May 06 2015

Gynecologist’s Studies Aim to Improve Adolescent Girls’ Health

adolescent girls' healthAdolescent gynecologist Aletha Y. Akers, MD, MPH, is a busy woman. Still relatively new to CHOP, Dr. Akers has already tackled her many responsibilities with aplomb: launching Children’s Hospital’s new adolescent gynecological consult service; seeing patients in the clinic; and leading two studies: a clinical trial, and an analysis of data from two large datasets of adolescent health in the U.S.

Dr. Akers’ clinical trial, funded by a grant from Bayer Healthcare is an investigation of the new Skyla intrauterine system (IUS, also known as an IUD), which was approved by the FDA in late 2013. Her second study is supported by an award from the NIH Dr. Akers received to study the role romantic and peer relationships play in the sexual behavior of obese and non-obese adolescent girls.

After spending eight years at the University of Pittsburgh Medical Center’s Magee-Womens Research Institute, Dr. Akers came to Children’s Hospital in August 2014. In addition to being a practicing gynecologist, Dr. Akers — who is also a faculty member at PolicyLab — conducts research focused on adolescent sexual behavior and reproductive health services. She is also director of the Division of Adolescent Medicine’s new Adolescent Gynecology Consultative Services, which she will be developing in conjunction with Hospital of the University of Pennsylvania (HUP) gynecologists.

Investigating Contraceptive Pain

Dr. Akers’ Skyla IUS trial is rooted in the fact that adolescents experience the highest rates of unintended pregnancy among women of all reproductive age groups, she said. Indeed, according to CDC data, the birth rate for teens aged 15 to 19 years old outpaces that of the general population, at 26.5 live births per 1,000 versus 12.4 births per 1,000.

Long-acting reversible contraceptives like IUDs are considered first-line options for pregnancy prevention in adolescents, and are very effective at treating menstrual disorders, but their uptake remains low among adolescents, Dr. Akers noted. Many adolescents cite the fear of pain during insertion of these devices as a major barrier to adoption.

While a number of studies have examined pain control options among adult women, few have been focused on adolescent women under age 21, who are unlikely to have ever had a pelvic exam or gynecologic procedure. To that end, Dr. Akers has been leading a study of pain associated with the latest intrauterine system (IUS) to hit the market, the Skyla. Manufactured by Bayer Healthcare, the Skyla IUS is the smallest IUS currently on the market. Skyla’s smaller size could mean its insertion is less painful than other, larger IUS devices.

With this trial Dr. Akers hopes to answer the question of how effective paracervical nerve blocks, in which pain medication is injected into sites around the cervix, are at reducing IUS pain in women aged 14 to 22 years. Subjects will be randomized to receive an anesthetic versus those who will receive a “sham” paracervical block, meaning they will be touched with the end of a Q-tip rather than injected.

Because adolescents often have less experience with gynecological procedures, they have less experience with discomfort in that part of the body, and can be more wary of vaginal examinations or procedures, Dr. Akers noted. And because Skyla doesn’t carry the same minimum uterus size restrictions as other IUS devices, it could be used in adolescents who need menstrual cycle control or help with family planning, she said.

Obesity and Sexual Behavior

Where her Skyla investigation is clinical, Dr. Akers’ second project, funded by the NICHD, is data-based. Over the course of the investigation, she will be examining the role social relationships play in the sexual behavior of obese and non-obese girls. By studying large datasets, Dr. Akers and her team hope to determine whether body mass index accounts for differences in how girls develop relationships, and whether that has an impact on their sexual practices.

“There is previous literature that shows that there is a relationship between obesity and reproductive health and relationship formation for women,” noted Dr. Akers.

Adolescent obesity is associated with higher rates of sexual risk-taking and drug use. For example, a 2014 Journal of Obesity study showed obese, sexually active adolescent girls were more likely to have multiple sex partners and engage in unprotected intercourse. And work by Dr. Akers, published in Pediatrics in 2009, showed girls who perceive themselves to be overweight may be less likely to negotiate condom use and more likely to initiate sex early. Moreover, the relationship between obesity and sexual behaviors varied significantly by race.

In their current investigation, the researchers will be making use of two datasets: the Pittsburgh Girls Study which completed 14 years of data collection in 2013 and the National Longitudinal Study of Adolescent Health, which started in 1994 and is currently collecting its fifth wave of data. Both are large datasets and compliment each other.

The overall point of the work, Dr. Akers said, is to ask, “if we look at how peer relationships develop for children, and if we look more at how romantic relationships develop … is there a relationship between the two, and can we identify some key factors that begin to help us to think about how we may want to structure prevention efforts, educational efforts for these girls?”

