Bench to Bedside

March 2016

CPR for Children Gets Smarter


Heart-stopping. Critical moment. Life-or-death. The catchphrases that have come to define powerful dramatic scenes have real-life antecedents in pediatric intensive care units (PICUs), where sick children are at the highest risk of cardiac arrest in the hospital. More than half of children who experience cardiac arrest in this setting do not survive to hospital discharge.

That life-or-death balance is tipping in favor of survival, however, thanks to clinicians’ and research scientists’ persistent push toward discovery. Research at The Children’s Hospital of Philadelphia, combining basic and translational investigation with bedside implementation of clinical therapies, is at the forefront of that decades-long effort to make cardiopulmonary resuscitation (CPR) smarter.

More than 3,000 children die each year in the U.S. alone after cardiac arrest in hospitals, the equivalent of one full school bus crashing with no survivors each day. Unlike adult cardiac arrest victims who may have complex underlying health conditions, among children who need CPR, the average age is 3, and many of the causes are rapidly reversible. The number of high quality of life years saved by implementation of CHOP’s pioneering approach to resuscitation is enormous.

“It is amazing that a persistent, systematic translational approach making small changes to our everyday protocols can add up to innovations that make a huge difference for so many children,” said Vinay Nadkarni, MD, MS, a critical care physician at CHOP and professor at the Perelman School of Medicine at the University of Pennsylvania.

Vignette: A Child’s Cardiac Arrest

To see some of the ways CHOP’s spectrum of activity in CPR quality research has been saving more lives, imagine the scene when a little boy’s heart suddenly stops. Count up the steps that contribute to making CHOP a “clinical learning laboratory” with a culture of continuous resuscitation learning and quality improvement.

One: When the child is admitted to CHOP’s PICU, the care team identifies him as being at high risk for a cardiac arrest, based on his clinical situation. They begin preparing family and staff about what to do in the event it actually occurs — a series of steps that simply does not occur at most other hospitals.

Two: It happens. Alarms blare from equipment at the child’s hospital bed when he goes into cardiac arrest. At CHOP, bedside healthcare providers who arrive first to perform CPR have already practiced the technique earlier that same week using one of the unit’s unique rolling refresher carts — unlike the past standard practice of taking a refresher CPR course only once every two years or so, away from the site of care. This innovative approach was pioneered at CHOP by Dr. Nadkarni and Research Program Manager Dana Niles, MS, D.Phil (cand).

Three: In their efforts to resuscitate the little boy in arrest, clinicians focus their attention on the blood pressure reading on the patient’s continuous monitoring equipment to ensure their efforts have the intended physiological effect — improving upon the old methods, in which they focused predominantly on how fast and how deep they were compressing the child’s chest, regardless of measurable effect. (They have practiced this focus on blood pressure readings using a CHOP-developed training manikin, too.)

Four: Later, after the critical incident is over, the clinicians and trainees in the PICU gather to review the quantitative data that has been downloaded from the bedside monitors and compiled into a “report card” showing the strengths and weaknesses of the team’s performance. The debriefing resembles what professional sports teams do as they review the tapes of the game using guided reflection (coaching). Many in attendance at the debriefing were not assigned to this patient, or were not on duty during the arrest. Natural human curiosity and the desire of the CHOP team to optimize performance at these dramatic, life-or-death situations, draws a crowd to these sessions.

The CHOP team has demonstrated that its model of post-arrest debriefings significantly improved both CPR quality and patients’ survival. Patient survival with favorable neurological outcomes has doubled.

Expanding Impact Through Clinical Research Networks and Beyond

With a new grant from the National Institutes of Health awarded this spring, CHOP research scientists aim to disseminate this single-site success via a multi-site national clinical trial. In the study, the CHOP team will test whether the bundled approach of bedside refresher training, resuscitation to physiologic blood pressure targets, and post-arrest debriefing for the entire unit, leads to similar improvements in outcomes at other children’s hospitals throughout the Collaborative Pediatric Critical Care Research Network, (CPCCRN, pronounced “Capcorn”).

Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, CPCCRN comprises a core group of eight top-tier medical centers with an intense focus on studying resuscitation improvement in pediatric ICUs. This and other larger clinical research networks for resuscitation, such as the pediatric Resuscitation Collaborative (RES-Q) led by CHOP and supported by an unrestricted educational grant from the Zoll Corporation, extend the work CHOP does as a single center into a more robust national and international hub of quality improvement and clinical research. The evidence-based methods that demonstrate success in these concentric circles of broader networks, in turn, shape the guidelines of organizations such as the American Heart Association (AHA), which set the standard for how all hospitals handle resuscitation nationwide.

