UPMC Physician Resources

Pitt Team Identifies Genes that Play Critical Role in the Development of Congenital Heart Disease

PITTSBURGH, March 25, 2015 – Fetal ultrasound exams on more than 87,000 mice that were exposed to chemicals that can induce random gene mutations enabled developmental biologists at the University of Pittsburgh School of Medicine to identify mutations associated with congenital heart disease in 61 genes, many not previously known to cause the disease. The study, published online today in Nature, indicates that the antenna-like cellular structures called cilia play a critical role in the development of these heart defects.

The findings are the culmination of an effort to find the genetic determinants of structural heart disease in the “Bench to Bassinet” program, launched six years ago by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, led at Pitt by principal investigator Cecilia Lo, Ph.D., professor and chair of the Department of Developmental Biology, Pitt School of Medicine.

“This project has given us new insights into the biological pathways involved in development of the heart,” Dr. Lo said. “The genes and pathways identified in our study will have clinical importance for interrogating the genetic causes of congenital heart disease in patients.”

For the study, Dr. Lo’s team mated mice exposed to chemicals that could create random genetic mutations, resulting in 87,355 pregnancies. They scanned each fetus using noninvasive ultrasound and recovered over 3,000 independent cases of congenital heart defects, all incompatible with life. They sequenced the genes of mutant animals and compared them to those of unaffected offspring to identify 91 recessive mutations in 61 genes.

“We were surprised to learn many of these genes were related to the cilia, or cilia-transduced cell signaling,” Dr. Lo said. “These findings suggest cilia play a central role in the regulation of heart development, including patterning left-right asymmetry in the cardiovascular system critical for efficient oxygenation of blood.”

She added that pathways recovered in the mouse study show overlap with those associated with de novo, or spontaneous, mutations identified in congenital heart disease patients. Co-investigators of the project include other researchers from the University of Pittsburgh; the University of Massachusetts Medical School; the Jackson Laboratory; and Children’s National Medical Center.

The project was funded NHLBI grants HL098180 and HL098188; National Institute of Mental Health grant MH094564; National Human Genome Research Institute grant HG000330; and the University of Pittsburgh School of Medicine.

Rebooting Cell Programming Can Reverse Liver Failure, Says Children’s Hospital/Pitt Study

PITTSBURGH, March 16, 2015 – It might be possible to heal cirrhotic liver disease by rebooting the genes that control liver cell function, according to researchers at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. If validated in human studies, the game-changing strategy, described today in the online version of the Journal of Clinical Investigation, could potentially treat patients who are too sick for liver transplantation and, in the future, reduce the need for transplants.

The project grew out of the observation that not everyone who develops cirrhosis, or scarring of the liver, progresses to liver failure and its life threatening complications, explained Ira Fox, M.D., professor of surgery, Pitt School of Medicine, and director of the Center for Innovative Regenerative Therapies at Children’s Hospital and the McGowan Institute for Regenerative Medicine.

“Even with the large amount of scar tissue that comes with cirrhosis, there should be enough cells left to carry out the normal functions of the liver,” Dr. Fox said. “So when the liver fails, it is the liver cells themselves that aren’t working properly. In this study, we demonstrate what has caused the problem, and more importantly, a way to repair it.”

His team developed a rat model of liver disease that mimics the form of human cirrhosis that progresses to organ failure. In previous work, they found that liver cells taken from animals with cirrhosis, but no liver failure, immediately functioned properly when transplanted into another animal. But cells transplanted from animals with both cirrhosis and liver failure did not function normally at first, indicating that both the liver cells and the liver tissue environment were damaged.

The researchers then compared the genes in the liver cells of the two groups of cirrhotic rats and found unusually low activity levels of the genes that control proteins which play a central role in liver cell function, the most important being a factor called HNF4.

In the new paper, they showed that restoring production of HNF4 by gene therapy reboots the liver cells to normal function. The team first showed this in lab tests and then in rats with liver failure.

“We were pleased to see that the animals got better almost immediately. Remarkably, our tests indicated that it wasn’t stem cells, regeneration or growth of new liver cells that caused improvement. Instead, the diseased cells had healed,” Dr. Fox said. “It seems that in at least some forms of cirrhosis, chronic injury reprograms the liver cells to shut down HNF4 production, a dysfunction that eventually causes liver failure.”