To learn more about Dr. Akers’ work and adolescent medicine at CHOP, see the April edition of Bench to Bedside.

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May 05 2015

New Guideline Curbs Overuse of Antibiotics for Tonsillectomies

tonsillectomyAntimicrobial resistance is spreading around the world, hampering physicians’ capacity for treating bacterial infections swiftly and reliably. Partly to blame is clinical overuse of antibiotics, so researchers are examining ways that clinicians can change or improve their antibiotic stewardship practices.

For example, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published a guideline in 2011 recommending that “clinicians should not routinely administer or prescribe perioperative antibiotics to children undergoing tonsillectomy.”

“This is a big deal because tonsillectomy is the second most common surgical procedure in kids — each year, more than 500,000 children undergo the procedure in the U.S.,” said Jeffrey S. Gerber, MD, PhD, MSCE, an attending physician in Infectious Diseases at The Children’s Hospital of Philadelphia. “Just at CHOP and our satellite ambulatory surgical centers, we perform about 3,000 tonsillectomies per year.”

Tonsillectomy is usually an outpatient procedure in which a surgeon removes a child’s tonsils. In many cases, the reason for a child having a tonsillectomy is a history of recurrent throat infections or obstructive sleep apnea.

Prior to the implementing the AAO-HNS guideline, patients undergoing tonsillectomy at CHOP received antibiotics in the operating room and then were sent home with a prescription for three to five days of outpatient oral antibiotics. Do some quick math, and that equals about 12,000 additional patient-days of antibiotic use. Reducing children’s exposure to antibiotics not only would help to combat antimicrobial resistance, but it also would avoid antibiotics’ adverse side effects, such as allergic reactions, and reduce drug costs.

Dr. Gerber and colleagues designed a study to see what happened at CHOP after this guideline was published. If clinicians followed the guideline, did this change in practice have any effect on patients’ health? In order to assess these trends, they conducted a time series analysis, which basically is a before-and-after study that takes into account trends over time. They used data from CHOP’s shared electronic health record and narrowed it down to 5,359 routine tonsillectomy cases performed from January 2009 through August 2012.

The results showed “a dramatic decrease in perioperative antibiotic use in concordance with the guideline’s recommendation,” wrote the study’s lead author, Edmund A. Milder, MD, of the Naval Medical Center in San Diego, in JAMA Otolaryngology-Head & Neck Surgery.

The findings suggest that CHOP’s group of 10 ear, nose, and throat surgeons quickly adapted their practices to meet the new guidelines, essentially stopping cold turkey from prescribing perioperative antibiotics for tonsillectomies. The researchers reported a 91 percent decrease in perioperative antibiotic use.

“That is pretty impressive,” Dr. Gerber said. “They perform operations at three different sites, and they were all doing things in a standardized, guideline-adherent way, which was terrific.”

The potential rub of the study, however, is that the researchers uncovered a small but statistically significant increase in the rate of post-tonsillectomy bleeding in the month following guideline publication. Other clinical complications were uncommon, and there was no increase in the rate of surgery office visits, emergency department visits, or hospital admissions.

The researchers found the increased rate of bleeding surprising, Dr. Gerber said, because there is not a plausible biological mechanism to explain to why antibiotics would prevent bleeding or, on the other hand, why it would be an unintentional consequence of the practice change to decrease antibiotic use. The study team plans to investigate this unexpected outcome further in a larger, multicenter study that is underway.

“We are looking at a database of 48 children’s hospitals across the country,” said Dr. Gerber, who also is associate director for Inpatient Research Activities for CHOP’s Center for Pediatric Clinical Effectiveness and director of CHOP’s Antimicrobial Stewardship Program. “We’ll see if other hospitals, in addition to CHOP, changed their practice according to the guideline, and if so, is there a relationship between antibiotic use and post-tonsillectomy bleeding?”

The study team’s goal is to have some preliminary data ready to present at ID Week, an international infectious disease meeting being held in San Diego this October.

Mark Rizzi, MD, a CHOP otorhinolaryngologist and assistant professor of Clinical Otorhinolaryngology in the department of Head and Neck Surgery at the Perelman School of Medicine of the University of Pennsylvania; Knashawn Morales ScD, assistant professor of Biostatistics and Epidemiology at UPenn; Rachael Ross, MPH, of CHOP’s division of Infectious Diseases and the Center for Pediatric Clinical Effectiveness; and Ebbing Lautenbach, MD, MPH, MSCE, chief of the division of Infectious Diseases and associate director of the Clinical Epidemiology Unit at the Center for Clinical Epidemiology and Biostatistics at UPenn, contributed to the JAMA Otolaryngology-Head & Neck Surgery article.