CHOP experts themselves play important roles in guiding these national practice shifts. For example, Dr. Nadkarni chairs the scientific advisory board of the AHA Get with the Guidelines-Resuscitation national registry of CPR and its International Liaison Committee linking the AHA with global counterpart resuscitation councils. Alexis Topjian, MD, MSCE, chairs the pediatric research task force for AHA’s national resuscitation registry. Peter Meaney MD, MPH, leads the AHA Pediatric International Task Force on Resuscitation and developed a Saving Children’s Lives program that is taking these programs globally.

Years of Research Underlying a Personalized Approach to Resuscitation

The newly funded CPCCRN-wide trial incorporates physiologic targets for CPR, a shift that makes the technique much more personalized to each patient.

“Not only does it make sense clinically to pay attention to blood pressure, when restoring blood flow is the desired outcome, it’s also practical in that, when you run to the bedside and look at the monitor and someone is delivering CPR, the blood pressure number is right there,” said Robert Sutton, MD, MSCE, an attending critical care physician and associate professor at Penn, who is principal investigator of the new multi-site trial.

Before these methods could ever be tried on patients, though, researchers at CHOP tested their efficacy in laboratory settings. Dr. Sutton’s studies in the lab of Critical Care Division Chief and Penn Professor Robert Berg, MD, showed that targeting physiological outcomes improves survival after resuscitation of large animals compared to standard rate- and depth-based targets, across a wide range of disease models.

To bring this more personalized approach into the clinic, where most clinicians in most hospitals are not taught to use patients’ available physiologic readings such as blood pressure to guide CPR performance, the CHOP team further needed to create effective training tools and methods.

Making Training Manikins Better

During her fellowship several years ago, Heather Wolfe, MD, now an attending critical care physician at CHOP and assistant professor at Penn, worked with Matthew R. Maltese, PhD, to develop a training manikin that could be used to train clinicians to perform CPR targeting physiologic readings. Dr. Maltese, the department’s director of biomechanics research, a research assistant professor at Penn, and lead for the FDA-funded Philadelphia Pediatric Medical Device Consortium, oversees resuscitation-related research efforts that include modifying training manikins and building models to test pressure impacts on a child-sized chest with potential novel CPR methods.

As part of a long-term successful engineering training program in which students at Drexel and Penn learn while working at CHOP, Drs. Wolfe and Maltese guided Drexel student Veronika Legkobitova who helped build prototypes of a manikin that felt lifelike while delivering realistic data to an attached display monitor with simulated blood-pressure readings.

Subsequently, Dr. Wolfe led a six-month study comparing CPR training methods for clinicians at CHOP using the new manikin.

“We found that at the end of just three months the providers that were trained using a blood pressure target were retaining skills better than providers trained on the same manikin but taught to focus only on depth and rate targets,” Dr. Wolfe said.

Dr. Wolfe also leads the debriefings to follow up after each cardiac arrest incident in the PICU. In the new multi-site trial, she will develop and use telemedicine and site visits to train CPCCRN-participating hospitals to replicate the format of these debriefings.

From Discovery to Impact

While CHOP leads ongoing efforts to improve CPR, it is clear that the research to date has already had a major impact on practice nationally and internationally.

“CHOP has led the field in discovering what is important for the quality of CPR for children, in the knowledge exchange and implementation science of how to perform and disseminate high quality CPR, and in modeling how CPR affects outcomes and quality of life for critically ill and injured children,” Dr. Nadkarni said. “Kids are not just little adults. We’ve led the field in trying to figure out the impact of age, size, and developmental life cycle on performance and outcomes of CPR.”

In 2015, the Institute of Medicine (IOM) issued a report highlighting strategies to improve survival following cardiac arrest for patients of all ages, including collecting and centralizing data about cardiac arrest treatment outcomes (a process CHOP began more than 15 years ago), improving care delivery through continuous quality improvement programs (a point of pride in CHOP’s programs), and investing in research (a comprehensive undertaking, as described above).

“Seeing how well what we did here pioneered exactly what the IOM now prescribes is amazing; I’m stunned actually,” Dr. Berg said.

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Intergenerational Family Services: Serving Caregivers, Improving Child Health


As a practicing pediatrician, David Rubin, MD, MSCE, saw firsthand how parents and guardians often were dealing with myriad issues that lessened his ability to help their children. Families would not fill prescriptions due to financial hardships, for example, or a parent with emotional disturbances would forget to pick up or administer her child’s medications. He realized that many other medical professionals shared these same kind of unfortunate anecdotes.

When Dr. Rubin became founding director of PolicyLab at The Children’s Hospital of Philadelphia in 2008, these experiences motivated him to engage in research and practice initiatives focused on intergenerational family services – health services provided to parents and caregivers in pediatric medical settings. Research conducted by PolicyLab experts and others has shown that innovative initiatives emphasizing family-centered care can have a powerful effect on the health and well-being of children. In other words, children do better when their caregivers do better.

PolicyLab recently launched an intergenerational family services research portfolio that will research, implement and test innovative ways to engage parents and guardians around their own physical and mental health needs and therefore improve their children’s health outcomes.