HNF4 gene therapy provided unique insight into the cause of liver failure and has significant potential for human therapy, but the investigators are now looking for other gene targets to develop simpler therapies, such as drugs that block the pathways that mediate failure. The team also is confirming their results with human liver cells.

Co-investigators include Alejandro Soto-Gutierrez, M.D., Ph.D., Joseph Locker, M.D., Ph.D., and other researchers from Children’s Hospital, Pitt School of Medicine and the McGowan Institute; Kyoto Prefectural University of Medicine, Japan; and the University of Pennsylvania.

The project was funded by National Institutes of Health grants DK48794, DK099320 and DK099257, as well as grants from the U.S. Department of Defense.

Pitt Experts Present at AAP Annual Meeting

SAN ANTONIO, March 16, 2015 – The University of Pittsburgh was well-represented at the recent Association of Academic Physiatrists (AAP) Annual Meeting in San Antonio. Faculty research was featured in oral and poster presentations throughout the conference, including:

Two physical medicine and rehabilitation residents also received awards for the following presentations:

For more information, or to view a complete list of presentations at the AAP Annual Meeting, please visit the conference page.

 

Pitt, CMU, UPMC Form Alliance to Transform Health Care through Big Data

PITTSBURGH, March 16, 2015 – Today’s health care system generates massive amounts of data – patient information in the electronic health record, diagnostic imaging, prescriptions, genomic profiles, insurance records, even data from wearable devices. Information has always been essential for guiding the care of individuals, but computer tools now make it possible to use that data to provide deeper insights into disease itself.

Leveraging “big data” to revolutionize health care and wellness is the focus of the new Pittsburgh Health Data Alliance, a powerful collaboration announced today by Carnegie Mellon University, the University of Pittsburgh and UPMC.

For example, the use of smart data could help hospitals and doctors rapidly detect potential new outbreaks and immediately alert staff and authorities to take appropriate actions. Systems based around this principle of finding emerging events in complex data sets have already been made possible by collaborations among UPMC, Pitt, and CMU.

This one-of-a-kind alliance is a wide-reaching commitment to advance technology and create new data-heavy health care innovations over the coming years, resulting in spin-off companies and furthering economic development in the region.

The alliance, funded by UPMC, will see its work carried out by Pitt-led and CMU-led centers, with participation from all three institutions. The centers will work to transform the explosion of health-related data into new technologies, products and services to change the way diseases are prevented and how patients are diagnosed, treated and engaged in their own care.

Using health care data to its full potential will require close collaboration among the leading health sciences research at Pitt, world-class computer science and machine learning at CMU, and the clinical care, extensive patient data and commercialization expertise at UPMC. The close proximity and world-leading talent among these organizations provide the ideal setting to transform all aspects of health care, not only in western Pennsylvania but around the world.

“The complementary strengths of the alliance’s partner institutions will allow us to re-imagine health care for millions of people in our shared, data-driven world,” said Subra Suresh, president of CMU. “Through this collaboration, we will move more rapidly to immediate prevention and remediation, further accelerate the development of evidence-based medicine, and augment disease-centered models with patient-centered models of care.”

The new research centers at CMU and Pitt will be funded over the next six years by UPMC and also will benefit from several hundred million dollars in existing research grants at all three institutions. They promise to create what UPMC CEO Jeffrey Romoff calls an “innovation ecosystem” for health data in the region.

“We are unlocking the potential of data to tackle some of our nation’s biggest challenges: raising the quality and reducing the cost of health care. Not only will this effort benefit patients, but it also will accelerate Pittsburgh’s revitalization,” said Mr. Romoff. Corporate partners and entrepreneurs from around the world will want to be close to this health care data hub, he predicted, just as Google, Apple and Disney already have space in or near Oakland to be close to CMU’s and Pitt’s talented faculty and students.

The alliance will support applied research and commercialization, along with basic foundational research in medicine and computer science. “Through this partnership, our brilliant scientists at Pitt and CMU will have unprecedented resources for turning their innovative ideas into products and services that can truly better the lives of patients and society,” said Patrick Gallagher, chancellor of the University of Pittsburgh. “The knowledge created here will result in the spin-off of many new companies and thousands of new jobs over the next decade.”

