”

Research has shown that African-American students, males in particular, are at risk for being unfairly disciplined, being discouraged from taking advanced classes or receiving lower grades than they deserved, all because of their race. Other studies point to negative peer treatment because of race — getting into fights, being bullied or not being selected for teams or activities.

The study explored how racial discrimination relates to students’ educational outcomes, specifically grade-point averages, educational aspirations, the sense of belonging to a school and cognitive engagement, which is the initiative a student takes in his or her own learning. And researchers set out to determine how the outcomes are affected by parental racial socialization.

Unlike other studies that focus on low-income families, this project involved participants from a wide range of socioeconomic backgrounds.

Overall, the study found racial pride to be the most powerful factor in protecting children from the sting of discriminatory behavior. It directly and positively related to three out of four academic outcomes — grade-point averages, educational aspirations and cognitive engagement — and was directly related to resilience in the face of discrimination. Preparation for bias was directly related to only one outcome: the sense of belonging to a school.

Wang plans to conduct similar research with Latino and Asian American teenagers.

The study was supported by the National Institute of Child Health and Human Development.

Molecule that targets TB lung infection discovered

The presence of a certain molecule allows the immune system to police tuberculosis (TB) of the lungs and prevent it from turning into an active and deadly infection, according to a study led by researchers at the School of Medicine and Children’s Hospital.

Their findings appear in the Journal of Clinical Investigation.

More than 2 billion people — or one-third of the world’s population — are infected with mycobacterium tuberculosis, the bacterium that causes TB, said senior author Shabaana A. Khader, pediatrics faculty member. The infection is challenging to treat partly because the bacillus is able to enter cells and linger for years without causing symptoms, known as latent TB. Then, typically when the immune system becomes impaired due to other reasons such as age or HIV, the infection becomes active and causes the cough, night sweats, fever and weight loss that characterize the disease.

“A hallmark of TB that we see on chest X-rays is the granuloma, a collection of immune cells that surround the infected lung cells,” Khader said. “But what we didn’t know was the difference between a functioning protective granuloma, as in latent TB, and a non-protective granuloma seen in active TB patients. We aimed to find immunologic markers that could show us the status of the infection.”

Researchers studied human TB-infected cells as well as animal models of the disease. They discovered that immune cells called T cells had a surface marker molecule called CXCR5, which tells the immune cells where to focus their attention to contain TB. Delivery of CXCR5 T cells from donor animals to TB-infected mice that lacked CXCR5 led to decreased susceptibility to TB.

“The protective power of CXCR5 points us in a novel direction for future management of TB,” Khader said. “These findings have powerful implications for the development of vaccines to prevent infection.”

Co-authors included researchers from the University of Rochester Medical Center, Tulane National Primate Research Center, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” National Institute of Psychiatry “Ramon de la Fuente Muñiz” and The American British Cowdray Medical Center, Mexico.

The study was funded by NIH and Children’s Hospital.

Transplants give Crohn’s patients normal diet, no disease recurrence

After undergoing intestinal or multi-visceral transplants, patients suffering from severe Crohn’s disease who had been unable to tolerate intravenous feedings were able to return to a normal oral diet and saw no clinical recurrences of the disease, according to a study of cases at UPMC over more than 20 years.

The study was presented at the clinical and research conference of the Crohn’s and Colitis Foundation last month.

Said Guilherme Costa, faculty member in the Department of Surgery, who presented the study: “Intestinal transplantation was developed here at UPMC  and, as international leaders in this specialized surgery, we have a wealth of data that other centers don’t.” Costa also is interim director of the UPMC Intestinal Rehabilitation and Transplantation Center.

Crohn’s is a chronic bowel disease that can cause inflammation, ulcers and bleeding in the digestive tract. Patients suffering from a severe form of the disease often have irreversible intestinal failure and sometimes need to receive nutrition through a tube inserted into a vein, known as total perenteral nutrition (TPN). Patients unable to tolerate TPN often are referred for an intestinal transplant.

The study found the patient survival rate was 90 percent at one year, 74 percent at three years, 56 percent at five years, and 43 percent at 10 years. Inclusion of a donor liver transplant was associated with better long-term survival outcome. All survivors had an unrestricted oral diet after transplant.

Biologist gets NSF award

Tia-Lynn Ashman, a biological sciences faculty member, was awarded $2 million from the National Science Foundation to study ecological impacts and diversity of the wild strawberry. This research will provide clues to the genetic diversity of 30-80 percent of all plants worldwide.

Said Ashman: “This deeply integrated comparative study of the wild relatives of the cultivated strawberry — a species of world-wide economic importance — will provide foundational knowledge and contribute unparalleled resources that may be harnessed in efforts to ensure the sustainability of the strawberry and related crops such as the cherry, peach or apple in the face of stress from non-living factors,” which can include the availability of proper soil nutrients, climate and temperature, sunlight and water.