“We’re trying to move the needle on complex outcomes that may be driven by social determinants of health, such as what is going on within the home environment,” said Meredith Matone, DrPH, MHS, deputy director of PolicyLab who is overseeing the intergenerational family services research portfolio.

Novel Intervention for Postpartum Depression

Consider a new mom who has been diagnosed with postpartum depression, an incapacitating illness affecting anywhere from 10 to 20 percent of new mothers. She may feel too overwhelmed to seek healthcare services for herself or find a postpartum support group. If she happens to be a single parent in a low-income household, it also may be difficult for her to arrange childcare and transportation to attend traditional in-person meetings.

A novel intervention that is being evaluated by PolicyLab could be an opportunity in this case for mom to connect with peers, learn about postpartum depression, and reinforce good parenting skills — without needing to leave home. James Guevara, MD, a founding member of PolicyLab, and colleagues are developing a parent-coaching program for women with postpartum depressive symptoms, utilizing a social media format to enhance participation.

In a pilot randomized controlled trial, the study team is comparing the social media format to traditional in-person group formats and determining how the parent coaching affects new mothers’ depressive symptoms, sense of parenting confidence and parenting interactions with their infants. The Maternity Care Coalition of Philadelphia is collaborating with the study team to assess the feasibility and acceptability of the intervention in a community setting.

Evaluating Home Visitation Programs

Another example of PolicyLab’s ongoing intergenerational family services research is a statewide project for Pennsylvania that Dr. Matone and Dr. Rubin, who also is a professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania and a senior fellow at the Leonard Davis Institute of Health Economics, are leading to evaluate federally-funded home visitation programs for families of young children.

So far, their results suggest that mothers who are participating in home-based services are more likely to receive the appropriate number of prenatal care visits, which potentially protects their infants from adverse birth outcomes. After they are born, those infants also are more likely to receive the recommended number of well-child visits.

“Doing this home-visiting evaluation for the past few years has reinforced for me the value of the delivery of care to parents and children together,” Dr. Matone said.

Transition to Accountable Care Organizations Ideal Timing

When PolicyLab announced in late 2015 its long-term strategy on intergenerational family services research efforts, it was ideal timing, Dr. Matone said. Healthcare reform has accelerated the transition to accountable care organizations (ACOs), of which CHOP is one. ACOs emphasize improving quality, value and patient outcomes using evidence-based prevention and care management strategies. The ambitious projects included in PolicyLab’s intergenerational family services research portfolio may provide helpful insights on how ACOs could possibly achieve those goals while reducing healthcare expenditures using holistic, family-centered programs and partnerships with community health organizations.

“At PolicyLab, our goal is to figure out how our investigators can take advantage of the tremendous health system that we’re in and our strengths as clinician-scientists to demonstrate innovation from here out,” Dr. Rubin said. “How do we start to implement and test these solutions?”

PolicyLab experts are embarking on a new project that will involve in-depth interviews with advocates, policymakers and other hospital administrators across the country to get a sense of the current landscape of intergenerational family services. This beginning phase will be the foundation for a plan to create a comprehensive set of informed recommendations for healthcare systems to incorporate effective intergenerational family services into pediatric practice.

Expanding Opportunities for Intergenerational Family Services Research

Meanwhile, Dr. Matone is always on the lookout for other policy opportunities on the national level that could be bolstered by intergenerational family services research. She pointed to the U.S. Preventive Services Task Force’s new recommendations for the delivery of maternal depression screening during pregnancy and the postpartum period. As a result, those screenings are now to be covered under the Affordable Care Act. This creates new research possibilities to explore how the policy change may translate into improved pediatric care.

Within PolicyLab, news of the intergenerational family services research portfolio has opened the doors for investigators to collaborate on ideas to promote family-based care, Dr. Matone said. It also has encouraged a discussion across CHOP and the Research Institute about the parent engagement side of various departmental initiatives, such as violence screening within the emergency department.

“Having this portfolio has allowed us to start to have more intentional conversations about activities that may be considered intergenerational family services, the success of those services, what assistance may be needed and their vision for moving forward,” Dr. Matone said. “We can help the institution be a leader in this area.”

Dr. Rubin expects these efforts will create a breadth of services that the medical community can access to support not just children but their parents. Fast-forward to a future well-child visit where he meets a new mother who seems to be struggling to care for her newborn.

“I’ll know how to help that mom by identifying her depression, following up with the appropriate resources, and every time she comes into my office, checking in on her progress,” Dr. Rubin said. “And that family will do better as that child grows up because I was working with her on that issue. That’s what it’s all about.”

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Seeing the Impact of a Decade of Genomics Discoveries


When The Children’s Hospital of Philadelphia established the Center for Applied Genomics (CAG) in 2006 with a $40 million commitment, it was one of the largest single investments in a research program at the hospital’s history. The ambitious idea spearheaded by CAG’s founder and director, Hakon Hakonarson, MD, PhD, was to establish the world’s largest pediatric genomics biobank and to use that vast quantity of genetic data to discover the causes of disease and disability hidden within a population’s genes.