Initially, the Pittsburgh Health Data Alliance will include two research and development centers: the Center for Machine Learning and Health (CMLH), led by founding director Eric Xing, Ph.D., a CMU professor in the Department of Machine Learning; and the Center for Commercial Applications of Healthcare Data (CCA), spearheaded by Michael Becich, M.D., Ph.D., chair of the Department of Biomedical Informatics at Pitt. Scientists from all three institutions will participate in the work of each center.

The CMLH will work on challenging problems at the intersections of health care and machine learning. Data from sources as varied as electronic medical records, genomic sequencing, insurance records and wearable sensors will be utilized to directly improve health care. For example, imagine a smartphone app that suggests the single dietary change that will most improve your health, based on your genetic makeup and medical history. Or suppose a physician receives an automatic alert when a patient enters the earliest stages of rejecting a transplanted organ and can react while the condition is most easily treatable. The center will focus on five areas: big health care data analytics; personalized medicine and disease modeling; issues of privacy, security and compliance in the context of big data; data-driven patient and provider education and training; and a new general framework for big data in health care.

The CCA at the University of Pittsburgh will research and invent new technology for potential use in commercial theranostics and imaging systems for patients and doctors. (Theranostics works to develop individualized therapies for various diseases, and to combine diagnostic and therapeutic capabilities.) These technologies will be based on intelligently engineered big data solutions. Some areas of focus for CCA will be: personalized medicine for understanding diseases such as cancer and various lung disorders; genomics and imaging data; and methods for data capture and health care analytics. A key goal is new technologies and methods to create actionable information.

UPMC Enterprises, the commercialization arm of UPMC, will lead the efforts to turn these innovative ideas into new, for-profit companies and jobs, building on its nearly 20-year track record of investing in and growing companies that solve health care problems.

For more information about the Pittsburgh Health Data Alliance, visit www.healthdataalliance.com.

Prakash Jayabalan, MD, PhD, Selected for Outstanding Resident and Best Paper Awards at AAP Annual Meeting

SAN ANTONIO, March 16, 2015 – Prakash Jayabalan, MD, PhD, a fourth-year physical medicine and rehabilitation resident at the University of Pittsburgh, was chosen for the Association of Academic Physiatrists (AAP) McLean Outstanding Resident/Fellow Award. The award was presented Friday at the AAP annual Meeting in San Antonio.

The McLean Outstanding Resident/Fellow Award honors an AAP member who demonstrated outstanding academic performance in academic leadership, teaching and education, and research.

Dr. Jayabalan and co-author Gwendolyn Sowa, MD, PhD, also were honored with an AAP Best Paper Award for their presentation of “The Effect of Walking Exercise Regimens on Gait Parameters and Cartilage Turnover in Patients with Knee Osteoarthritis.”

Dr. Jayabalan completed his medical degree at King’s College London School of Medicine. His research interests include the development of biomarkers for degenerative musculoskeletal conditions, the development of more efficacious therapy protocols for osteoarthritis, and the use of visual feedback to improve motivation to continue therapy.

For more information, please visit the AAP Awards page.

Physiatry Resident Chosen for Best Paper Award at AAP Annual Meeting

SAN ANTONIO, March 15, 2015 – Jessica Ziebarth, DO, a fourth-year physical medicine and rehabilitation resident at the University of Pittsburgh, was selected for an Electrode Store Best Paper Award by the Association of Academic Physiatrists (AAP). Dr. Ziebarth’s paper, “Impact of Early Mobility on Length of Stay in the Acute Care Hospital Setting,” was presented during a plenary session at the 2015 AAP Annual Meeting this week in San Antonio.

The Electrode Store Best Paper Award encourages young researchers and strengthens investigation in the field of physical medicine and rehabilitation. One paper is chosen from resident submissions by the AAP Program Committee.

Dr. Ziebarth completed her medical degree at Lake Erie College of Osteopathic Medicine. Her research interests include outpatient care for patients with spinal cord injuries, heterotopic ossification in patients with lower limb amputations, performing arts medicine, and early mobility in hospitalized and critically ill patients.

For more information about AAP and the Electrode Store Award winners, please visit the accepted abstracts page.