In addition to addressing the mysteries of multi-chromosome plants, the project is developing new educational offerings for participants from all levels of education — from middle school students and their teachers to undergraduate and graduate students. The project also involves two collaborating laboratories in China and an exchange of scientists between the two countries.

Older patients have normal life expectancy after mitral valve repair

Heart surgery to repair the mitral valve is safe and leads to a better quality of life for older patients long-suspected to be too high-risk for the operation, according to research from the School of Medicine.

The results, published in the December issue of the Annals of Thoracic Surgery, provide data on patients 65 years and older that could guide future treatment recommendations for people with severe heart disease.

When the mitral valve malfunctions, blood doesn’t flow the way it should, which can lead to congestive heart failure.

Vinay Badhwar, a surgery faculty member, said: “It is widely accepted that mitral repair is the treatment of choice for people with severe heart disease caused by a leaking mitral valve, and it can restore life expectancy to normal.

“However, in older patients, current guidelines recommend initial medical management of the disease, delaying surgery until symptoms are very advanced. In some cases, delays in surgery can lower quality of life and make the eventual surgery riskier as the patient’s health further deteriorates.”

Badhwar, co-director of the UPMC Center for Mitral Valve Disease and chief of cardiac surgery at UPMC Presbyterian hospital, and his team collected national data on 14,604 people age 65 and older who had mitral valve repair operations between 1991 and 2007.

Less than 3 percent of the patients, who had an average age of 73, died during surgery. The five-year survival rate was nearly 75 percent, and the 10-year survival rate was more than 57 percent — comparable to the average age-matched U.S. population without heart disease.

Five years after surgery, 3.7 percent of the patients had to have another mitral valve operation; 18.4 percent experienced heart failure; 7.2 percent were readmitted for bleeding, and 7.7 percent had a stroke. Readmissions were most common in patients who had surgery late in their illness from mitral valve disease.

“Our data show that not only is mitral valve repair a safe option for elderly patients because of its excellent early outcomes and the low incidence of late stroke and bleeding, but it also is a well-tolerated and lasting solution for the treatment of severe heart disease,” Badhwar said.

The research — completed in collaboration with Duke University, University of South Florida College of Medicine, Harvard and the universities of Michigan, Colorado, Florida and Maryland — was supported by the Society of Thoracic Surgeons Research Center through the Adult National Cardiac Database.

UPCI targets aggressive, common brain tumor

University of Pittsburgh Cancer Institute (UPCI) researchers have identified more than 125 genetic components in a chemotherapy-resistant, brain tumor-derived cell line that could offer new hope for drug treatment to destroy the cancer cells.

The results are the cover story of December’s issue of the journal Molecular Cancer Research.

The potential drug targets were identified after testing more than 5,000 genes derived from glioblastoma multiforme, an aggressive brain tumor. The genes were evaluated for their role in responding to the chemotherapy drug temozolomide.

Said lead author David Svilar, a student in the medical scientist training program in the School of Medicine: “The current standard of care for people with this type of cancer is to remove as much of the tumor as possible, and then treat with radiation and temozolomide. However, glioblastoma multiforme is highly resistant to this chemotherapy drug, so we need to find better treatments to improve the patient survival rate.”

According to the National Cancer Institute, glioblastoma multiforme is the most common type of brain tumor in adults. It accounts for about 15 percent of all brain tumors, and typically occurs in people between the ages of 45 and 70. Patients with glioblastoma multiforme usually survive less than 15 months after diagnosis, and there are no effective long-term treatments for the disease.

Temozolomide, also known by the brand name Temodar, works by modifying the cancer’s DNA in a way that triggers cell death. It has been approved by the Food and Drug Administration for use in brain tumors and is in clinical trials for other cancers, such as melanoma and leukemia. It is well-tolerated in most patients.

Senior author Robert W. Sobol, faculty member in pharmacology and chemical biology and in human genetics, said: “Unfortunately, some cancers — particularly glioblastoma multiforme — are able to repair the DNA damage done to the tumor by temozolomide before the cancer cells are destroyed. Clinical trials are underway to test drugs and chemotherapy dosing schedules to inhibit this repair, but none has proven effective to date.”

Sobol, a scientist at UPCI, and his colleagues identified multiple “druggable” targets that could make the cancer more sensitive to temozolomide, as well as the processes that allow the tumor to survive the onslaught of surgery, radiation and chemotherapy.

“Our hope is that drug companies will use our findings to develop adjuvant chemotherapy drugs that will vastly improve patient survival from this deadly cancer,” said Sobol.

This research, co-authored by other Pitt faculty (Ashley R. Brown, Jiang-bo Tang, Jianfeng Li, Peter McDonald, Tong Ying Shun, Andrea Braganza, Xiao-hong Wang, Salony Maniar, Claudette M. St Croix, John S. Lazo and Ian F. Pollack) as well as faculty members at the University of Albany, was supported by grants from the National Brain Tumor Society and NIH and a New York State Office of Science, Technology and Academic Research James Watson Award.