Success was by no means assured. But today, as CAG approaches its 10th anniversary, its influence is evident across the research landscape. That impact is poised to grow as more of the center’s genomic discoveries move toward clinical applications.

Biobank Powered by Family Participation Powers CAG’s Success

“This is by far the biggest pediatric biobank in the world,” Dr. Hakonarson said. “No one has anything remotely close to what we have built here at CHOP.”

This enormous collection now totaling DNA samples from more than 400,000 people, including about 100,000 CHOP patients and their family members, is housed at CHOP and used for a vast range of research discoveries. It would not have grown into the world’s largest pediatric biobank if not for early success with recruiting large numbers of patients and families at CHOP.

From the earliest days after CAG was established, well over 100 CHOP investigators were eager to participate. Together with members of the CAG staff, many of whom have been with the program since its inception in 2006, they have contributed to patient recruitment, phenotyping and sample collections from the participating families. The CAG staff has been exceptional, according to Dr. Hakonarson, and their collaborative work on the biobank has subsequently led to many groundbreaking discoveries.

“One of the most remarkable things about the biobank is that more than 80 percent of the patient-families we ask to donate samples to it say yes,” CHOP’s CEO Madeline Bell wrote in a recent message to CHOP employees. She highlighted the biobank as a “CHOP treasure” and cited the appreciation of the value of such research among families who chose to participate.

With such a large number of samples, CHOP investigators have great statistical power to detect genetic variations underlying diseases in the population. In addition, CAG investigators and their collaborators have helped hundreds of families to resolve the underlying genetic causes of their extremely rare diseases.

What makes the biobank even more powerful and unique is the complementary data associated with each biological sample. Each one is linked to a patient’s continuously updated electronic health record — giving researchers a deeper insight into later diagnosed conditions even after the time when participants enroll. Plus, many participants who contributed to the biobank signed an innovative consent form that allows researchers to contact their families again to request additional information, such as information about environmental exposures, family history that was not already part of their record, or even samples from additional family members. The informed consent and information about the CAG operation can be found at

“This was very, very unique,” Dr. Hakonarson said. “No one was doing this type of consent at the time we started the project.”

The volume and statistical power of the biobank has also positioned CHOP as a hub for pediatric genomics research. As a result, CHOP’s initial investment in developing CAG and the biobank has evolved into a self-sustaining enterprise, funded by major research grants and contracts for research services.

Decade of Discoveries and Impact on Research

The volume of samples in CAG’s biobank combined with the scientific prowess of researchers at CHOP has allowed the discovery of links between genetic underpinnings and the disease phenotypes in patient populations. Based on analyses of biobank samples, CHOP researchers have published more than 450 papers in scientific journals, many of them in the top-tier ones such as Nature and Cell. They have made landmark discoveries in the gene variations and genetic pathways involved in a wide range of conditions, including asthma, autism spectrum disorder, cancers, schizophrenia, and Type 1 diabetes.

“That has led to huge visibility to CHOP as a mecca of pediatric genomics today,” Dr. Hakonarson said. “These efforts have really transformed genomics research at CHOP.”

 Dr. Hakonarson was recently recognized by Thomson Reuters as one of the most highly cited researchers across all disciplines. The “highly cited” status can be seen as an independent verification of his program’s research impact; not only is the CAG team publishing papers in well-regarded journals, but other researchers build on that work often enough that they cite those papers with exceptionally high frequency.

Emerging Impact on Clinical Care

The impact goes beyond research. CHOP researchers have begun to translate more and more of CAG’s genomic discoveries into therapies.

One of the earliest such successes stems from a 2008 discovery by a team led by CHOP pediatric oncologist and Penn Assistant Professor Yael Mossé, MD. They found that a mutation in the gene ALK was a driver of most cases of rare, inherited neuroblastoma, a pediatric nervous system cancer. The pharmaceutical company Pfizer had been working on an ALK-inhibitor drug, crizotinib, which had been approved for adults with lung cancer.

“It was about seven months after making this discovery that patients at CHOP were receiving this drug,” Dr. Hakonarson said.

Dr. Mossé and colleagues have continued to build on this work as well, identifying more effective ALK inhibitors to help patients whose tumors were less responsive to crizotinib. She is working to launch a clinical trial for a new drug this year.

Looking beyond rare cancers, Dr. Hakonarson is excited about a broad-scale population impact of more recent CAG discoveries of mutations in multiple genes that are part of a neurotransmitter signaling pathway regulating memory, attention, cognition, learning, behavior, among other biological processes. They found these mutations to be associated with several neuropsychiatric conditions in children including attention deficit hyperactivity disorder (ADHD) and have already completed the first proof of concept clinical trial in ADHD. These findings could rapidly lead to clinical therapies, as an investigational drug that targets this pathway is already in use in clinical trials for ADHD led by Medgenics Inc. (Medgenics licenses certain CAG assets and funds some of Dr. Hakonarson’s research.)*

“This discovery alone may have a huge impact on millions of kids down the road,” Dr. Hakonarson said. “It would never have been discovered if not for the CHOP biobank we built.”