Mark Gladwin, M.D., Named New Chair of Department of Medicine at Pitt School of Medicine

PITTSBURGH, March 6, 2015 – The University of Pittsburgh School of Medicine has chosen one if its own renowned faculty members to be the next chair of the Department of Medicine, which ranks among the nation’s largest clinical and research departments with divisions in cancer, cardiology, endocrinology, gastroenterology, geriatrics, infectious diseases, kidney, lung and allergy, and rheumatology.

Mark T. Gladwin, M.D., who assumed his new role on March 1, will remain the director of Pitt’s Heart, Lung, Blood, and Vascular Medicine Institute and will continue to see patients in the critical care units at UPMC Presbyterian. He was recognized as a Distinguished Professor of Medicine in 2014.

“Dr. Gladwin will be taking on critical responsibilities in a time when the scientific opportunities to improve the human condition have never been greater, but the funding to address these opportunities has never been more threatened,” noted Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine. “I have great confidence in his ability to rise to these challenges and take the Department of Medicine to the highest achievements in medical education, as well as research and clinical excellence.”

The Department of Medicine is home to 650 faculty members and 10 divisions, including Pulmonary, Allergy, and Critical Care Medicine (PACCM), which Dr. Gladwin chaired for the past six years. Last year, the department’s direct research expenditures were $94 million, and its physicians saw 340,000 outpatients.

“I am honored to be selected to play this key role in the School of Medicine,” Dr. Gladwin said. “We face many opportunities to translate the remarkable progress in genetics and science to better care for our patients and to develop new therapies. I am convinced that Pittsburgh will continue to be home and catalyst for new models of efficient and high quality patient-centered care and the training of future generations of physicians and scientists. Our work and success will enhance our regional economy, with science and medicine bringing National Institutes of Health grants to the community and attracting new businesses and industry partnerships that will take our exciting discoveries to the patient at the bedside and the clinic.”

Dr. Gladwin will continue his research into the role of nitrite and nitric oxide (NO) in vascular medicine. Among his major scientific discoveries is the finding that the nitrite salt is a biological signaling molecule that regulates physiological and pathological hypoxic responses, blood pressure and flow, and dynamic mitochondrial electron transport. His 2003 Nature Medicine paper on proteins that regulate NO production has been cited more than 1,000 times, is listed in the journal’s top 10 “Classic Collection,” and has led to the development and licensing of intravenous, oral and inhaled nitrite as a human therapeutic agent, currently in clinical trials. He also has characterized a novel mechanism of disease called hemolysis-associated endothelial dysfunction, a state of resistance to NO in patients with sickle cell disease, malaria, the transfusion of aged blood, and other conditions of damaged red blood cells.

Dr. Gladwin received his bachelors of science and medical degrees from the University of Miami. He completed his internship and chief residency in internal medicine at the Oregon Health Sciences University in Portland, followed by a critical care medicine fellowship at the National Institutes of Health and a pulmonary fellowship at the University of Washington. He returned to NIH for postdoctoral research fellowships in cell and molecular biology and later served as chief of the Pulmonary and Vascular Medicine Branch of the National Heart, Lung, and Blood Institute, part of NIH. He joined Pitt as chief of PACCM in August 2008.

Among Dr. Gladwin’s numerous academic awards are: the U.S. Public Health Service Achievement Award, the NIH Director’s Award for Mentoring, the NIH Clinical Center Director’s Award for Science, and the Recognition Award for Scientific Accomplishments from the American Thoracic Society.

He succeeds John Reilly, M.D., who is now dean of the University of Colorado’s medical school.

Workplace Lifestyle Intervention Program Improves Health, Reduces Diabetes and Heart Disease Risks

PITTSBURGH, March 6, 2015 – A healthy lifestyle intervention program administered at the workplace and developed by the University of Pittsburgh Graduate School of Public Health significantly reduces risk factors for diabetes and heart disease, according to a study reported in the March issue of the Journal of Occupational and Environmental Medicine.

The program was well-received by participants at Bayer Corp., who lost weight and increased the amount of physical activity they got each day, when compared with a control group in the study, which was funded by the National Institutes of Health.

