Jun 27 2014

CHOP Announces Fetal Neuroprotection Program

Fetal Neuroprotection Program_2The Children’s Hospital of Philadelphia launched the Fetal Neuroprotection and Neuroplasticity Program which builds onto already growing evidence of the interaction of heart disease and brain development in the fetus. This program will systematically investigate innovative therapies to protect brain development and to prevent brain injury as early as possible before birth.

A joint project of the hospital’s Cardiac Center, the Fetal Heart Program, the Center for Fetal Diagnosis and Treatment, and the Division of Neurology, it is the first-ever comprehensive program dedicated to prenatal neuroprotection. While this program initially will focus on the fetus with congenital heart disease (CHD), it will expand in the future to include fetuses with other birth defects, such as congenital diaphragmatic hernia and pulmonary hypoplasia.

In the U.S., approximately one in every 120 newborns is diagnosed with CHD, making it the most common birth defect. Many newborns with CHD require either corrective or palliative open-heart surgery. As recently as the 1960s, only 20 percent of newborns with critical CHD survived to adulthood.

“Today, thanks to better diagnostic technologies and methods, including prenatal diagnosis, advances in surgery, and improved postoperative care, early survival is over 90 percent,” said J. William Gaynor, MD, cardiac surgeon and director of the Fetal Neuroprotection and Neuroplasticity Program. “However, with improved early outcomes has come the sobering recognition that there is an ongoing risk of late mortality as well as significant morbidity for these children. Indeed, neurodevelopmental disability is now recognized as the most common complication of critical CHD – those patients requiring cardiac surgery in infancy – and has the most negative impact on quality of life, academic performance, and opportunity for independence as an adult.”

Convincing evidence suggests that in order to prevent brain injury and improve outcomes, treatment to protect the brain must be initiated before birth. This research, much of it developed at CHOP, shows that in utero brain development is abnormal in fetuses with CHD, leading to delayed maturation, poor growth, and white matter injury.

“The lifetime continuum of care for congenital heart disease starts in utero,” said N. Scott Adzick, MD, surgeon-in-chief at CHOP.  “We now have an opportunity to not only offer the best diagnostic care to the fetus with heart disease, but to also begin to explore ways in which we can optimize long-term outcomes from the neurocognitive perspective.”

The focus of the new program will be to investigate the factors that cause abnormal brain development in the fetus with a congenital heart defect and to conduct clinical trials of fetal interventions to determine whether novel prenatal treatments can reduce brain injury and improve neurodevelopmental outcomes in newborns with CHD who subsequently undergo cardiac surgery. The first such study will evaluate whether the hormone progesterone, administered prenatally to the mother, has a neuroprotective effect on brain development.

The Children’s Hospital of Philadelphia has long been a leader in pediatric cardiac care. More than 30 years ago, CHOP pioneered life-saving early surgeries for children with complex heart defects. Today, most forms of heart disease can be detected prior to birth.

“The Fetal Neuroprotection and Neuroplasticity Program is another innovative initiative in a long series of identifying opportunities to ensure that children with CHD not only survive, but truly thrive, as they grow into adulthood,” Dr. Gaynor said. “This program allows us to enhance our continuum of care from conception through adulthood.”

For more information, please visit The Children’s Hospital of Philadelphia’s Fetal Neuroprotection and Neuroplasticity Program.

Permanent link to this article: http://www.research.chop.edu/blog/chop-announces-fetal-neuroprotection-program/

Jun 25 2014

New Teen Drivers Benefit From Practice Quantity, Variety

Teen_Driving_FullWhen a teen learning to drive sits behind the wheel with sweaty palms, it is often up to the parent to keep their child calm and focused on the road. But how can parents prepare to steer these driving lessons in the right direction?

Research released by the Center for Injury Research and Prevention (CIRP) at The Children’s Hospital of Philadelphia found that TeenDrivingPlan (TDP), a web-based intervention designed to help parents more effectively supervise driving practice, improved the driving performance of pre-licensed teenagers. Inexperience is a contributing factor in car crashes involving novice drivers.

“Supervised practice during the permit phase is a common provision of Graduated Driver Licensing programs in most states, yet there is a lack of evidence-based interventions available to support families,” said Jessica H. Mirman, PhD, lead author of the study and a CIRP developmental psychologist. “Evidence-based interventions like TeenDrivingPlan can address this problem by helping busy parents make the most of supervised practice time.”

The goal of TDP is to increase the quantity and variety of parent-supervised practice to develop teenagers’ driving skills before licensure. It offers three main activities for families:

  1. Learning: 53 brief videos guide parents in creating a positive learning environment in the car and provide structure for practice activities across multiple driving environments — from rainy highways to sunny country roads
  2. Planning: helps families to select concrete goals for each practice session
  3. Logging and rating: tracks practice hours and collects information on goal performance.