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May 04 2015

Precision Medicine Trial to Focus on Children With Advanced Cancers

cancer treatmentWhen a clear, curative pathway is not available for pediatric cancers that relapse, families often will turn to new, experimental treatments being studied by The Children’s Oncology Group with hopes of exploring other options to care for their children. A new research opportunity under development as part of its Project:EveryChild, called Project:EveryChild Pediatric MATCH (Molecular Analysis for Therapy Choice), aims to use the power of precision medicine to potentially provide investigational therapies for some children with advanced cancers.

The Children’s Oncology Group, a collaboration of more than 220 leading children’s hospitals, universities, and cancer centers from across the globe — including The Children’s Hospital of Philadelphia — is the world’s largest organization devoted exclusively to childhood and adolescent cancer research.

Each year, nearly 13,500 children and teens are diagnosed with numerous types of cancer. Within those types of cancer, there are multiple subsets of disease. Some are harder to treat than others. Scientists suspect that the tumors involved in those stubborn cases may have different genetic alterations that help them to resist standard therapy and begin to grow.

“Pediatric MATCH will try to match genomic changes in certain children’s cancers with drugs that are either approved for adult cancers or with drugs that are still under investigation and not yet approved,” said Peter Adamson, MD, chair of the Children’s Oncology Group and a pediatric oncologist at CHOP. “The other goal is to try to understand if there is a genomic basis for when our treatments fail and how the cancers may have changed from the time of original diagnosis.”

While Pediatric MATCH is still under development, Dr. Adamson expects that the study enrollment will include about 300 children each year with advanced cancers that have progressed on standard therapy. Although only some of these children will have cancers that can be matched to a new drug, a significant aspect of Pediatric MATCH is those children with matches will be assigned to a phase II research protocol based on the genetic abnormality that seems to be fueling their disease progression, not the type of cancer.

After the child undergoes a tumor biopsy at relapse, some of the tissue will be sent to a centralized center for specific tests that may include next-generation DNA sequencing. Once investigators identify the tumor’s genomic changes and characteristics, they will sort through a group of 20 to 25 selected targeted drugs to see if one has shown some efficacy against tumors with the same genetic alterations. Should a match be found, the child will then be able to receive that drug to see if it is of some potential benefit.

“What we know to date about the genomics of cancer at diagnosis and at relapse is that perhaps there are somewhere in the order of about 15 percent of cancers that may have a finding for which we may have a drug,” Dr. Adamson said.

In a unique arrangement, the Pediatric MATCH trial is a combined effort of the Children’s Oncology Group, the National Cancer Institute (NCI), and a range of pharmaceutical companies that already have committed to providing drugs to be tested in an adult NCI MATCH Trial slated to begin this year. Dr. Adamson anticipates that many of this similar counterpart trial’s pharmaceutical agreements will carry over to Pediatric MATCH. New drugs could be added to the trials over time.

“That is of great importance to this project because all childhood cancers are rare diseases, and there generally isn’t an economic model for pharmaceutical companies to study childhood cancers,” Dr. Adamson said.

While the Children’s Oncology Group has partnered successfully in the past with companies to provide two different experimental drugs in a single research trial, Pediatric MATCH will be a significant leap beyond that model. Dr. Adamson estimates up to 10 companies will be participating in Pediatric MATCH, and each will receive information that will advance knowledge, may benefit children, and also could help the companies to accelerate their drug development.

“We hope that we will be able to see signals of efficacy that these drugs are working that would then lead to potentially additional trials that become disease-specific for that drug,” Dr. Adamson said. “Well-defined genomic testing may one day provide a lead to having a portfolio of drugs that may be of benefit to the child.”

The Pediatric MATCH study team also will share tumor analysis results with the child’s cancer specialists to help them guide the family’s treatment choices. In addition, the tissue samples will be highly valuable to future researchers as they try to explain the basis of cancer treatment failure and relapse.

“If we find that a certain pathway is very important for a disease or subset of diseases, we can build upon that and perhaps bring new treatments into that disease area, not only for relapsed cancer, but potentially to move those treatments earlier into therapy for appropriate populations,” said Dr. Adamson, who also is a professor of pediatrics and pharmacology at the Perelman School of Medicine at the University of Pennsylvania.

Pediatric MATCH is a high priority for the Children’s Oncology Group, Dr. Adamson said, with five working groups focused on an aggressive timeline of launching the trial toward the beginning of 2016.