“Health care expenditures associated with diabetes are spiraling, causing widespread concern, particularly for employers who worry about employee health and productivity,” said lead author M. Kaye Kramer, Dr.P.H., assistant professor in Pitt Public Health’s Department of Epidemiology and director of the school’s Diabetes Prevention Support Center. “This leads to an interest in workplace health promotion; however, there are very few evidence-based programs that actually demonstrate improvement in employee health. This study found that our program not only improves health, but also that employees really like it.”

This demonstration program is based on the U.S. Diabetes Prevention Program (DPP), a national study that found people at risk for diabetes who lost a modest amount of weight through diet and exercise sharply reduced their chances of developing diabetes, outperforming people who took a diabetes drug instead.

Dr. Kramer and colleagues built on the DPP to create a group-based program that puts the findings into practice, called Group Lifestyle Balance. The program is divided into 22 sessions over a one-year period and aimed at helping people make lifestyle changes to improve health. The sessions can be done as a group with a lifestyle coach or through a DVD coupled with brief weekly phone or, in certain cases, email consultations with the lifestyle coach. The option of the DVD with lifestyle coach support not only served as the main intervention option for those employees who traveled or who did not want to participate in the program in a group venue but also offered a valuable replacement for employees who chose to participate via group setting but had to miss an occasional session.

“Our Group Lifestyle Balance program has proven successful in diverse community settings, so we adapted it for the workplace since we found that there was a real need for effective programs that could fit into people’s work lives,” said senior author Andrea Kriska, Ph.D., professor in Pitt Public Health’s Department of Epidemiology and principal investigator of the study. “This current effort in the worksite shows clearly that a proven healthy lifestyle program, like the Group Lifestyle Balance program, offered to people where they work is not only feasible but effective in reducing risk factors for diabetes and heart disease for participating employees.”

A total of 89 employees at Bayer Corp. in Robinson Township, Pa., who were at risk for diabetes or heart disease were enrolled in the demonstration program in the fall of 2010 and followed for 18 months.

Over the course of a year, participants lost an average of 5 percent of their body weight (10 pounds), shrunk their waistlines by about 2 inches and brought down the levels of fat and sugar in their blood – all measures that reduce the risk of heart disease and diabetes. They also increased their physical activity by almost twofold.

Of the participants, 96 percent said they felt it was beneficial to offer the program at the worksite, and 99 percent said they would recommend it to their co-workers.

“The positive results that employees experienced from this lifestyle program speak to the benefits of personalized health programs in the workplace,” said Phil Franklin, M.D., U.S. corporate medical director, Bayer Corp. “I would like to congratulate the University of Pittsburgh researchers on the study.”  

Additional authors on this research are Donald Molenaar, M.D., Veterans Health Administration in Minneapolis; Elizabeth Venditti, Ph.D., Western Psychiatric Institute and Clinic of UPMC; and Vincent C. Arena, Ph.D., Rebecca Meehan, M.S., R.D., L.D.N., Rachel Miller, M.S., Karl Vanderwood, Ph.D., and Yvonne Eaglehouse, M.S., M.P.H., all of Pitt Public Health.

This research was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases (R18 DK081323–04).

Pediatric Rehabilitation Chief Asked to Participate in CDC, AAP Activities

PITTSBURGH, March 5, 2015 – Amy Houtrow, MD, PhD, MPH, chief, Division of Pediatric Rehabilitation Medicine and a member of the Brain Care Institute at Children’s Hospital of Pittsburgh of UPMC, recently was invited by the Centers for Disease Control and Prevention (CDC) to participate in its National Center on Birth Defects and Developmental Disabilities (NCBDDD) and the Division of Human Development and Disability. Selected for her expertise in the area of disability and health, Dr. Houtrow also serves as associate professor and vice chair in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh. The group’s goal is to develop concrete recommendations to inform a current and innovative Disability and Health Branch roadmap over the next decade.

Dr. Houtrow also has been asked to serve on the American Academy of Pediatrics (AAP) National Conference & Exhibition Planning Group, a cross-section of more than two dozen practicing pediatricians, medical, and surgical pediatric subspecialists. The group reviews and accepts approximately 350 sessions — out of more than 500 proposals — that comprise the conference program.