The research, published in JAMA Pediatrics, involved five years of formative research followed by a randomized, controlled trial of 151 young drivers and their parent supervisors. Youth with learner’s permits who were assigned to use TDP over a 24-week period were 65 percent less likely to fail a rigorous on-road driving assessment administered prior to licensure compared to those who followed a usual practice “control” condition.

Overall, 6 percent of the pre-licensed teenagers in the TDP group had their on-road driving assessment terminated due to unsafe driving performance as compared to 15 percent of those in the control group. Families who used TDP also reported more driving practice in various environments, at night, and in bad weather.

A corresponding CHOP research article, published this month in the Journal of Adolescent Health, examined how TDP exerted its effect on driver performance and found that both greater quantity and variety of practice were associated with better driving performance, but TDP’s effectiveness was primarily through greater practice diversity. Additionally, families in the TDP group reported more parent engagement and support.

A third CHOP analysis, published in Injury Prevention, used state-of-the-art software to capture TDP use data, and researchers examined its association with practice diversity. The results suggest that initiatives aimed at new drivers should provide important information early in the learner period when engagement is greatest.

Future CHOP studies will further explore ways to enhance TDP’s positive effects on young driver performance and supervised practice to develop teenagers’ driving skills before licensure.

Through its multidisciplinary Teen Driver Safety Research program, the CIRP is working continually to reduce the frequency and severity of motor vehicle crashes, which remain the number one cause of death for teens.

State Farm Mutual Automobile Insurance Company (State Farm®) funded this research.

To learn more about CHOP’s TeenDrivingPlan research, visit teendriversource.org.

Permanent link to this article: http://www.research.chop.edu/blog/new-teen-drivers-benefit-practice-quantity-variety/

Jun 23 2014

Gene Study Points to Novel Pathway for Diabetes Treatment

Diabetes_Treatment_ContentNew research from The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania details how a diabetes-related gene functions on a biological pathway that affects the release of insulin. Finding drugs that act on that pathway may eventually lead to a new treatment for type 1 diabetes.

“In 2007, our genomics team found the first gene in a genome-wide search to play a major role in type 1 diabetes, but we did not know its function,” said co-study leader Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP. “Now we understand how this gene plays a critical role in regulating insulin metabolism.”

The current finding builds on a 2007 genome-wide association study by Dr. Hakonarson and colleagues at CHOP showing that variations in the KIAA0305 gene, also known as CLEC16A, correlate with higher risk of type 1 diabetes and other autoimmune diseases.

The research team subsequently developed a strain of mice in which the CLEC16A gene was deactivated. They then collaborated with endocrinology expert Doris A. Stoffers, MD, PhD, of the Institute for Diabetes, Obesity and Metabolism at UPenn to breed a subset of the knockout mice in which only the pancreatic cells were affected. Dr. Stoffers was co-senior author with Dr. Hakonarson, and is the corresponding author of the study, which appears online in the journal Cell.

The investigators show that the CLEC16A gene acts upon a pathway crucial to insulin secretion. The gene normally helps protect mitochondria, the tiny energy-producing components of cells, but when the CLEC16A gene is knocked out, damaged mitochondria are then digested — a process called mitophagy — and the resulting loss of energy output disrupts beta cells in the pancreas in their normal job of secreting insulin.

“The ultimate result of the deletion of CLEC16A is an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta cells,” said Dr. Stoffers.

In humans, an inability to produce insulin is the hallmark of type 1 diabetes. The study team showed that humans with single-base variants in CLEC16A have reduced beta cell function, although with less extreme effects than in the knockout mice.

The researchers showed that the CLEC16A biological pathway has downstream effects on a protein called Parkin, already known to be a master regulator of mitophagy. The current study is the first to link the CLEC16A pathway with regulation of Parkin-mediated mitophagy and to suggest how this process may affect diabetes by dysregulating insulin secretion.

If drugs can be developed to act on the CLEC16A pathway, they could provide a new, targeted therapy for patients with type 1 diabetes who harbor risk variants in the CLEC16A gene, said Hakonarson.

More information about the study is available here.

Permanent link to this article: http://www.research.chop.edu/blog/gene-study-points-novel-pathway-diabetes-treatment/

Jun 19 2014

Early Childhood Bone Density Reference Data Needed

bone densityIn the past decade, clinicians have made significant advancements in the diagnosis of pediatric bone disorders, particularly because national reference data is now available for bone density in children older than 5; however, clinicians do not have the appropriate tools for bone health assessment and research in early childhood.