*In addition, Dr. Hakonarson indirectly owns stock in Medgenics and CHOP and Dr. Hakonarson could benefit financially from their relationships with Medgenics.

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A Molecular Balancing Act to Fight Autoimmune Disease and Cancer


Wayne Hancock, MBBS, PhD, has spent more than a decade trying to strengthen the activity of certain cells in the body that could help control conditions including autoimmune diseases and organ transplant rejection. When his efforts inadvertently weakened those cells, he used to throw those failed results away, along with the experimental drugs that produced them.

“Now we’re a bit cleverer, and we’re using them for cancer,” said Dr. Hancock, chief of the Division of Transplant Immunology at The Children’s Hospital of Philadelphia, and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Hancock was recently awarded two new grants from the National Institutes of Health to discover drug targets and therapies to manipulate these cells, called T-regulatory cells or Tregs, for each of these opposite effects.

“If we have insufficient numbers of Tregs or they don’t work properly, we get multiple sclerosis, diabetes, asthma, and autoimmune diseases,” Dr. Hancock said. “If we have too many, that might predispose us to cancer. We want to live in that balanced area where there’s not too much and not too little.”

Increasing Treg Activity to Dial Down Excess Immune Response

Tregs play an important role by quieting the immune response at times when it gets overzealous and attacks healthy cells and tissues instead of only foreign materials, a situation that occurs in autoimmune diseases and after a transplant procedure.

Injecting Treg cells into the body is one popular experimental approach to treating these conditions. The NIH has dedicated millions of dollars into clinical trials for these Treg cell therapies.

“I think that’s short-sighted,” Dr. Hancock said. “Even under ideal conditions, these are short-lived cells, and in inflammatory conditions they’re even shorter lived.”

Instead, he aims to make Tregs stronger through drug therapies.

In the first of his newly funded studies, he is testing and developing potential drug therapies in a mouse model that could increase the activity of Treg cells by increasing the activity of the protein Foxp3 within them, as well as further describing the molecular mechanisms affecting the activity of Foxp3 in Treg cells.

Foxp3 is a transcription factor, a type of molecule that controls which genes are expressed in the cell. The presence and activity of Foxp3 is what makes a Treg a Treg, and not any other type of cell. Even in Treg cells, though, the activity of Foxp3 is still repressed most of the time. Dr. Hancock has identified some of the molecules that put the brakes on Foxp3 in Treg cells, and he is testing drug compounds that may take away or block those braking mechanisms.

Specifically, in previous research Dr. Hancock identified the molecules HDAC7 and HDAC9 as brakes that suppress another family of transcription factors called Mef2. Mef2 molecules activate the expression of Foxp3. Working with collaborators at other institutions, he has identified several drug compounds that inhibit these HDAC molecules, and in the new project he will develop and further test these potential drugs.

He also aims to further describe the mechanisms by which HDAC and Mef2 molecules regulate Foxp3 in Treg cells by finding out which Mef2 molecule or molecules in particular may be more important to the process. This would help narrow down the target to select drugs that act precisely to increase Treg activity, with less risk of side effects on other cells and processes.

Decreasing Treg Activity to Dial Up Immune Response to Cancer

On the opposite side of the balancing act, Dr. Hancock is researching ways to make Tregs function worse, thereby dialing up the body’s immune reactivity to cells and materials that seem foreign.

“Degrading Treg function sounds like an unhealthy proposition,” Dr. Hancock said.

In fact, wiping out Treg functions entirely would be unwise, because it would cause the immune system to attack the body with such potency that a person would die of autoimmune disease.

“But it turns out that in cancer, many cancer therapies are less effective because the immune system is not active against the tumor. If you can make the immune system stronger, you can make the cancer therapy more effective.”

Dr. Hancock’s second newly funded NIH grant allows him to continue preclinical screening of potential drug compounds that have shown promise decreasing the activity of Tregs.

In the first phase of this research, Dr. Hancock has already shown that tumors only shrink in animals with normal immune systems that receive these compounds, and not in immunodeficient animals, suggesting that it is indeed the immune modulatory effect of the drug that prompts the body to attack the tumor. With the next phase of funding, awarded to Progenra Inc., as a phase 2 Small Business Innovation Research project with Dr. Hancock as the principal academic partner at CHOP, he is working to further optimize the compounds and to identify their mechanism of action.