Technology produces mind-controlled robot arm

New brain-computer interface (BCI) technology and training programs developed at Pitt have allowed a patient to intentionally move her arm, turn and bend her wrist, and close her hand for the first time in nine years.

Reaching out to “high five” someone. Grasping and moving objects of different shapes. Feeding herself dark chocolate. For patient Jan Scheuermann, 53, and a team of researchers from Pitt’s School of Medicine and UPMC, accomplishing these seemingly ordinary tasks demonstrated for the first time that a person with longstanding quadriplegia can maneuver a mind-controlled, human-like robot arm in seven dimensions to consistently perform many of the natural and complex motions of everyday life.

The study was published in the online version of The Lancet.

Said senior investigator Andrew B. Schwartz, faculty member in neurobiology: “This is a spectacular leap toward greater function and independence for people who are unable to move their own arms. This technology, which interprets brain signals to guide a robot arm, has enormous potential that we are continuing to explore.”

In 1996, Scheuermann was a 36-year-old mother of two young children, running a business and living in California when she noticed her legs seemed to be dragging behind her. Within two years, she required a wheelchair as well as an attendant to assist her with dressing, eating, bathing and other daily activities. After returning home to Pittsburgh in 1998 for support from her extended family, she was diagnosed with spinocerebellar degeneration, in which the connections between the brain and muscles slowly, and inexplicably, deteriorate.

On Feb. 10, 2012, co-investigator and UPMC neurosurgeon Elizabeth Tyler-Kabara, a neurological surgery faculty member, placed two quarter-inch square electrode grids with 96 tiny contact points each in the regions of Scheuermann’s brain that normally would control right arm and hand movement.

The electrode points pick up signals from individual neurons and computer algorithms are used to identify the firing patterns associated with particular observed or imagined movements, such as raising or lowering the arm, or turning the wrist, explained lead investigator Jennifer Collinger of physical medicine and rehabilitation. That intent to move then is translated into actual movement of the robot arm, which was developed by Johns Hopkins University researchers.

Two days after the operation, the team hooked up the two terminals that protrude from Scheuermann’s skull to the computer. “We could actually see the neurons fire on the computer screen when she thought about closing her hand,” Collinger said. “When she stopped, they stopped firing.”

Within a week, Scheuermann could reach in and out, left and right, and up and down with the arm, giving her three-dimensional control.

Before three months had passed, she also could flex the wrist back and forth, move it from side to side and rotate it clockwise and counter-clockwise, as well as grip objects. Scheuermann guided the arm to pick up various objects and put them on a nearby tray, and was able to grasp, transport and position other objects with precision.

“Our findings … suggest that it’s possible for people with long-term paralysis to recover natural, intuitive command signals to orient a prosthetic hand and arm to allow meaningful interaction with the environment,” said Schwartz.

The next step for BCI technology likely will use a two-way electrode system that can capture the intention to move and will stimulate the brain to generate sensation, potentially allowing a user to adjust grip strength to firmly grasp a doorknob or gently cradle an egg.

The BCI projects were funded by the Defense Advanced Research Projects Agency, NIH, the U.S. Department of Veterans Affairs, the UPMC Rehabilitation Institute and the University of Pittsburgh Clinical and Translational Science Institute.

DOE awards researcher 91 million core computing hours

Kenneth Jordan, computational chemistry faculty member and co-director of Pitt’s Center for Simulation, is a member of an international team of researchers recently awarded one of the Department of Energy’s 2013 Innovative and Novel Computational Impact of Theory and Experiment (INCITE) awards, totaling 91 million core hours on the Oak Ridge National Laboratory’s Cray XK7 Titan and the Argonne National Laboratory’s IBM Blue Gene/Q Mira supercomputers.

Both computers are capable of performing a quadrillion (a thousand trillion) operations each second. The calculations will employ simultaneously up to 100,000 computer cores.

The research project will elucidate the role of hydrogen bonding in complex materials and the unique properties of water, both by itself and interacting with other substances. Although water is the most studied substance on earth, many of its properties are not fully understood. For example, it has not yet been possible to develop a model of water that gives accurate predictions of the melting point of ice and the value of the dielectric constant of both liquid water and ice, which measures the tendency of the dipoles associated with the individual molecules to align. The high value of the constant for water allows water to be such an effective solvent. There is also a current debate as to whether various types of ions are preferentially located at the water/vapor interface or in the bulk liquid; the preference of certain ions for the interface would have profound ramifications for atmospheric chemistry on aerosol particles.

Jordan is collaborating with researchers from University College, London; the Fritz Haber Institute, Berlin, and the Argonne National Laboratory.

—Compiled by Marty Levine

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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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