A study at The Children’s Hospital of Philadelphia aims to address this gap by establishing reference data for children ages 1 to 5 using dual-energy X-ray absorptiometry (DXA), a test that measures bone density. The investigators also will examine factors that influence bone density and bone mineral accrual in this age group. Identifying children at risk for bone fragility is important because inadequate bone accretion may have lifelong consequences, such as susceptibility to fractures and osteoporosis.

“The first main goal of the study is to develop the equivalent of a growth chart for bone density,” said Babette Zemel, PhD, who is a co-principal investigator of the study. “Clinicians will be able to request a DXA scan, interpret it, and get an idea of where a child is relative to normal children of the same age, sex, and ancestry.”

Many serious clinical conditions in childhood threaten bone health due to inflammation and malabsorption, for example major cardiac disease, liver disease, and pulmonary disease. Or a child may have primary bone disorder that is genetic, such as osteogenesis imperfecta, which is characterized by bones that break easily, often from little or no apparent cause. Also, some young children with neuromuscular conditions have delayed gross motor skills and restricted mobility that may adversely affect bone accrual.

Accurate reference data will allow clinicians to identify bone deficits in these patient groups and to monitor how well treatment is working.

“It’s one thing for a healthy child to be running around, fall down, and break a bone, but there are some children who have pretty serious health problems, and they’re just not gaining bone the way that they should,” said Dr. Zemel, who is part of the division of gastroenterology, hepatology, and nutrition at CHOP and a research professor of pediatrics with the Perelman School of Medicine’s Institute for Translational Medicine and Therapeutics.

To give an idea of the scope of the problem posed by compromised bone strength, the Center for Bone Health team at CHOP looked at how many of the patients that they had treated who had already experienced a fracture, and it was more than 30 percent, Dr. Zemel said.

One of the challenges to conducting the current study is that toddlers cannot stay still long enough to complete a full body DXA scan. Dr. Zemel and her research team will use the latest generation of DXA technology, which provides more enhanced resolution that improves the accuracy for measuring small, less dense bones. They will conduct regional scans of the lumbar spine, forearm, and lateral distal femur that are feasible in young children because the scan time is 30 to 60 seconds, and the child can be held still without interfering with the scan.

Dr. Zemel anticipates that participant enrollment will open in April at two study sites – CHOP and Cincinnati’s Children’s Hospital Medical Center (CCHMC). Half of the study’s sample population will be African-American, and the other half will be non-African American. The study will involve a longitudinal cohort that will consist of 280 children ages 1 to 2 years who will be evaluated every six months for three years, resulting in data spanning ages 1 to 5 years. A cross-sectional cohort will include 240 children ages 1 to 1.5 years and 4.5 to 5 years who will undergo the same measurements at one time point. Data from both cohorts will be combined to create the reference curves.

Early childhood is a period of rapid development, so the researchers also will examine how changes in bone mineral content and density are related to growth, body composition, motor development, and physical activity. While previous research of older children has shown that greater growth status, more lean muscle mass, and more weight-bearing physical activity is related to higher bone density, Dr. Zemel pointed out that clinicians have little evidence that applies to the 1 to 5-year-old age range.

“With early identification of compromised bone health, improved awareness of the condition, and better understanding of the mechanisms involved, there is hope that this may soon translate into new and improved therapy for children at-risk for poor bone mineral accrual,” Dr. Zemel said.

An innovative part of the study is its application of new techniques for estimating body composition — the amount of muscle, fat, and bone in the body. A group of physicists from the University of California, San Francisco (UCSF) who are experts in bone and body composition imaging will use novel analysis to determine body composition from all of the children’s regional DXA scans, separating bone from soft tissue and air, and then calculating lean muscle and fat mass.

Since this technique is not yet validated, Dr. Zemel and her team will conduct anthropometric exams at all visits. Anthropometry is the collection of high quality body measurement data using standardized examination procedures and calibrated equipment. Trained anthropometrists will obtain skinfold thickness measurements that can be used in prediction equations, yielding excellent body composition estimates.

In a subset of 120 participants, the researchers will compare DXA and anthropometric body composition methods to the current gold standard, which uses isotope dilution to measure total body water and calculate fat and fat-free mass.

Heidi Kalkwarf, PhD, RD, a nutritional epidemiologist at CCHMC, is co-principal investigator of the study, which received funding from the National Institutes of Health.

Permanent link to this article: http://www.research.chop.edu/blog/early-childhood-bone-density-reference-data-needed/

Jun 17 2014

Concussion Prevention, Care Are Key Targets for Research


Annually, young people make nearly 250,000 visits to emergency rooms in the U.S. to be treated for brain injuries from sports and recreation, according to the Centers for Disease Control and Prevention.