Pervasive Chemical Potentially Alters Levels of a Pregnancy Hormone that Influences Sex Development

PITTSBURGH, March 5, 2015 – Exposure to hormone-altering chemicals called phthalates – which are found in many plastics, foods  and personal care products – early in pregnancy is associated with a disruption in an essential pregnancy hormone and adversely affects the masculinization of male genitals in the baby, according to research led by the University of Pittsburgh Graduate School of Public Health.

The findings, presented today at the Endocrine Society’s 97th annual meeting in San Diego and funded by the National Institute of Environmental Health Sciences, focus on the role of the placenta in responding to these chemicals and altering levels of a key pregnancy hormone. These results suggest that there may be reason to push routine clinical testing earlier in pregnancy to check for the effects of chemicals and help guide potential interventions to protect the health of the baby.

“Phthalates are pervasive,” said Jennifer Adibi, M.P.H., Sc.D., assistant professor of epidemiology at Pitt Public Health. “Reducing exposure to phthalates and other hormone-disrupting chemicals is something that needs to be addressed at a societal level through consumer advocacy and regulation, and education of health care providers.”

The research builds on a study led by Shanna S. Swan, Ph.D., of the Icahn School of Medicine at Mount Sinai that was published in February in the journal Human Reproduction. Dr. Swan is senior investigator on this presentation, which provides new information about how phthalates target a key pregnancy hormone called human chorionic gonadotropin (hCG), which is made by the placenta and can be measured in the mother’s blood and urine.

“The placenta, which is an extension of the fetus and a target of the chemicals in our bodies, broadcasts information early in pregnancy, through hCG, about what might be occurring to the fetus from chemical exposure,” said Dr. Adibi. “A long-term benefit of this research might be the development of new knowledge and methods for earlier screening in pregnancy, with the potential to act on this information to improve the long-term health of the future child.”

Dr. Adibi and her colleagues analyzed data collected from approximately 350 women and their babies who participated in a multicenter investigation called The Infant Development and the Environment Study (TIDES). Between 2010 and 2012, the women gave blood and urine samples in their first trimester of pregnancy and allowed researchers to take measurements of the babies at birth.

Higher levels of two molecules that are produced when phthalates are digested – mono-n-butyl and monobenzyl phthalate – in the mothers’ urine early in pregnancy were significantly associated with lower levels of hCG in women carrying male babies and with higher hCG in those carrying female babies.

The new research also looked at hCG in relation to a biological marker called anogenital distance, which is the distance between the anus and genitals. In men, a short anogenital distance is associated with decreased sperm count and infertility.

Higher levels of hCG in the mother’s blood were associated with a shorter anogenital distance in male babies. The researchers estimate that about 20 to 30 percent of the phthalate effect on the babies’ genitals could be attributed to the influence of phthalates on hCG, specifically mono-n-butyl and mono-ethylhexyl phthalate.

“Our study is the first to look at hCG as a target of phthalate exposure in pregnancy,” said Dr. Adibi. “There is growing societal concern over pediatric disorders that have a basis in the fetal period and which may be more common in one sex or another, such as autism, attention deficit disorder, obesity, asthma and infertility. It is important to find out if chemicals in our food or environment might influence these conditions.”

The participants in this study were enrolled at prenatal clinics in California, Washington, Minnesota and New York. Dr. Adibi is looking ahead to future studies where she will enroll women in the earliest stages of pregnancy at clinics in Pittsburgh to assess exposures to endocrine disruptors and measure effects on the placenta and the baby.

Additional researchers on this study are Myoung Keun Lee, M.S., of Pitt; Ashley I. Naimi, Ph.D., of McGill University; Emily Barrett, Ph.D., of the University of Rochester; Ruby Nguyen, Ph.D., and Bruce Redmon, M.D., both of the University of Minnesota; Sheela Sathyanarayana, M.D., M.P.H., of the University of Washington; and Kara Saperston, M.D., Mari-Paule Thiet, M.D., Sarah Janssen, M.D., Ph.D., M.P.H., and Lawrence Baskin, M.D., all of the University of California.

This research was funded by National Institutes of Environmental Health Sciences grants 1 K99 ES017780-01 and 5 R00 ES017780-06. TIDES was funded by National Institute of Environmental Health Sciences grants R01 ES016863-04 and R01 ES016863-02S4.

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