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Children’s Hospital of Pittsburgh of UPMC Named One of America’s Top 10 Children’s Hospitals for Sixth Consecutive Year

PrintPITTSBURGH, June 9, 2015 – Children’s Hospital of Pittsburgh of UPMC has once again been named one of America’s Best Children’s Hospitals by U.S. News & World Report, making this the sixth consecutive year the hospital has been listed on the Honor Roll.

Children’s Hospital ranks eighth on the magazine’s 2015-16 Honor Roll of America’s Best Children’s Hospitals, which was released today. Children’s also ranks in each of the 10 pediatrics specialties ranked by U.S. News.

The Best Children’s Hospitals rankings highlight the top 50 U.S. pediatric hospitals in each of 10 specialties: cancer; cardiology and heart surgery; diabetes and endocrinology; gastroenterology and GI surgery; neonatology; nephrology; neurology and neurosurgery; orthopedics; pulmonology; and urology.

The hospital ranked in the top 25 in nine of the specialties, including second in gastroenterology and GI surgery; third in diabetes and endocrinology; sixth in pulmonology; and 10th in three categories: cardiology and heart surgery, neonatology, and neurology and neurosurgery.

“This recognition speaks to the talent, passion, and dedication of our physicians, nurses, staff, and volunteers,” said Christopher Gessner, president, Children’s Hospital. “We are proud to have built a reputation of excellence over our 125-year history and we’re grateful to have those efforts recognized.”

The 2015-16 Best Children’s Hospitals rankings will be released online today and also will be published in the U.S. News “Best Hospitals 2016” guidebook, available in September.

U.S. News introduced the Best Children’s Hospitals rankings in 2007 to help families of children with rare or life-threatening illnesses find the best medical care available. The rankings open the door to an array of detailed information about each hospital’s performance.

In addition to Children’s Hospital of Pittsburgh of UPMC, the other hospitals named to U.S. News’ Honor Roll of Best Children’s Hospitals for 2015-16 are:

  • Boston Children’s Hospital
  • Children’s Hospital of Philadelphia
  • Cincinnati Children’s Hospital Medical Center
  • Texas Children’s Hospital, Houston
  • Children’s Hospital Colorado, Aurora
  • Seattle Children’s Hospital
  • Children’s Hospital Los Angeles
  • Nationwide Children’s Hospital, Columbus, Ohio
  • Children’s National Medical Center, Washington, D.C.
  • Ann and Robert H. Lurie Children’s Hospital of Chicago
  • Children’s Healthcare of Atlanta

Children’s Hospital of Pittsburgh of UPMC and Its Foundation Celebrate 125 Years of Caring

PrintPITTSBURGH, June 4, 2015 – Children’s Hospital of Pittsburgh of UPMC opened its doors on June 4, 1890, and today kicks off a yearlong celebration of 125 years of caring for kids.

From our beginning — a single cot endowed by Kirk LeMoyne, son of local pediatrician Frank LeMoyne, to be used for children and infants at a local hospital — to present day, Children’s Hospital has grown to become one of the world’s top pediatric hospitals with a reputation for innovation as well as superior care and successful treatment of kids with highly complex medical issues.

Children’s medical team treats rare diseases, defines new standards of care, pioneers research and treatment protocols, and provides patient- and family-centered services in a top-of-class environment. Every discovery, milestone and advancement is rooted in the same mission and supported by the same essence of community philanthropy established 125 years ago.

“Today, with 125 Years of Caring, we celebrate the tremendous work of our staff and physicians and all that they do for patients and families in the region,” said Christopher Gessner, president, Children’s Hospital. “We are extremely grateful for the generous community support that enables us to continue to provide the world-class care that has catapulted Children’s to the forefront of pediatric health care.”

Throughout the year, Children’s Hospital of Pittsburgh Foundation will carry on a campaign — “Give Kids a Chance to be Kids” — celebrating 125 years of caring and the important role of community support for the clinical and research advances at Children’s. The campaign will raise funds for patient care and research, attract a new generation of support from leading organizations and individuals throughout the region and beyond, and engage the community with a collective goal: Cures for childhood illness and diseases.