Few healthcare issues reach the presidential podium and ESPN headlines, but the topic of sports-related concussions in youth scored both, gaining momentum as a national priority.

President Obama hosted the first-ever White House Healthy Kids & Safe Sports Concussion Summit May 29, where key stakeholders gathered to promote new efforts that will increase research to expand knowledge of concussions and create a culture of safety that supports children in disclosing symptoms and optimizing their recovery.

“We want our kids participating in sports,” Obama told the audience. “I’d be much more troubled if young people were shying away from sports. As parents, though, we want to keep them safe, and that means we have to have better information.”

A concussion is a mild traumatic brain injury caused by a blow or jolt to the head or body that causes the brain to shake. Annually, young people make nearly 250,000 visits to emergency rooms in the U.S. to be treated for brain injuries from sports and recreation, according to the Centers for Disease Control and Prevention. Some concussion symptoms may appear immediately after the injury, while others may not show up for several days. They can include headache, nausea, dizziness, sleep problems, difficulty concentrating, and moodiness.

Pediatric sports medicine specialist Christina Master, MD, and President and Chief Operating Officer Madeline Bell of The Children’s Hospital of Philadelphia were in attendance at the summit as it was announced that CHOP will begin development of a comprehensive pediatric and adolescent concussion registry. It will provide a database of information about concussion cases to inform scientific research to improve care.

The registry is a result of a Department of Pediatrics Chair’s Initiative project at CHOP called Minds Matter that involved a multidisciplinary team who set out to create tools to standardize and streamline concussion diagnosis and management across the CHOP Care Network so that primary care providers could handle the majority of concussion cases more efficiently and seamlessly.


CHOP will begin development of a comprehensive registry of concussion cases to inform scientific research to improve care.

“We incorporated a SmartSet feature into CHOP’s electronic medical record that gives providers standardized and evidence-based guidance on how to clinically evaluate and manage concussions,” said Kristy B. Arbogast, PhD, director of engineering for CHOP’s Center for Injury Research and Prevention, who led the Minds Matter team along with Dr. Master. “We coupled that with in-person training, and the response has been great. We believe kids are getting much better care.”

The clinical demand for concussion care throughout the CHOP system remains high, with a total of about 12,800 concussion visits in 2013 alone. Consequently, the need for pediatric research is great. Dr. Arbogast contributed to an Institute of Medicine report in 2013 that revealed many gaps in researchers’ understanding of the causes and consequences of sports-related concussions.

“A lot of what we think we know about concussion and prevention, if you pull the curtain back, the fundamental data supporting those ideas aren’t there,” Dr. Arbogast said.

In his remarks at the summit, Obama announced several public-private partnerships to support new concussion research. For example, the National College Athletics Association (NCAA) and the Department of Defense are jointly launching a $30 million effort to fund a comprehensive clinical study of concussion and head impact exposure. And the National Institutes of Health is using funding from the National Football League to begin a longitudinal research effort to detect, characterize, and measure the chronic effects of repetitive concussions.

With so many entities willing to take the ball and run to improve concussion diagnosis, management and prevention, the fundamental science in changing quickly, Dr. Arbogast said. Finding the best way to translate that research into evidence-based advocacy will be the next challenge that she hopes to tackle in her new role as a member of the National Council on Youth Sports Safety.

David Satcher, MD, former U.S. Surgeon General, and Eliot Sorel, MD, a global health expert from George Washington University School of Public Health and Health Services, convened a multidisciplinary panel of experts to form the national council. They invited Dr. Arbogast, the NCAA’s chief medical officer, Safe Kids Worldwide’s chief executive officer, and two former professional football players, among others.

“Its mission is to raise awareness and apply an integrative approach to create a culture of prevention and reduce the number of injuries that children sustain in sports,” Dr. Arbogast said. “We want to think about youth sports in a way that children can gain the benefits of physical activity, leadership, and character development while ensuring that they are as safe as possible while they play.”

During their inaugural meeting in February, the council identified several sports safety concerns — concussion, overuse injury, heat illness, and sudden cardiac death — and decided that their first goal would be to take aim at changing the culture around concussion. Workgroups hold virtual strategy meetings on a monthly basis, and they anticipate that their efforts will culminate in a best practices tour in 2015.

Council members will visit about 10 localities and host town-hall like events that will feature innovative practices and approaches to concussion prevention, diagnosis, treatment, and management. While the spotlight will be on sharing knowledge, they anticipate some sports players will lend their star power to help change society’s norms. Athletes, parents, coaches, school professionals and healthcare providers must realize that, “shake it off” is not an acceptable response to concussion; it is a brain injury that deserves serious attention.