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May 01 2015

New CHOP Research Center Will Address Pediatric Health Disparities

health disparitiesThough clinicians are tasked with doing their very best to extend the same level of care to all patients, the fact remains disparities exist in care and health outcomes, especially in pediatric patients. A new center at The Children’s Hospital of Philadelphia Research Institute will seek to support these most vulnerable patients by conducting research to better understand the root of disparities — be they racial, gender-based, or caused by geography.

The Center for Perinatal and Pediatric Health Disparities Research (CPHD) will work to “identify, describe, and understand disparities in care and care practices among perinatal and pediatric patients.”

The new Center will be led by Scott Lorch, MD, MSCE, the Harriet and Ronald Lassin Endowed Chair in Pediatric Neonatology. Dr. Lorch is also director of the Neonatal-Perinatal Medicine Fellowship Program in the Division of Neonatology and Deputy Director of the Center for Outcomes Research at CHOP, as well as an associate professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

“Research in adult patients has shown that there are extensive disparities in the care received by minority patients, particularly Hispanic and African-American patients,” said Dr. Lorch. “CPHD, through multidisciplinary academic and clinical research, aims to understand how these same disparities apply to the perinatal population, where the mother-fetal interaction is of primary importance, and the pediatric population, where family/mother-child interaction is of primary importance.”

Dr. Lorch is an ideal choice to lead the new Center, because his work — focused on health disparities, the economics and geography of healthcare, and perinatal epidemiology — dovetails nicely with the Center’s mission. In addition to currently overseeing several federally funded investigations, Dr. Lorch has contributed to recent papers in the American Journal of Obstetrics and Gynecology, Pediatrics, JAMA Pediatrics, and The American Journal of Public Health.

Other faculty associated with the new Center include Nadia Dowshen, MD; Kristin Feemster, MD, MPH, MSHP; Chén Kenyon, MD, MSHP; and Saba Khan, MD. The Center’s Associate Director is Ashley E. Martin, MPH, while Molly Passarella, MS, will perform statistical programming for the CPHD.

And though it was only recently established, the CPHD has already announced its first round of pilot project funding for junior investigators associated with CHOP. Designed to support pediatric and perinatal health disparities projects, the CPHD Pilot Grant Program “aims to engage fellows and junior faculty in HD research and to assist established faculty in developing new lines of research in this area,” said Martin.

The CPHD has also partnered with a number of community organizations and other partners to advance its goals of identifying and addressing pediatric and perinatal disparities. They range from the governmental to those in higher education, such as the University of Pennsylvania’s Netter Center for Community Partnerships, and nonprofit organizations like Public Citizens for Children and Youth.

Indeed, one of Dr. Lorch’s current investigations, on obstetric (OB) unit closures in Philadelphia, involved working with obstetric department chairs, leaders of private obstetric groups, and others to understand the impact OB unit closures can have on patients and hospital.

All of the Center for Perinatal and Pediatric Health Disparities Research’s work seeks to better understand and confront disparities. Ultimately, Dr. Lorch said, with its work the Center hopes to inspire the next generation of pediatric medical researchers to conduct health disparities research, and to start a dialogue about pediatric and perinatal health disparities, with the ultimate goal of improving outcomes for patients.

To learn more about the Center for Perinatal and Pediatric Health Disparities Research, see the April issue of Bench to Bedside.

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Apr 30 2015

Researchers Developing Registry for Pediatric Pulmonary Hypertension

hypertensionWhile pulmonary hypertension (PH) is a relatively rare problem in pediatrics, the frequency of the diagnosis and PH-related hospitalizations are rising. PH complicates a number of different disease processes, including congenital heart disease, chronic lung disease of prematurity, and genetic disorders. In other cases, the cause of PH may be unknown.

“Without being melodramatic, pulmonary hypertension is a massive problem in the U.S.,” said Brian Hanna, MDCM, PhD, director of the pulmonary hypertension program at The Children’s Hospital of Philadelphia that follows more 650 children and adolescents with PH. “It consumes a huge amount of resources, not just hospital beds. We consult with virtually every service in the hospital — catheterizations, echocardiograms, laboratories, pharmacy, and others.”

Pulmonary hypertension occurs when the arteries of the lungs (the pulmonary arteries) have high blood pressure. Over time, the pulmonary arteries narrow, making the right side of the heart work harder. While researchers have come a long way in the past few decades in terms of understanding the disease, there is no cure or FDA-approved therapies for pediatric PH.

“We still have more questions than answers,” said Rachel Hopper, MD an attending cardiologist in pulmonary hypertension at the CHOP Cardiac Center  and assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Who gets pulmonary hypertension? Why do they get pulmonary hypertension? Why do some children with hypertension improve over time, while others will end up needing a lung transplant? We need to collaborate as practitioners to pool enough data to answer those questions.”