“Immuno-oncology, modulating the immune response to tumors, is now the hottest area in cancer work,” Dr. Hancock said. “This is a completely new spin on it, so it will be very exciting if it turns out to work. With the transplant work, people are putting all their eggs in Treg cell therapy, so, again, we’re the lone voice in the wilderness. I think with time pharmacologic regulation of Treg will have significant impact because the experimental work is very compelling.”

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Concussions’ Unpredictability Underscores Need for Follow-Up Care


Concussions do not come with easy answers. Michael Nance, MD, director of the pediatric trauma program at The Children’s Hospital of Philadelphia, recently reinforced that lesson with research looking for simple tests to guide follow-up care for youth who come to the emergency department (ED) with these mild traumatic brain injuries.

In CHOP’s clinical care practices, families are encouraged to bring children with suspected concussion to their primary care doctors, who have received comprehensive concussion-related training and who are part of a network-wide, streamlined process for follow-up care.

“The ED is going to be one common portal of entry for kids with concussion who are not in the CHOP system,” said Dr. Nance, who is also an investigator with CHOP’s Center for Injury Research and Prevention (CIRP) and a professor of Surgery at the Perelman School of Medicine at the University of Pennsylvania.

About 80 percent of the 1.7 million Americans who sustain a head injury each year are treated and released from the ED — so if there were a simple predictive test that worked well in the ED to triage these patients and differentiate individuals with greater immediate and future care needs, it could potentially help a large population which commonly receives little post-release guidance beyond “take it easy.”

But Dr. Nance and his colleagues found no such luck with a simple test.

Researchers Analyze Usefulness of Neurocognitive Test in ED

As they reported in the journal Brain Injury earlier this year, they evaluated the use of a widely used and validated neurocognitive test, a computer program called Immediate Post-concussion Assessment and Cognitive Testing (ImPACT©), to measure performance of youth with blunt trauma head injuries while they are in the ED. They compared these youth to a control group with lower extremity injuries, to rule out the possibility that any poor performance scores could be the result of the stressful experience of ED treatment itself.

They did find that the test was feasible to administer in this setting, and that the youth with head injuries had significantly higher symptom scores and performed worse on neurocognitive measures than the control group, although the difference was statistically significant in only two neurocognitive domains. Plus, they pointed out that the test had potential to be a practical choice because many schools require that student athletes take this test to get personal baseline measurements while they are healthy.

Ultimately, though, they concluded that the test will not become useful as a triage tool in the ED. (This month, a Canadian team published a larger study in the Journal of the American Medical Association, showing only modest success using a more complex predictive scoring measure for the same purpose. They also did not yet recommend clinical use of the predictive scoring tool.)

“The bottom line is that we found all the kids with concussions demonstrated significant abnormalities,” Dr. Nance said. “You probably can’t predict who will have what outcome that early. With the pervasiveness of symptoms in the ED population, our findings strongly argue for structured follow-up after discharge from the emergency department.”

Training Physicians on Front Line of Concussion Care

At CHOP’s primary care practices, structured follow-up for concussion has become part of standard practice in recent years.

“Pediatricians do not receive a lot of concussion-specific training in medical school or residency,” said Christina Master, MD, a sports medicine pediatrician at CHOP and associate professor at Penn.

Recognizing that shortfall in training and the rapid growth in knowledge about concussion care needs, Dr. Master, along with colleagues from CHOP Sports Medicine and CIRP, launched an interdisciplinary, research-basedMinds Matter: Improving Pediatric Concussion Care for Children” program that includes up-to-date training for primary care pediatricians in CHOP’s network.

Through this program, CHOP pediatricians have received education about how to serve as the front line in treatment and monitoring recovery of children and teens with concussions, including concussion-specific training, tools for clinical diagnosis and management, and family education resources. Their offices are equipped to see patients within days after a minor head injury to ensure early diagnosis, adequate rest, and coordination with schools to manage recovery. Most patients seen in the ED at CHOP for concussion now receive discharge instructions to follow up with their primary care pediatrician.

“Part of the reason why primary care pediatricians are well suited to this is that they have existing relationships with these children and families, and can therefore be sensitive to how concussion may present itself for that particular child,” said Kristy Arbogast, PhD, co-scientific director and director of engineering at CIRP and an associate professor at Penn.

Primary care pediatricians are also prepared to use a variety of clinical observation and testing skills to monitor their patients and diagnose and treat concussion-related concerns. Although neurocognitive tests are popular among youth and families because they are conducted in many school sports settings, they are not necessarily required for a clinical diagnosis or clinical planning.

“That testing is one of the tools in the tool box but certainly not the only tool,” Dr. Arbogast said.

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Using Doctors’ Certification Requirements to Increase HPV Vaccination


Children’s health outcomes can improve, and pediatricians can be satisfied with the process, when the doctors participate in quality-improvement (QI) programs that are required to maintain their board certification. Researchers at The Children’s Hospital of Philadelphia demonstrated such success with a low-cost program designed to improve vaccination rates for human papillomavirus (HPV), a common sexually transmitted infection that can cause cervical and other cancers. The project results, reported in the journal Pediatrics, provide needed evidence for how such required programs can work effectively.