“I like being part of an entity that is tasked with shaping the national tone on this issue,” Dr. Arbogast said. “And I am excited about the opportunities to possibly highlight some of the phenomenal clinical care CHOP sports medicine, primary care, and trauma doctors are providing for kids with concussions and to show that CHOP is a thought leader on this issue.”

Permanent link to this article: http://www.research.chop.edu/blog/concussion-prevention-care-key-targets-research/

Jun 16 2014

Researcher Strives to Add Youth Voices to Health Measures

youth voicesAs any pediatrician will tell you, children are not just little adults. Assessing and treating pediatric health issues is not the same as assessing and treating adult health issues, only in miniature. Children are different from adults in myriad ways — physically, developmentally, and emotionally.

They also use language differently than adults do. For one, children have much smaller vocabularies than adults. And according to the American Speech-Language-Hearing Association, even children without language disorders may have issues with language pragmatics, such as using language appropriately and following conversational rules.

Acknowledging that children use language in unique ways, one CHOP researcher has been striving to incorporate their voices into public health measures. With the support of the Philadelphia-based Stoneleigh Foundation, The Children’s Hospital of Philadelphia’s Roy Wade, Jr., MD, PhD, MPH, has been working on a new project that will add children’s voices and language feedback to tools used to assess and respond to childhood adversity. An attending physician and public health researcher, Dr. Wade’s current investigation builds on the results of a major study published today in Pediatrics.

Focus on Low-Income Urban Youth

Dr. Wade’s Pediatrics study, which he conducted alongside Children’s Hospital’s Joanne Wood, MD, MSHP, and David Rubin, MD, MSCE, as well as the University of Pennsylvania’s Judy A. Shea, PhD, sought to add the perspectives of low-income inner-city youth to measures of adverse childhood experiences (ACEs). The Pediatrics study follows the CDC’s landmark Adverse Childhood Experiences Study, which was initially conducted from 1995 to 1997. Designed to assess the associations between adverse childhood experiences and “later-life health and well-being, the CDC study’s findings “suggest that certain experiences are major risk factors for the leading causes of illness and death as well as poor quality of life in the United States,” according to the CDC site.

Dr. Wade’s research seeks to build on the original ACE study by adding youth voices. For example, chronic ACEs experienced by inner-city youth like pervasive community violence, economic hardship, and racial discrimination were not assessed in the CDC study. Therefore, by partnering with community organizations in Philadelphia, for the Pediatrics study Dr. Wade conducted a series of focus groups with low-income inner-city young adults aged 18 to 26 years old to get their perspectives on ACEs.

After meeting with a total of 105 participants, the researchers found that stress related to family relationships (such as domestic substance abuse and domestic violence) was the most common ACE cited. The second most commonly cited area was community stressors, including “neighborhood violence, crime, and death.”

Chronic exposure to violence has been associated with a number of adverse outcomes, including a propensity to engage in or commit acts of violence. In addition, per a study led by New York University’s Patrick Sharkey, PhD, experiencing community violence such as homicides “generates acute psychological distress among caregivers and impairs children’s self-regulatory behavior and cognitive functioning.”

Overall, Dr. Wade and his team note assessments of childhood adversity “should include experiences relevant to the target population,” and ACE research “should be broadened to include stressors experienced by youth in low-income urban settings.”

From Youth to Younger Children

youth voicesWhich is precisely what Dr. Wade’s current project, funded both by the Stoneleigh Foundation as well as the Perelman School of Medicine’s Center of Excellence for Diversity in Health Education and Research, aims to do. Over the course of this three-year project, Dr. Wade will be working “to build a youth-informed measure of childhood adversity that is informed by kids but is also informed by the organizations that actually use the instrument,” he said.

He has been collaborating with organizations across healthcare, social service, and youth mentoring groups to create the measure, which will eventually be adopted by the partner organizations. The measure itself will be a series of questions, Dr. Wade said, as part of interviews that will be concerned with validating the framework of areas of concern established by the Pediatrics study.

Dr. Wade then plans to gauge the impact of the tool and adversity assessment on each organization’s work, seeking to measure how it changes practice “in unforeseen ways,” he said.

In contrast to the Pediatrics study, with this project Dr. Wade is looking to recruit children as young as 8 years old. And because the children involved could be so young, Dr. Wade said he will be looking to use the kids’ language to reform questions and fill holes in the questionnaire. For example, in Dr. Wade’s measure he might avoid using words like “incarcerated” (used in the original CDC study) in favor of simpler language.

“We’re giving these kids a voice where they didn’t have one,” he said, adding that the project will give children who have experienced adversity “an opportunity to speak about their life experiences.” After all, Dr. Wade said, it is the children who experience trauma who “are the true experts in understanding what childhood exposures were stressful and traumatic for them.”