That is why Dr. Hanna and Dr. Hopper are excited that The National Heart, Lung, and Blood Institute recently awarded a grant to support the nine pediatric centers, including CHOP, that are members of the Pediatric Pulmonary Hypertension Network (PPHNet) in their efforts to build an informatics registry.

For research purposes, a registry provides a shared infrastructure and standardized data collection in a single resource so that investigators can evaluate specific outcomes for a group of patients who share the same condition. For example, the PPHNet registry could help researchers determine the response of children with PH to certain therapies. On its own, an individual pediatric PH center would not be able to gather this information for a large enough number of children with PH.

Traditionally, registries are expensive to run because they require diligent maintenance to ensure that the data is precisely collected and valid for research. A unique feature of the PPHNet project is that it aims to determine if it is possible to obtain the same type of data using computer software to crawl through electronic health records (EHRs). The researchers will compare the value of both methods and determine if the data generated produce the same results upon analysis during an observational study.

As they figure out the most efficient and accurate way to collect and store registry information about children with PH, the researchers also hope to gain important insights into the causes, clinical course, and diagnostic approaches to the diverse conditions associated with PH that will lead to better treatment.

Unfortunately, many of the current care practices for children with PH are based on findings from adult studies, Dr. Hanna pointed out. Clinicians do not know, for instance, if a 13-year-old who has PH on a genetic basis and starts medicines earlier than a 35-year-old with the exact same genetic mutation will have a longer, better life.

“The concept of pooling and precisely phenotyping children is going to make a huge difference,” said Dr. Hanna, who is also a clinical professor of pediatrics for the Perelman School of Medicine at the University of Pennsylvania. “A key thing is that we eventually will be able to make diagnoses and conduct research protocols all the same way. We’ll be able to advance the science faster and understand it better, so that we’ll be to answer questions about pediatric pulmonary hypertension.”

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Apr 28 2015

Antipsychotic Use May Increase Diabetes Risk in Some Children

diabetesResearchers from The Children’s Hospital of Philadelphia’s PolicyLab recently published the largest study to date documenting the significant risks to children’s health associated with prescription antipsychotics, a powerful a class of medications used to treat mental and behavioral health disorders.

The results, which were published in JAMA Pediatrics, suggest that initiating antipsychotics may elevate a child’s risk not only for significant weight gain, but also for Type II diabetes by nearly 50 percent. Moreover, among children who are also receiving antidepressants, the risk may double. Previous PolicyLab research showed that one in three youth receiving antidepressants in the Medicaid program were receiving an antipsychotic at the same time.

In a blog post about the study, Policylab co-Director David Rubin, MD, MSCE, notes, “These new findings should give us pause. With such vast numbers of children being exposed to these medications, the implications for potential long-lasting harm can be jarring.”  Dr. Rubin is also a professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Traditionally, antipsychotics have been narrowly prescribed to children with a diagnosis of schizophrenia or bipolar disorder, or to those with significant developmental delays who were displaying aggressive behaviors that were potentially injurious to themselves or others. However, in recent years, antipsychotics are increasingly being prescribed in the absence of strong supporting safety and efficacy data to treat healthier children and adolescents with disruptive behaviors, such as those who are diagnosed with attention-deficit/hyperactivity disorder.

The JAMA Pediatrics study, which used Medicaid data on more than 1.3 million youth ages 10 to 18 with a mental health diagnosis from the Centers for Medicare and Medicaid Services, must be interpreted in the context of emerging evidence that Medicaid-enrolled children are far more likely than privately insured children to be prescribed antipsychotic medications. Overall, over 25 percent of Medicaid-enrolled children receiving prescription medications for behavioral problems were prescribed antipsychotics by 2008, largely for less severe disorders.

Despite the number of children being exposed to antipsychotics, the researchers remain cautious about over-reacting to these findings.

“We need to incorporate these new revelations about the risk for diabetes into a more thoughtful consideration of the true risks and benefits of prescribing an antipsychotic to a child,” Dr. Rubin said. “Yes, we should try, by all means possible, to minimize the numbers of children and adolescents exposed to these powerful medications. But for some children in immediate crisis, we must also concede that the benefit of the antipsychotic for acute management may still outweigh the risk.”

The study’s authors recommend that clinicians and families who are making medication decisions periodically revisit the treatment strategy to address challenging behaviors. For example, when planning to prescribe antipsychotics to a child, professional organizations recommend beginning cautiously with the lowest dose possible, while strictly monitoring for early evidence of weight gain or abnormal lab tests that often predict later onset of diabetes.

Ultimately, say Dr. Rubin and his co-authors, the prescription of antipsychotics to children and adolescents is likely to continue, reflecting a growing demand to address very challenging behaviors in children.