Several years ago, the American Board of Pediatrics changed its maintenance of certification (MOC) requirements for pediatricians to add required participation in certain QI activities. The move met with controversy, in part due to the limited evidence base for the impact of these physician-only programs.

“The evidence about how that requirement affects patients is lacking, as is information on how you really best do MOC in a way that respects clinicians’ other commitments and works in the context of the practice setting,” said Alexander Fiks, MD, MSCE, who led the CHOP study that now helps to fill some of that evidence gap.

Dr. Fiks is associate medical director for CHOP’s Pediatric Research Consortium; associate director of the Center for Pediatric Clinical Effectiveness; a founding member of the Department of Biomedical and Health Informatics; a PolicyLab faculty member; and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Co-authors included Xianqun Luan, MS, from CHOP’s Office of Clinical Quality Improvement and Stephanie Mayne, MHS, from the Center for Pediatric Clinical Effectiveness and PolicyLab.

A total of 27 primary care pediatricians in the CHOP Care Network from various locations in Pennsylvania and New Jersey participated in the QI program. Dr. Fiks and colleagues designed and led the program, focused on improving HPV vaccination rates, for pediatricians to meet MOC requirements. Elements of the program included an educational component delivered via webinar, personalized quarterly performance feedback reports summarizing individual and practice- and network-level vaccination rates, and quarterly teleconferences to discuss results of the feedback reports and plan improvement strategies for the next quarter.

Numerous national health authorities support the need to improve rates of HPV vaccination, which are low both in absolute terms and in comparison to other vaccines provided during adolescence. Earlier this year, the 68 National Cancer Institute-designated cancer centers issued a joint statement recognizing low HPV vaccination rates as a significant public health threat, and calling on parents, young adults, and healthcare providers all to contribute to preventing cancer by requesting or recommending this vaccine.

Overall, adolescents cared for by pediatricians participating in the CHOP MOC program received the HPV vaccine more often than those cared for by peer physicians who did not participate in the program. These rates were easy to measure and compare because both participating and non-participating pediatricians used the same type of electronic health records, which captured this data.

Participants in the MOC program increased their rates of offering eligible patients the first dose of HPV vaccine during preventive care visits by 10 percent, compared to a 4.2 percent increase during the same period by non-participating providers in the network. Participating pediatricians also had smaller statistically significant, measurable improvements relative to non-participants in offering the first or second dose of the vaccine during acute care visits.

Dr. Fiks noted a major value of his team’s study is that this program’s success informs the design of effective QI programs that are offered to fulfill MOC requirements. Participating physicians reported a high level of satisfaction with the program, with 96 percent agreeing that the effort they invested was warranted. Physicians reported appreciating group collaboration on improvement strategies, and they valued group accountability and competition among participants to improve their vaccination rates.

Dr. Fiks noted that elements of the program that made it easy and affordable to implement included the use of electronic health records for physician feedback, allowing participants to focus on improvement and not measurement, and the relatively low-cost setup of implementing the program through a webinar and conference calls.

The main barriers to the program’s success were that some physicians found it difficult to participate in scheduled group calls (and therefore listened to a recorded call later), and that some physicians remained reluctant to vaccinate children starting at age 11.

“The gains we saw were modest,” Dr. Fiks noted. “To see more blockbuster results, it may be important to go beyond engaging the physicians to engaging the administration and the rest of the care team. More work is needed to determine how to do that more effectively.”

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Researchers Examine Obesity, Cardiovascular Risks in Down Syndrome


Children with Down syndrome (also known as Trisomy 21) are prone to obesity. Their families may be concerned about their future risks for cardiovascular problems as well as their quality of life.

Although Down syndrome is the most common chromosomal anomaly in humans, affecting about 5,000 babies born each year and more than 350,000 people in the U.S., the population is understudied, according to Andrea Kelly, MD, MSCE, an attending physician in the division of Endocrinology and Diabetes at The Children’s Hospital of Philadelphia, and Sheela N. Magge, MD, MSCE, director of research in the division of Endocrinology and Diabetes at Children’s National Health System.

They are both principal investigators of a multidisciplinary team — including experts in pediatric growth and metabolism, psychology, cardiology, and statistics — that is studying body composition measures and cardiometabolic risk factors in 150 adolescents with Down syndrome and in a matched control group.

BMI Not a One-Size-Fits-All Marker for Obesity

In the typically developing pediatric population, body mass index (BMI, a calculation based on weight and height) is the standard way in the U.S. to screen for obesity. If a child or teen’s BMI is high, it could be an indicator of higher risk for certain health problems such as heart disease, high blood pressure, and type 2 diabetes. Yet, the usefulness of BMI in individuals with Down syndrome is not known in that it might not be appropriate as a one-size-fits-all marker for obesity.