To read more, see the Stoneleigh Foundation page about Dr. Wade’s new project. And for more information about his study with Drs. Wood, Rubin, and Shea, see Pediatrics.

Permanent link to this article: http://www.research.chop.edu/blog/researcher-strives-add-youth-voices-health-measures/

Jun 13 2014

Exploring Vitamin Supplementation and Disease

vitaminVitamins are essential to growth and development, especially for children. Unfortunately, many pediatric diseases are associated with suboptimal levels of vitamins and vitamin deficiencies. One Children’s Hospital investigator, Kelly A. Dougherty, PhD, works to better understand the connection between childhood diseases and vitamin levels. Dr. Dougherty recently received an award from the NIH that will support her investigation of vitamin A supplementation and sickle cell disease. Additionally, she also contributed to an article in the Journal of the Pediatric Infectious Diseases Society that examined vitamin D deficiency in children with HIV.

The NIH award will support Dr. Dougherty’s investigation of vitamin A deficiency in children with type SS sickle cell disease (SCD). In addition to being most famous for anemia and episodes of pain, SCD is also linked to suboptimal levels of vitamin A, which can lead to poor growth and hospitalizations. Vitamin A deficiency is associated with vision problems and a decreased ability to fight infections.

Dr. Dougherty’s project builds on research led by CHOP’s Virginia Stallings, MD, published in The American Journal of Clinical Nutrition in 2012. That study sought to determine whether supplementation could optimize vitamin A status in children with type SS sickle cell disease. However, despite 12 months of study, the investigators found vitamin A supplementation at doses recommended for healthy children did not improve the patients’ serum retinol levels. For her new investigation, Dr. Dougherty will study the safety and efficacy of much higher doses of vitamin A — 2500 and 5000 international units (IU) per day, versus the 2012 study’s ceiling of 2000 IU. The researchers plan to test what effect these higher doses of vitamin A have on children with SCD compared to healthy subjects.

The big question posed by the 2012 American Journal of Clinical Nutrition study is where the vitamin A went — in other words, did the patients eliminate it via urination or a bowel movement, or was it still in their bodies, or sequestered in the liver? — so with her new project Dr. Dougherty is looking to get a sense of the patients’ “total body vitamin a status,” she said.

From SCD to HIV

The Journal of the Pediatric Infectious Diseases Society (JPIDS) study, meanwhile, explores a different vitamin in a different patient population. Namely, vitamin D in children with HIV. While HIV-related research is a newer area for Dr. Dougherty, the HIV research makes sense as she is “interested in physical activity and nutrition issues in children with chronic diseases,” and “children with HIV have been shown to be deficient with vitamin D,” Dr. Dougherty said.

With this investigation, the researchers sought to determine the vitamin D dose needed to bring HIV patients with suboptimal levels of vitamin D up to normal levels. Suboptimal vitamin D “is common in HIV infected individuals and associated with increased risk of HIV disease severity and death,” the authors note. In general, vitamin D deficiency is associated with the possibility of developing rickets in children or osteoporosis in adults.

44 subjects aged 8.3 to 24.7 years old — 57 percent of whom had behaviorally acquired HIV and 43 percent of whom had perinatally acquired HIV — were given either vitamin D supplements at 4,000 or 7,000 IU/day and assessed at 6 and 12 weeks. The researchers found a dose of 7,000 IU/day was “safe and effective in children and young adults with HIV.”

Overall, the goal of all of Dr. Dougherty’s work is to find ways to improve outcomes and quality of life for pediatric patients suffering from chronic disease, she said.

To learn more about AIDS/HIV, sickle cell disease research, clinical nutrition, and healthy diets, see The Children’s Hospital of Philadelphia website.

Permanent link to this article: http://www.research.chop.edu/blog/exploring-vitamin-supplementation-disease/

Jun 11 2014

Autism Gene Networks Could Offer Treatment Targets


Many of these genes with very rare defects belong to gene families that may offer druggable targets.

After analyzing the DNA from thousands of patients, investigators from Children’s Hospital have uncovered several gene networks that may play important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.

Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, and his team also found that one of the autism-related gene pathways also affects some patients with attention deficit hyperactivity disorder (ADHD) and schizophrenia, which raises the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. Dr. Hakonarson and his team note that recent investigations suggest that up to 400 distinct ASDs exist.

The investigators conducted a genome-wide association study that drew data from CHOP’s genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks. The study compared more than 6,700 patients with ASDs to over 12,500 control subjects and represents one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

The study focused on CNVs within defective gene family interaction networks (GFINs) — groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was the metabotropic glutamate receptor (mGluR) signaling pathway, defined by the glutamate receptor metabotropic (GRM) family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention, and behavior.