“At the end of the day, the approach to the individual child who is in crisis is still a case-by-case decision between a family and the treating provider,” said Dr. Rubin. “We can only hope that those decisions are made in full recognition of our findings, and that for some children, alternatives to these powerful medications—such as counseling or other supportive services, will be considered first.”

For more information about the study, see the full press release. To learn more about PolicyLab’s portfolio of work on antipsychotic medications, visit

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Apr 27 2015

Minimal Improvement in Infants’ Neurodevelopment After Cardiac Surgery

neurodevelopmentCardiac specialists have concentrated for many years on helping high-risk infants with complex congenital heart disease (CHD) to survive surgery. As advances in surgical and perioperative care have improved their success rates dramatically, researchers, clinicians, and families now are able to turn their attention to these children’s long-term outcomes.

The most common complication for children who undergo CHD surgery in infancy is neurodevelopmental disability. Previous research has shown that they have lower abilities with reasoning, learning, executive function, inattention and impulsive behavior, language skills, and social skills compared to the general pediatric population.

The International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators looked at trends over a 14-year interval in neurodevelopmental outcomes for survivors of CHD surgery. Twenty-six institutions from six countries — the U.S., Canada, Austria, New Zealand, Japan, and Switzerland — submitted study participant data for the pooled analysis project. The study team evaluated 1,770 children born between 1996 and 2009 who underwent CHD surgery, which is the largest cohort reported to date.

The investigators assessed the study participants’ scores at age 14.5 months on the Bayley Scales Version 2, a standard series of measurements that examine multiple facets of child development. They reported that these scores were significantly lower than expected compared with the general population.

“We showed that over the last 15 years, despite all the improvements in care, we have really made very little progress in improving the long-term neurodevelopmental outcomes for these kids,” said J. William Gaynor, MD, first author of a Pediatrics article that reported the ICCON investigators’ results. “Once you’re past the excitement and stress of the operation, this is what parents really care about: Is my child going to need special education? Is my child going to have attention-deficit/hyperactivity disorder? Is she going to be able to have a job? Is he going to be able to have a family? That’s what we’re trying to answer.”

The ICCON investigators will continue their worldwide collaboration to study factors that may explain the lack of greater improvement in early neurodevelopmental outcomes over the study period. The study team already is gathering data to determine if there is any relationship between intraoperative management strategies and neurodevelopmental outcomes. Another possibility is that brain development in children with CHD is immature prior to birth.

“The data here is suggestive that if you’re going to make these kids better, we’ve got to make their brains better before they’re even born,” said Dr. Gaynor, who is an attending cardiothoracic surgeon at The Children’s Hospital of Philadelphia and associate professor of surgery at the University of Pennsylvania School of Medicine. “Our goal is that when you meet these kids, if you didn’t see the scar on their chests, you would not know that they had heart surgery because they’re completely like every other kid in every other way. We’re not there yet, but this is the type of research that we need to get us there.”

The pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation.

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Apr 24 2015

Scientists Explore Gene Silencing as Novel Approach to Dystonia

dystoniaMany of us take for granted our ability to control our bodies and muscles. We type on keyboards and stretch at our desks without much thought. Such everyday actions can be challenging for children with early onset genetic dystonia — the most common form is called DYT1 — who begin to experience involuntary twisting movements, usually in a foot, leg, or arm, around age 10. Within two to three years, the muscle contractions can affect all of their body parts.

A team of scientists at The Children’s Hospital of Philadelphia are comparing two molecular therapy techniques — RNA interference (RNAi) and antisense oligonucleotides (ASOs) — to help answer critical questions in the field of DYT1 research. Could the symptoms of this disabling neurological disorder that affects about one in 30,000 Americans be reversible? What are the biological bases of DYT1’s characteristic motor dysfunction?

“In contrast to many other brain diseases that affect motor function, there is no known loss of brain cells in DYT1,” said Pedro Gonzalez-Alegre, MD, PhD, principal investigator of the research project that recently received funding for three years from the U.S. Department of Defense (DOD). “The brain cells just are not working properly, so there is a lot of potential for this to be reversible.”

Scientists know that the mutated gene TOR1A causes DYT1. The TOR1A gene provides instructions for making a protein called torsinA. When TOR1A is mutated, it produces an altered torsinA protein that may disrupt chemical signaling between nerve cells that control movement. In previous research, Dr. Gonzalez-Alegre achieved successful gene silencing  in cultured cells using RNAi and ASOs to prevent neurons from making the mutated or “toxic” protein.

“If we can eliminate the expression or down-regulate the expression of this gene, could that restore normal brain function?” Dr. Gonzalez-Alegre asks in the current research project.