“The 125th anniversary will celebrate Children’s Hospital’s history and build momentum for what can be accomplished for our children’s children with continued community support and engagement,” said Greg Barrett, president, Children’s Hospital of Pittsburgh Foundation. “Every gift, large or small, directly impacts the lives of children. By giving to Children’s, we truly are giving kids a chance to be kids.”

Today, Children’s officially began the celebration with a 125th anniversary kickoff event in the Eat’n Park Atrium at Children’s main campus in Lawrenceville. During the event, the Foundation announced a $1.25 million partnership with PNC as the lead corporate sponsor for the 125th Anniversary campaign. In addition, Jay Costa, State Senate Minority Leader; Wayne D. Fontana, State Senator, Democratic Caucus Chair; Rich Fitzgerald, Allegheny County Executive; and Bill Peduto, Mayor of Pittsburgh, all read proclamations.

Children’s Hospital of Pittsburgh Foundation also unveiled the “Giving Booth,” an interactive video booth that will travel throughout the region to various events encouraging individuals to share a childhood memory or a Children’s Hospital memory. All videos will be uploaded to the Foundation’s 125th Anniversary webpage where participants will be able to watch and share videos and encourage their friends and family to do the same, as well as make a donation to support Children’s. The 125th Anniversary webpage also will feature memories shared by local and national celebrities.

For more information on the Foundation and the campaign, visit www.givetochildrens.org/125.

Lower Birth Weight Associated with Proximity of Mother’s Home to Gas Wells

PITTSBURGH, June 3, 2015 – Pregnant women living close to a high density of natural gas wells drilled with hydraulic fracturing were more likely to have babies with lower birth weights than women living farther from such wells, according to a University of Pittsburgh Graduate School of Public Health analysis of southwestern Pennsylvania birth records.

The finding does not prove that the proximity to the wells caused the lower birth weights, but it is a concerning association that warrants further investigation, the researchers concluded. The study was funded by The Heinz Endowments and published in the current issue of PLOS ONE.

“Our work is a first for our region and supports previous research linking unconventional gas development and adverse health outcomes,” said co-author Bruce Pitt, Ph.D., chair of Pitt Public Health’s Department of Environmental and Occupational Health. “These findings cannot be ignored. There is a clear need for studies in larger populations with better estimates of exposure and more in-depth medical records.”

Unconventional gas development includes horizontal drilling and high volume hydraulic fracturing, known as “fracking.” It allows access to large amounts of natural gas trapped in shale deposits. Prior to 2007, only 44 wells were known to be drilled in Pennsylvania’s Marcellus Shale with such technology. From 2007 to 2010, that expanded to 2,864 wells.

The Pitt Public Health research team cross-referenced birth outcomes for 15,451 babies born in Washington, Westmoreland and Butler counties from 2007 through 2010 with the proximity of the mother’s home to wells drilled using unconventional gas development. They divided the data into four groups, depending on the number and proximity of wells within a 10-mile radius of the mothers’ homes.

Mothers whose homes fell in the top group for proximity to a high density of such wells were 34 percent more likely to have babies who were “small for gestational age” than mothers whose homes fell in the bottom 25 percent. Small for gestational age refers to babies whose birth weight ranks them below the smallest 10 percent when compared to their peers.

The researchers took into account many factors that could influence a newborn’s weight – including whether the mother smoked, her prenatal care, race, education, age and whether she’d had previous babies, as well as the gender of the baby – and the finding still held.

“Developing fetuses are particularly sensitive to the effects of environmental pollutants,” said Dr. Pitt. “We know that fine particulate air pollution, exposure to heavy metals and benzene, and maternal stress all are associated with lower birth weight.”