In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very rare gene variants exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.

Dr. Hakonarson’s team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the GRM pathway, while other teams have implicated GRM gene defects in schizophrenia.

“Even though our own study was large, it captures only about 20 percent of genes causing ASDs,” said Dr. Hakonarson, who added that still larger studies are needed to further unravel the genetic landscape of autism. “However, strong animal data support an important role for the glutamate receptor pathway in socially impaired behaviors modeling ASDs. Because the GRM pathway seems to be a major driver in three diseases — autism, ADHD and schizophrenia — there is a compelling rationale for investigating treatment strategies focused on this pathway.”

Based on the results of the study, Dr. Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. “If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants,” he said.

The study appeared in the journal Nature Communications. Additional details are available here.

Permanent link to this article: http://www.research.chop.edu/blog/autism-gene-networks-offer-treatment-targets/

Jun 09 2014

Research Terminology Must Harmonize to Advance Science

research terminologyWhat one researcher describes as asthma, another might call reactive airway disease. Unfortunately, such examples demonstrate the lack of a common pediatric research terminology, which presents a barrier to data reuse, sharing, and integration.

Thought leaders at The Children’s Hospital of Philadelphia published a state-of-the-art review article in the March issue of Pediatrics that encourages the research community to start talking the same language. They described a project under way, called the Pediatric Terminology Harmonization Initiative, that aims to provide uniform definitions and descriptions of clinical observations and data in pediatric research.

The National Institute of Child Health and Human Development is coordinating the effort in collaboration with the Enterprise Vocabulary Services of the National Cancer Institute, in order to fill a gap in the pediatric research infrastructure in the U.S.

“It is of critical importance to address this gap if we’re going to advance our scientific understanding of the causes of childhood disease,” said Christopher B. Forrest, MD, PhD, professor of pediatrics at CHOP. “Science advances through reproducibility. And when we all use different terms, we’re not able to reproduce research.”

Dr. Forrest compared the initiative to the Rosetta Stone, an ancient tablet with passages of identical meaning written in three languages that helped to decode the riddle of hieroglyphics.

“The Rosetta Stone was a big advance that allowed us to translate different languages,” Dr. Forrest said. “That’s what the terminology project does. It’s a common language that eventually will act as a Rosetta Stone for different research projects. It will allow communication across research studies.”

Traditionally, when a research team sets up a study, they have many questions in mind to tackle. But perhaps another study team across the country with the same study concept phrases their questions in an entirely different way. This could convolute attempts to pool the results.

Michael A. Padula, MD, MBI, medical director of informatics for the Division of Neonatology at CHOP, gave an example from three studies that the National Institutes of Health had funded about the off-label use of nitric oxide in premature infants. The New England Journal of Medicine published the three studies’ results: Two found it not to be beneficial, but the other found it was beneficial. The NIH convened a panel to interpret the results, but they were unable to make any conclusions because each study used slightly different definitions of bronchopulmonary dysplasia, which was the main outcome that the studies measured.

“They spent a great deal of money to fund these studies, but in the end they weren’t much farther along,” Dr. Padula said. “It was a missed opportunity. Had they been able to retrieve a granular level of data to allow them to harmonize the different definitions, then they would have been able to make a more definitive conclusion about the therapy.”

It can be a challenge for the research community to reach consensus on an accurate definition of a complex disease such as bronchopulmonary dysplasia or even on a common condition such as asthma. Some researchers may be reluctant to embrace a set vocabulary because they prefer certain customized terms. L. Charles Bailey, MD, PhD, an assistant professor in CHOP’s divisions of oncology and hematology, used the analogy of how people describe different shades of colors — red vs. rose, for instance.

“The research community must make a conceptual leap to say that we’re all going to agree to call this red in certain contexts, even though we can tell the shades apart, because it is more important for us to collaborate than it is for me to say exactly that my color is rose,” Dr. Bailey said.

That is where subject matter experts assembled through the Pediatric Terminology Harmonization Initiative jump in to develop semantic interoperability. They systematically go piece by piece through each field of medical specialization to align like concepts, define them appropriately so that they relate to both research and clinical care, and then tether them to reference terminology sets that researchers can access easily.

Although the scope of the terminology project is substantial and time-consuming, CHOP’s experts explained why it is important to pursue it now. First, it is increasingly becoming important to perform collaborative pediatric research to answer questions from broader perspectives.

For example, PEDSnet is a national initiative of children’s hospitals and disease specific networks that are working together to reduce the barriers to rapid and better clinical research. PEDSnet will tap into the pediatric research terminology effort as it begins to create a common data model, said Dr. Forrest, who is principal investigator of PEDSnet.