The study team will test their theory in rats bred to express the human DYT1 mutant gene. They will pursue the two complementary gene silencing approaches in parallel, measure if they are able to reverse or improve DYT1-linked motor dysfunction, and observe if any side effects occur.

First, the scientists have designed ASOs that they will deliver directly into the rats’ central nervous system in order to broadly suppress TOR1A’s toxic activity. ASOs block disease processes by altering the synthesis of a particular protein.

Next, the study team will rely on the expertise of co-investigator Beverly L. Davidson, PhD, director of CHOP’s Center for Cellular and Molecular Therapeutics, who has pioneered methods that allow scientists to infuse RNAi into cells via viral vectors to individually turn off genes associated with brain disease. They will introduce RNAi into parts of the rats’ brains called the striatum and cerebellum. Pinpointing these brain regions as the primary sites responsible for DYT1 dysfunction could help to establish anatomical targets for future therapeutics.

Only about 30 percent of people who carry the DYT1 mutation go on to develop symptoms, Dr. Gonzalez-Alegre pointed out, so he is encouraged that these investigations will show evidence that the inherited disease is potentially reversible. If they can demonstrate that DYT1 is an ideal candidate for gene silencing, the study team will be on track to develop novel treatments to improve the quality of life of patients.

Dr. Gonzalez-Alegre cares for DYT1 patients as a movement disorder neurologist and works closely with The Dystonia Medical Research Foundation, which has successfully lobbied the DOD to include dystonia in its list of medical conditions eligible for funding under the Congressionally Directed Medical Research Program. In addition to inherited dystonia, many other types of dystonia can occur, such as in veterans who experience a traumatic brain injury.

“By studying the genetic form of dystonia, we hopefully will learn new things that can expand our understanding of multiple forms of the disease,” said Dr. Gonzalez-Alegre, who is also an associate professor of neurology in the Department of Neurology at Penn Medicine.

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Apr 23 2015

Center for Injury Research and Prevention Engineering Students Honored

Center for Injury Research and PreventionTwo undergraduate engineers from the Center for Injury Research and Prevention (CIRP) were recently honored during CHOP Research Poster Day. Held February 25, 2015 Poster Day was the 25th anniversary of the event, and 40 researchers’ work was selected by a faculty panel to receive awards. Among a collection of hematologists, oncologists, and neonatologists, the research Richard Hanna and Todd Hullfish presented — focused on child restraint systems and side air bags, respectively — stood apart.

Currently in his final year at Drexel University, Richard Hanna has been working toward a Master of Science in Biomedical Engineering. Since coming to CIRP in June 2014 through CIRP’s National Science Foundation (NSF)-funded Injury Science Research Experiences for Undergraduates program, he has assisted with data analysis and co-authored a paper to be presented at the SAE World Congress and Exhibition in April.

Todd Hullfish, meanwhile, has been studying toward a Bachelor of Science in Mechanical Engineering and has been at CIRP since September 2013. At CIRP Hullfish has analyzed motor vehicle crashes, worked on an IV monitoring system, and developed computer models of crash scenarios. Hullfish came to CHOP through Drexel University’s Co-op program, in which Drexel students gain experience in their future fields at employers across the United States and internationally.

Both Hanna and Hullfish have been working with the Center for Injury Research and Prevention’s Aditya Belwadi, PhD. A member of CIRP since 2011, Dr. Belwadi studies injury biomechanics and injury causation, and has published recent papers in Traffic Injury Prevention and the Annals of Advances in Automotive Medicine, among others.

Modeling Child Restraint Systems with Kinect

Richard Hanna’s award-winning project was focused on using the Microsoft Kinect for Windows motion-sensing device. Perhaps best known as an Xbox peripheral (allowing users to play games with gestures rather than a controller), Hanna used the device in a novel way: to create three-dimensional digital models of 48 child restraint systems (CRS) representing close to 300 child seats in the US market as of March 2015.

According to a 2013 CIRP report on child passenger safety, motor vehicle crashes remain the leading cause of death for children older than 4 years and resulted in 952 fatalities in 2010 for children age 15 and younger. Although the number of children restrained in CRS has risen due to awareness and legislation, unintentional misuse of these restraints remains an issue; a 2004 NHTSA survey found that 72.6 percent of child restraints observed in parking areas throughout the United States had at least one “critical” misuse.

With this study, Hanna and Dr. Belwadi sought to make it easier for vehicle manufacturers to evaluate CRS-to-vehicle fit early on in the design phase, rather than an after-thought process once the CRS has been purchased. Currently, there is no standard method of quantifying child restraint systems’ geometry and volume, and the Kinect presents a simple, economic alternative to methods currently used by manufacturers.