In southwestern Pennsylvania, the waste fluids produced through hydrofracturing, called “flowback,” can contain benzene. Unconventional gas development also creates an opportunity for air pollution through flaring of methane gas at the well heads and controlled burning of natural gas that releases volatile organic compounds, including benzene, toluene, ethylbenzene and xylene. Increased truck traffic and diesel-operated compressors also can contribute to air and noise pollution.

“It is important to stress that our study does not say that these pollutants caused the lower birth weights,” said Dr. Pitt. “Unconventional gas development is dynamic and varies from site to site, changing the potential for human exposure. To draw firm conclusions, we need studies that thoroughly assess the exposure of a very large number of pregnant women to not just the gas wells, but other potential pollutants.”

Shaina L. Stacy, Ph.D., a recent graduate of Pitt Public Health, is lead author on this research, and Evelyn Talbott, Dr.P.H., epidemiology professor at the school, is senior author. Additional authors are LuAnn L. Brink, Ph.D., and Bernard D. Goldstein, M.D., both of Pitt Public Health; and Jacob C. Larkin, M.D., and Yoel Sadovsky, M.D., both of Magee-Womens Research Institute and Pitt School of Medicine.

UPMC-Managed Transplant Hospital Drives Major Economic Benefits for Sicily, Study Finds

PITTSBURGH, May 28, 2015 ISMETT, a leading transplant hospital managed by UPMC in Palermo, Italy, boosted the Sicilian economy by €132.5 million in expenditure in 2013, generated nearly 2,000 jobs and provided a net benefit of more than €73 million by retaining patients who otherwise would have traveled outside of Sicily for care, according to a new study by the Battelle Memorial Institute. At the same time, the partnership with UPMC provided access to research, training and advanced health care management that is transforming Sicily into a biomedical hub for the entire Mediterranean basin.

Formally known as the Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, ISMETT has performed more than 1,600 transplants since it began operations in 1999. An unusual public-private partnership among UPMC, the Region of Sicily and Cervello and Civico hospitals, ISMETT is the only hospital in Italy designed and intended exclusively for solid organ transplantation and highly specialized therapies. It boasts patient survival rates that are among the best in Europe and treats more than 30,000 patients a year with severe organ disease.

“The results of this study reach beyond ISMETT and Sicily, and are evidence of the positive economic benefits generated when high-quality health care combines with cutting-edge research,” said Bruno Gridelli, M.D., chief executive officer of ISMETT and executive vice president of UPMC International Services. “When health care and its various elements—therapy, training and research—are properly managed, they can be powerful forces in the financial and social growth of an entire region.”

To identify and quantify the economic and social benefits of ISMETT for Sicily, UPMC commissioned this detailed analysis from Battelle’s Technology Partnership Practice. The study examined the direct impact of expenditures made by ISMETT, its employees and visitors, as well as the indirect, or multiplier, effects. The researchers also assessed the many and varied “functional impacts” of ISMETT, or those generated by its clinical services, research and development activity, and education of medical staff.

In 2013, the overall impact of ISMETT’s expenditures on the Sicilian economy included €67.9 million directly and €64.5 million through the indirect, multiplier effect. ISMETT and its related economic activities generated 1,793 jobs in Sicily—862 direct and 931 indirect. Battelle estimated that Sicily receives €3.1 million in annual taxes because of ISMETT’s operations, while the Italian national government receives approximately € 19.6 million annually.

As expected when ISMETT was created, the hospital’s presence has reversed the trend of Sicilian patients traveling abroad to receive transplants and high-specialty care, which means more convenience for patients and their families and significant savings for the regional government. According to Battelle, the presence and operation of ISMETT retained a net €73.2 million in the Sicilian economy that otherwise would have been spent outside the region to pay for care, patient transportation and associated costs. Ninety-two percent of ISMETT’s patients are from Sicily, while the rest come from other Italian regions or from abroad.

ISMETT also is an institution that is helping Sicily to build a reputation for science, technological advancement, research and specialty medical training. This has helped to pave the way for the planned Biomedical Research and Biotechnology Center in Carini, which will employ more than 600 people when it opens in 2017. The government-funded center will operate under the leadership of the Ri.MED Foundation, a partnership of UPMC, the government of Italy, the Region of Sicily and the Italian National Research Council.