A common pediatric research terminology also will be an essential part of the National Children’s Health Study, led by Steven Hirschfeld, MD, PhD, who co-authored the Pediatrics article. The National Children’s Health study will be collecting huge amounts of data that must be aligned to allow translation of the evidence into clinical practice.

Second, the era of health care information exchange is creating a sea change because the care that clinicians provide is now linked to electronic health records (EHRs) that operate using specific languages and terminologies. However, most EHR systems currently do not describe pediatric conditions thoroughly or support pediatric research. Organizers of the pediatric terminology project want to get their foot into the door as EHRs are constructed so that they all map to the same standardized concepts when referring to pediatric patients.

“From the research side, this is a fabulous opportunity because all kinds of information are being collected,” Dr. Bailey said.

Yet, one of the biggest barriers to widespread adoption of a common pediatric research terminology is raising awareness, Dr. Bailey said. The NICHD website already has harmonized several terminology reference subsets for pediatric specialties that researchers can consult and begin to deliberately design studies to be consistent and interoperable.

“Start thinking about how the research you’re doing connects to the questions that your colleagues are trying to answer and how everyone could benefit from shared terminology,” Dr. Bailey said.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-must-talk-talk-advance-science/

Jun 06 2014

Capturing a Snapshot: the CHOP Scientific Symposium

Scientific SymposiumWith more than 500 investigators (plus fellows, assistants, and a staff in the thousands) spread across a campus comprising more than 1.5 million square feet of space, The Children’s Hospital of Philadelphia Research Institute is a big place. Research Institute investigations run the gamut of scientific inquiry, from those focused on injury research to genomic studies to clinical and surgical projects.

Now in its 11th year, the Research Institute Scientific Symposium aims to capture a snapshot of some of the groundbreaking work going on at the Institute every day. This year’s Symposium, featured presentations on the role of the circadian rhythm in lung function, the effects of brain tumors on survivors and their families, and genetic investigation of rare pediatric diseases.

In his opening remarks — which focused on genomics and politics — Philip R. Johnson, MD, Chief Scientific Officer and director of the Research Institute, noted that when it comes to detailed biological and genetic information, “the more we know the less we know.” For example, a person’s genome can now be sequenced in just a few days for several thousand dollars. But deciphering and managing the abundance of information generated by next-generation sequencing methods remains a challenge, Dr. Johnson said.

Touching on politics, Dr. Johnson noted unpredictable levels of federal support have led to uncertainty throughout the field. We need Congress to ensure a stable level of funding, Dr. Johnson said, because “basic science is where the real discoveries come from.”

“Fundamental, basic biological research is a very important part of what we do here at CHOP,” said one of the day’s presenters, Janis Burkhardt, PhD.

Sleep, Sheep, and Green

The day began with a series of mentored presentations, with senior and junior researchers presenting jointly. Phyllis Dennery, MD, and Shaon Sengupta, MDDS, MPH, led off with a talk on the role of the circadian rhythm in the neonatal lung. A key question of their research, Dr. Dennery said, was whether clinical care could be optimized to match circadian rhythms. For example, she pointed out, heart attacks are more likely in the morning than at night.

This talk was followed by a presentation led by fetal surgery pioneer Alan Flake, MD. Along with Emily Partridge, MD, Dr. Flake has been working on a groundbreaking project to develop an extrauterine life support system that could help improve outcomes for severely premature babies. A combined engineering and medical challenge, Drs. Flake and Partridge have been working on a tank-based external uterus, going so far as to raise several (now healthy) premature lambs.

In addition to mentored presentations, the 2014 Scientific Symposium also featured a number of collaborative talks, given by investigators who worked together on projects, often across disciplines. But the day’s highlights were its keynote speeches. The internal keynote speaker was Joseph W. St. Geme, III, MD, CHOP’s new Physician-in-Chief and Chair of the Department of Pediatrics at the University of Pennsylvania, who researches bacterial host-pathogen interactions. The Symposium’s external keynote speaker, meanwhile, was Eric Green, MD, PhD, director of the National Human Genome Research Institute. Dr. Green spoke about the history and future of genomic medicine.

Since the end of the Human Genome Project in 2001, “our knowledge of epigenomics has exponentially grown,” Dr. Green said. “We’ve learned a lot in 11 years, but we really have to be realistic and recognize that we’re probably going to study this for decades.”

“It is a remarkable time we’re living in,” Dr. Green opined.

To learn more about 2014 CHOP Research Scientific Symposium, see this month’s issue of Bench to Bedside.

Permanent link to this article: http://www.research.chop.edu/blog/capturing-snapshot-chop-scientific-symposium/

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