Dr. Belwadi recently wrote about CIRP’s use of the Kinect in a post on the CIRP blog, noting “results from this research can ultimately help to improve testing conditions for vehicle and restraint safety devices.”

Finite Element Modeling of Side Air Bag Effectiveness

Todd Hullfish’s project, meanwhile, explores the effectiveness of side air bags and their interaction with pediatric passengers, a little studied topic. While various types of side air bags have become standard in many vehicles, the degree to which they protect passengers is up for debate. To get a better sense of how side air bags affect children seated next to them, Hullfish used Finite Element Modeling to model computer simulations of side impact crashes with accurate anthropometric test devices (ATD), or crash test dummies.

What then is Finite Element Modeling? Last summer Hullfish wrote a post for CIRP’s blog about FEM, which he defined as “a method of computation that represents complex geometry with simple shapes, such as triangles and squares in what is referred to as a ‘mesh’.”

The researchers use of a computational model allowed them to examine in detail side air bags’ deployment and effectiveness. The researchers next plan on testing pediatric models, in a variety of CRS designs. Their work could help vehicle manufacturers and CRS companies design more effective systems for child passengers.

Going forward, Hanna has said he is interested in working in the medical device or automotive biomechanics industries, while Hullfish — who doesn’t graduate from Drexel until 2016 — is considering graduate school.

“I’m extremely proud of Rich and Todd’s accomplishments. For engineers to be recognized among the world-class clinicians at CHOP is truly remarkable,” said Dr. Belwadi.

For more information about research at CIRP, check out the Center for Injury Research and Prevention website and CIRP’s Research in Action blog. To read more about Richard Hanna and Todd Hullfish’s work, see the March 2015 edition of CHOP Research’s Bench to Bedside.

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Apr 22 2015

Investigation Bolsters Use of Variant Protein in Hemophilia Gene Therapy

hemophilia_gene_therapyUsing gene therapy to produce a mutant human protein with unusually high blood-clotting power, scientists have successfully treated animals with the bleeding disorder hemophilia, without triggering an unwanted immune response. In addition, the “turbocharged” clotting factor protein eliminated pre-existing antibodies that often weaken conventional treatments for people with hemophilia.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said the study’s leader, Valder R. Arruda, MD, PhD, a hematology researcher at The Children’s Hospital of Philadelphia (CHOP) and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Dr. Arruda and colleagues published their results in the recent print edition of Blood.

Hemophilia is an inherited bleeding disorder that famously affected European royal families descended from Queen Victoria. Most commonly occurring in two types, hemophilia A and hemophilia B, the disease impairs the blood’s ability to clot, sometimes fatally. When not fatal, severe hemophilia causes painful, often disabling internal bleeding and joint damage. Doctors treat hemophilia with frequent intravenous infusions of blood clotting proteins called clotting factors, but these treatments are expensive and time-consuming. Moreover, some patients develop inhibiting antibodies that negate the effectiveness of the infusions.

For more than two decades, research teams have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. However, this approach has been frustrated by the body’s immune response against vectors — the non-disease-causing viruses used to carry the DNA. Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent: higher amounts of vectors caused more powerful immune responses.

Dr. Arruda and colleagues therefore investigated gene therapy that used lower dosages of vector produce a more potent clotting factor — a variant protein called FIX-Padua.

In 2009, Dr. Arruda was part of a team that discovered this variant protein in a young Italian man who had thrombosis, excessive clotting that can dangerously obstruct blood vessels. A mutation produced the mutant clotting factor (named FIX-Padua after the patient’s city of residence), the first mutation in the factor IX gene found to cause thrombosis. All previously discovered FIX mutations lead to hemophilia, the opposite of thrombosis.

FIX-Padua is hyperfunctional — it clots blood 8 to 12 times more strongly than normal, wild-type factor IX. Therefore in the current study, the researchers needed to strike a balance: to relieve severe hemophilia by using a dose strong enough to allow clotting, but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans,” said Dr. Arruda, “by adapting this variant protein found in one patient to benefit other patients with the opposite disease.”

The recent Blood investigation tested the safety of FIX-Padua in animals, all with naturally occurring types of hemophilia B very similar to that found in people. The researchers found the gene therapy injections changed their hemophilia from severe to mild, with no bleeding episodes for up to two years. The animals did not develop inhibitory antibodies, nor was there evidence of thrombosis.

Another set of preclinical safety studies supported the safety and efficacy of gene therapy using FIX-Padua. However, Dr. Arruda noted additional work is needed to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B — at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

To read more about this encouraging work, see the full press release about the Blood study.

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