“Originally seen as an institution that would fill a gap in clinical services in Italy, ISMETT has succeeded beyond our expectations and has grown to become a major economic engine for the Sicilian economy,” said Dr. Gridelli. “Most importantly, ISMETT is improving the well-being of patients throughout Italy and beyond and promises to advance health and science for years to come.”

Fine Particulate Air Pollution Associated With Increased Risk of Childhood Autism

PITTSBURGH, May 21, 2015 – Exposure to fine particulate air pollution during pregnancy through the first two years of a child’s life may be associated with an increased risk of the child developing autism spectrum disorder (ASD), a condition that affects one in 68 children, according to a University of Pittsburgh Graduate School of Public Health investigation of children in southwestern Pennsylvania.

The research is funded by The Heinz Endowments and published in the July edition of Environmental Research.

“Autism spectrum disorders are lifelong conditions for which there is no cure and limited treatment options, so there is an urgent need to identify any risk factors that we could mitigate, such as pollution,” said lead author Evelyn Talbott, Dr.P.H., professor of epidemiology at Pitt Public Health. “Our findings reflect an association, but do not prove causality. Further investigation is needed to determine possible biological mechanisms for such an association.”

Dr. Talbott and her colleagues performed a population-based, case-control study of families with and without ASD living in six southwestern Pennsylvania counties. They obtained detailed information about where the mothers lived before, during and after pregnancy and, using a model developed by Pitt Public Health assistant professor and study co-author Jane Clougherty, Sc.D., were able to estimate individual exposure to a type of air pollution called PM2.5.

This type of pollution refers to particles found in the air that are less than 2.5 micrometers in diameter, or 1/30th the average width of a human hair. PM2.5 includes dust, dirt, soot and smoke. Because of its small size, PM2.5 can reach deeply into the lungs and get into the blood stream. Southwestern Pennsylvania has consistently ranked among the nation’s worst regions for PM2.5 levels, according to data collected by the American Lung Association.

“There is increasing and compelling evidence that points to associations between Pittsburgh’s poor air quality and health problems, especially those affecting our children and including issues such as autism spectrum disorder and asthma,” said Grant Oliphant, president of The Heinz Endowments. “While we recognize that further study is needed, we must remain vigilant about the need to improve our air quality and to protect the vulnerable. Our community deserves a healthy environment and clean air.”

Autism spectrum disorders are a range of conditions characterized by social deficits and communication difficulties that typically become apparent early in childhood. Reported cases of ASD have risen nearly eight-fold in the last two decades. While previous studies have shown the increase to be partially due to changes in diagnostic practices and greater public awareness of autism, this does not fully explain the increased prevalence. Both genetic and environmental factors are believed to be responsible.

Dr. Talbott and her team interviewed the families of 211 children with ASD and 219 children without ASD born between 2005 and 2009. The families lived in Allegheny, Armstrong, Beaver, Butler, Washington and Westmoreland counties. Estimated average exposure to PM2.5 before, during and after pregnancy was compared between children with and without ASD.

Based on the child’s exposure to concentrations of PM2.5 during the mother’s pregnancy and the first two years of life, the Pitt Public Health team found that children who fell into higher exposure groups were at an approximate 1.5-fold greater risk of ASD after accounting for other factors associated with the child’s risk for ASD – such as the mother’s age, education and smoking during pregnancy. This risk estimate is in agreement with several other recent investigations of PM2.5 and autism.

A previous Pitt Public Health analysis of the study population revealed an association between ASD and increased levels of air toxics, including chromium and styrene. Studies by other institutions using different populations also have associated pollutants with ASD.

“Air pollution levels have been declining since the 1990s; however, we know that pockets of increased levels of air pollution remain throughout our region and other areas,” said Dr. Talbott. “Our study builds on previous work in other regions showing that pollution exposures may be involved in ASD. Going forward, I would like to see studies that explore the biological mechanisms that may underlie this association.”

Additional co-authors of this study are Vincent C. Arena, Ph.D., Judith R. Rager, M.P.H., Drew R. Michanowicz, Dr.P.H., Ravi K. Sharma, Ph.D., and Shaina L. Stacy, Ph.D., all of Pitt Public Health.

Children’s Hospital of Pittsburgh of UPMC Lung Researcher Receives Prestigious Scientific Award

PrintPITTSBURGH, May 18, 2015John F. Alcorn, Ph.D., assistant professor of pediatrics in the Division of Pulmonology at Children’s Hospital of Pittsburgh of UPMC, has been selected as the 2015 recipient of the Parker B. Francis Jo Rae Wright Award for Scientific Excellence. The award has been established by the Parker B. Francis Fellowship Program and the Francis Family Foundation to honor Jo Rae Wright, Ph.D.

The award will be presented to Dr. Alcorn today at the Parker B. Francis Fellowship Reception at the American Thoracic Society meeting.

“The Parker B. Francis Fellowship Program and the Francis Family Foundation has been instrumental in my early career development to independence,” said Dr. Alcorn, also assistant professor of pediatrics, University of Pittsburgh School of Medicine. “Receiving this award is exceptionally meaningful to me as I previously completed my Ph.D. training under Jo Rae’s mentorship at Duke University. I am honored to be the recipient Jo Rae Wright Award and I hope to continue on the path toward becoming a leader in pulmonary research.”

Dr. Alcorn’s research focuses on T-cell mediated immunity during influenza infections and secondary bacterial pneumonia, as well as the role of T-cells in severe, steroid-insensitive asthma.

The Parker B. Francis Jo Rae Wright Award for Scientific Excellence is given annually to a recent graduate of the Fellowship Program whose research shows outstanding creativity and promise and who has demonstrated outstanding mentoring and professional leadership qualities. Dr. Alcorn will receive a one-time award of $5,000 to be used to support research costs.

Dr. Jo Rae Wright was a world-renowned scientist, devoted teacher and mentor, and a leader in academia and professional organizations. She served as dean of the Graduate School of Duke University and was president of the American Thoracic Society in 2008. She received the American Physiological Society’s Walter B. Cannon Award for lifetime achievements in research in 2005. She served as a member of the Parker B. Francis Fellowship Program Council of Scientific Advisors from 2004 through 2007 and was a mentor to Parker B. Francis Fellows.

For more information on Dr. Alcorn, visit www.chp.edu.

New Guidelines Aim to Resolve Conflicts in Treating Critically Ill Patients

PITTSBURGH, May 15, 2015 – Who should decide what life-prolonging medical treatments the intensive care patient should receive: the clinician or the patient’s family?  

The answer in almost all circumstances should be “both,” according to the authors of a new policy statement from the American Thoracic Society aimed at providing guidance for crucial decision-making for the care of patients with advanced critical illness while preventing conflicts between medical staff and family caregivers.

“Neither individual clinicians nor families should be given unchecked authority to determine what treatments will be given to a patient,” explained Douglas White, M.D., M.A.S., UPMC Chair for Ethics in Critical Care Medicine, associate professor in the University of Pittsburgh Department of Critical Care Medicine, and co-chair of the committee that produced these guidelines. “Clinicians should neither simply acquiesce to treatment requests that they believe are not in a patient’s best interest, nor should they unilaterally refuse to provide treatment. Instead, if conflicts arise between clinicians and patients’ families, a fair process of dispute resolution should be undertaken, in which neither individual can unilaterally impose his or her will on the other.”

The guidelines, which will appear in the June 1st issue of the American Journal of Respiratory and Critical Care Medicine and are available online Friday at http://www.atsjournals.org/toc/ajrccm/0/ja, are a new resource for an estimated 80,000 health professionals. They are supported by the Society of Critical Care Medicine, the American Association of Critical Care Nurses, the American College of Chest Physicians and the European Society of Intensive Care Medicine.

When a clinician is asked by the family of a critically ill patient to administer invasive interventions that the clinician believes will not benefit the patient, “such disagreements can present particular challenges, since they bring into conflict important interests of patients, clinicians and society,” Dr. White said. “The cases are difficult because there are generally no clear, substantive rules to appeal to and because ICU patients are especially vulnerable because of their overwhelming illness and lack of ability to seek out another doctor if they disagree with the plan.” 

The guidelines emphasize that conflicts in the ICU can and should be prevented through early and intensive communication between the patient’s family and the health care team. When conflicts cannot be resolved with ongoing dialogue, the policy statement recommends early involvement of expert consultants, such as palliative care and ethics consultants, to help find a negotiated agreement. If a dispute remains unresolvable despite intensive communication and negotiation, the committee recommends a fair process of dispute resolution, involving a review of the case by a multidisciplinary ethics committee within the hospital, ongoing mediation, a second medical opinion, offering family the option to seek to transfer the patient to an alternate institution, and informing the family of their right to appeal to the courts.

“Families need to be given a voice regarding what treatments are consistent with the patient’s values and preferences, and physicians’ professional integrity also needs to be respected, meaning that they should not be compelled to administer treatments that violate good medical practice,” Dr. White said.

The policy statement also outlines innovative procedures for two additional situations. When families request treatment that is truly futile, meaning that it simply cannot accomplish its physiologic aims, the clinician should refuse to administer the treatment and should clearly explain the rationale behind the treatment decision. In addition, for situations in which medical urgency does not allow compliance with the longer dispute resolution process, the committee has provided expedited steps that, nevertheless, ensure a fair process.

“These guidelines provide clinicians with a framework to manage treatment disputes with an emphasis on procedural fairness, frequent communication, expert consultation and timeliness,” said co-chair Gabriel T. Bosslet, M.D., assistant professor of clinical medicine at the Charles Warren Fairbanks Center for Medical Ethics at Indiana University. “We hope that states will adopt laws similar to these guidelines, so that all sides in a particular dispute can have the resources they need to come to a resolution.”

Co-authors of the guidelines include Thaddeus M. Pope, Hamline University Law School; Gordon Rubenfeld, M.D., Sunnybrook Health Sciences Center; Bernard Lo, M.D., University of California, San Francisco; Robert Truog, M.D., Harvard Medical School; Cynthia Rushton, Ph.D., R.N., Johns Hopkins University; J. Randall Curtis, M.D., University of Washington; Dee W. Ford, M.D., Medical University of South Carolina; Molly Osborne, M.D., Portland VA Medical Center, Oregon Health Sciences University; Cheryl Misak, M.A., University of Toronto; David H. Au, M.D., VA Puget Sound Health Care System, University of Washington; Elie Azoulay, M.D., Ph.D., Saint Louis Teaching Hospital and Paris 7 University; Baruch Brody, Ph.D., Baylor College of Medicine; Brenda Fahy, M.D., University of Florida; Jesse Hall, M.D., University of Chicago; Jozef Kesecioglu, M.D., Ph.D., University Medical Center-Utrecht, the Netherlands; Alexander A. Kon, M.D., University of San Diego; and Kathleen Lindell, Ph.D., R.N., University of Pittsburgh.

Pitt Physician Researchers Determine Elevated Peptide Level Associated With Mortality in HIV-Infected Women

PITTSBURGH, May 15, 2015 – Pulmonary medicine experts from the University of Pittsburgh have identified an elevated NT-pro-brain natriuretic peptide (NT-proBNP) level as being independently associated with all-cause mortality in HIV-infected women. NT-proBNP is a marker of cardiac ventricular strain and systolic dysfunction.

The authors, led by Matthew Gingo, MD, associate professor of medicine in the Division of Pulmonary, Allergy, and critical Care Medicine at the University of Pittsburgh, measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early, and 1082 HIV-infected and 448 HIV-uninfected women late in the highly active antiretroviral therapy (HAART) periods in the Women’s Interagency HIV Study.

They found that a NT-proBNP level above the 75th percentile was more likely in HIV-infected persons, but was only statistically significant in the late period. In HIV-infected participants, a NT-proBNP level greater than the 75th percentile was independently associated with worse five-year survival in the early HAART period and remained a predictor of mortality in the late HAART period, independent of other established risk covariates, such as age, race/ethnicity, body mass index, smoking, hepatitis C serostatus, hypertension, renal function, and hemoglobin. NT-proBNP level was not associated with mortality in HIV-uninfected women.

The authors concluded, “NT-proBNP is a novel independent marker of mortality in HIV-infected women both when HAART was first introduced and currently. As NT-proBNP is often associated with both pulmonary hypertension and left ventricular dysfunction, these findings suggest that these conditions may contribute significantly to adverse outcomes in this population, requiring further definition of causes and treatments of elevated NT-proBNP in HIV-infected women.”

Additional authors on the study were Yingze Zhang, PhD, Kidane Ghebrehawariat, Jong Jeong, PhD, Lorrie Lucht, Quanwei Yang, Yanxia Chu, Mark Gladwin, MD, Alison Morris, MD, all of the University of Pittsburgh; Jason Lazar, MD, of SUNY Downstate Medical Center in Brooklyn, NY; and David B. Hanna, PhD, of Albert Einstein College of Medicine in Bronx, NY.

To view the full abstract, please visit PubMed.gov.

X-linked Gene Mutations Cause Some Cases of Male Infertility, Pitt Study Says

PITTSBURGH, May 13, 2015 – Some cases of male infertility are due to mutations in the maternal X chromosome that prevent development of viable sperm, according to a study led by researchers at the University of Pittsburgh School of Medicine and the Magee-Womens Research Institute (MWRI). The study was published online today in the New England Journal of Medicine.

Nearly half of cases of male infertility not due to a physical obstruction are estimated to have genetic roots, and about 20 percent of infertile men have azoospermia, meaning they don’t make sperm, explained co-principal investigator Alexander Yatsenko, M.D., Ph.D., assistant professor of obstetrics, gynecology and reproductive medicine, Pitt School of Medicine, and an MWRI investigator. He noted the only causes for infertility that have been identified are defects of sex chromosomes, such as the deletions of the Y (male) chromosome or duplication of the entire X (female) chromosome in Klinefelter syndrome.

“Eight times out of 10, conventional genetic testing doesn’t reveal a chromosomal problem, so the cause is considered idiopathic or unknown,” Dr. Yatsenko said. “This study is among the first to describe specific gene mutations on the X chromosome that contribute to azoospermia and male infertility.”

First, the research team scanned the genomes of 15 men with azoospermia and found a deletion in part of the DNA coding of the testis-expressed gene 11 (TEX11) on the X-chromosome, which men inherit from their mothers. The alteration caused meiotic arrest, meaning the precursor cells could not properly undergo meiosis, the cell division process that produces daughter cells with half the parental chromosomes for reproduction.

Then, they found similar TEX11 gene mutations and meiotic arrest in two out of 49 men diagnosed with idiopathic azoospermia from the Center for Fertility and Reproductive Endocrinology at Magee-Womens Hospital of UPMC, and the Institute of Human Genetics of the Polish Academy of Sciences in Poznan, Poland. Also, TEX11 gene errors were found in five out of 240 infertile men from the Center of Reproductive Medicine and Andrology in Münster, Germany.

Dr. Yatsenko noted that it might be possible for an older father, whose precursor sperm cells have a greater likelihood of acquiring a mutation, to pass along the genetic error to his daughter, which could make it impossible for her son to make viable sperm. Also, men without seminal sperm who undergo a procedure to have a few rare, viable sperm extracted from the testes to attempt conception with in vitro fertilization could unknowingly pass a TEX11 gene mutation to a daughter, making her a carrier.

“This research suggests screening for TEX11 gene mutations might be useful in cases of otherwise unexplained azoospermia,” Dr. Yatsenko said. “It might be possible to one day correct these problems with gene therapy and other interventions. More work must be done to identify other genetic causes of male infertility.”

The team included co-senior author Frank Tüttelmann, M.D., and others from of the University of Münster, Germany; the University of Pittsburgh; and the Polish Academy of Sciences.

The project was funded by grant HD058073 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the Pennsylvania Department of Health; MWRI; the University of Pittsburgh; the Polish National Science Centre; and the German Research Foundation.

Computer Simulation Accurately Replicated Real-Life Trauma Outcomes, Says Pitt Team

PITTSBURGH, May 11, 2015 – A computer simulation, or “in silico” model, of the body’s inflammatory response to traumatic injury accurately replicated known individual outcomes and predicted population results counter to expectations, according to a study recently published in Science Translational Medicine by a University of Pittsburgh research team.

Traumatic injury is a major health care problem worldwide. Trauma induces acute inflammation in the body with the recruitment of many kinds of cells and molecular factors that are crucial for tissue survival, explained senior investigator Yoram Vodovotz, Ph.D., professor of surgery and director of the Center for Inflammation and Regenerative Modeling at the University of Pittsburgh School of Medicine. But if inappropriately sustained, the inflammatory response can compromise healthy tissues and organs.

“Thanks to life-saving surgery and extensive supportive care, most patients who require trauma care are now highly likely to survive,” Dr. Vodovotz said. “But along the way, they may experience a variety of complications, such as multiple organ failure, that are difficult to predict in initial assessment. Our current challenge is to identify which patients are vulnerable to certain problems so that we can better implement surveillance and prevention strategies and use resources more effectively.”

Building from a model developed for swine, the research team examined blood samples from 33 survivors of car or motorcycle accidents or falls for multiple markers of inflammation, including interleukin-6 (IL-6), and segregated the patients into one of three (low to high) categories of trauma severity. They were able to validate model predictions regarding hospital length of stay in a separate group of nearly 150 trauma patients. They then generated a set of 10,000 “virtual patients” with similar injuries and found the model could replicate outcomes in individuals, such as length of stay and degree of multi-organ dysfunction. Intriguingly, the in silico model also predicted a 3.5 percent death rate, comparable to published values and to the Pitt group’s own observations, even though the model did not include patients who didn’t survive their injuries.

The in silico model predicted that, on an individual basis, virtual patients who made more IL-6 in response to trauma were less likely to survive. But, as the model predicted, that was not true at the population level: Among nearly 100 real patients whose genetic predisposition to make more or less amounts of IL-6 had been determined, there was little difference in survival between high- and low-IL-6 producers.

“These findings demonstrate the limitations of extrapolating from single mechanisms to outcomes in individuals and populations, which is the typical paradigm used to identify potential treatments,” Dr. Vodovotz said. “Instead, dynamic computational models like ours that simulate multiple factors that interact with each other in complex diseases could be a more efficient and accurate way of predicting outcomes for both individuals and populations. Then we can pursue those avenues that have the greatest likelihood of success in clinical trials.”

“The potential impact of this work is high because clinical trials are difficult and expensive to carry out, and usually can test only a single dose of a drug,” noted co-investigator Timothy Billiar, M.D., George Vance Foster Professor and chair, Pitt Department of Surgery. “Determining the best dose, timing and biomarkers that would characterize patients likely to respond well to therapy is a major thrust of the pharmaceutical and biotechnology companies. This approach could help tailor treatments.”

The project was carried out by the Trauma Research Center, which is headed by Dr. Billiar, and included other researchers from the University of Pittsburgh, the McGowan Institute for Regenerative Medicine, Upstate Medical University in Syracuse, N.Y., and Immunetrics, Inc. It was funded by National Institutes of Health grants GM-53789 and HL-089082.

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