“Children and adults with Down syndrome tend to have short stature,” Dr. Kelly said. “We don’t know if BMI truly reflects body fat or adiposity in a group with altered body proportions. We wanted to explore that a little bit more, especially since older data suggested they might be protected from cardiovascular disease.”

The first-ever BMI charts for children with Down syndrome became available in the fall based on previous research conducted at CHOP by Babette Zemel, PhD, (also a co-investigator on the current study). The charts do not represent an ideal distribution of BMI, but only describe BMI distribution among the study participants. The current investigations should help to put these charts into better context and will compare them to the Centers for Disease Control and Prevention’s BMI charts, in order to give clinicians more guidance on how to screen patients with Down syndrome for excess body fat and associated health symptoms.

Looking at Other Measures of Body Composition

The study team aims to determine if BMI is the best way to define obesity in teens with Down syndrome or if there is another measure of body composition that could better predict cardiovascular and metabolic risk in this patient population. For example, the researchers are performing dual-energy X-ray absorptiometry scans to estimate study participants’ body fat. They also are looking at novel markers of cardiometabolic risk by performing subparticle analysis of the participants’ lipids and blood sugars. And they are using technology called pulse wave velocity to assess cardiac end organ injury.

“We are exploring these traditional and novel markers because if children with Down syndrome and obesity need to be more aggressively managed, we need to pay attention to that,” said Dr. Kelly, who also is an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania

Based on pathology studies conducted in the late 1970s, a belief that individuals with Down syndrome are protected from cardiovascular disease has persisted. But more recent research has contradicted this theory, suggesting that death from cardiovascular disease was more than six times great in the Down syndrome population, Drs. Kelly and Magge pointed out.

In addition to taking a comprehensive look at the relationship between BMI and cardiovascular risk factors, the study team wants to know more about the teens’ perceptions of their quality of life and if families identify any barriers to promoting exercise and a healthy lifestyle for their children with Down syndrome. The study participants will wear an armband accelerometer that monitors their physical activity for a week.

Future Goals: Prevention Programs Designed for Populations With Special Needs

Eventually, the investigators hope to use this research to build a foundation for future weight loss interventions and prevention programs that are targeted to pediatric populations with special needs.

“We’d like to work with the study team and ask, how can we prevent this from happening?” Dr. Kelly said. “Most families are very aware that their children are at risk for gaining excess weight, but we don’t know the best way for them to minimize that risk.”

At a Trisomy 21 Research Initiative meeting in October, Drs. Kelly and Magge gave an update on their research project to colleagues from the Intellectual and Developmental Disabilities Research Center at CHOP and Penn as well as other investigators from Kennedy Krieger Institute, Boston University, and University of California, Irvine. This meeting fostered a dialogue between these institutions and examined the Trisomy 21 research being done, in order to find potential extensions or amplifications of this work.

For more information on the IDDRC, contact Kristen Hearty.

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In the Neighborhood: Environmental Features Associated With Teen Homicide


It is not a pretty picture. Boarded up, dilapidated buildings. Overgrown vacant lots filled with debris. Security bars on homes and businesses. A landscape of disorder surrounds many urban youth who are at higher risk of homicide. A new study took a close look at Philadelphia neighborhoods to determine if certain environmental features could be associated with youth violence.

“A lot of blighted areas can erode the sense of security in a neighborhood and make people less likely to spend time outside in those spaces, and sometimes it can bring on opportunities for crime,” said Alison Culyba, MD, MPH, an adolescent medicine physician in the Craig-Dalsimer Division of Adolescent Medicine at The Children’s Hospital of Philadelphia, who was an integral part of the research team of epidemiology and violence prevention experts from The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

Unique Study Design and Field Research

The researchers conducted a unique, multifaceted study of teen homicides that occurred outdoors in Philadelphia. Their results, which appear online in JAMA Pediatrics, point toward neighborhood elements that could be good candidates for revitalization efforts. Prior work looking at low-cost place-based interventions to remediate urban land and buildings has shown promise in terms of reducing crime and violence as well as other negative health outcomes.

“Those findings motivated our work to uncover associations between features of the built environment and homicide, with the idea that we could potentially identify specific, modifiable neighborhood features that could be targeted in future place-based interventions to reduce violence in urban neighborhoods,” Dr. Culyba said.

Based on data from the Philadelphia Medical Examiner’s Office, the researchers identified 143 homicide victims age 13 to 20 from 2010 to 2012 who lived in Philadelphia. The Philadelphia Police Department provided additional details about the crime scene and circumstances of each homicide.

The study team recruited 155 matched control participants in the same age range who were also outside in Philadelphia at roughly the same time that each homicide took place. The researchers had to act quickly in order to find control participants who could recollect their whereabouts outdoors in the city within a three-hour window before or after each homicide had occurred. The study team then compared the homicide locations with the locations of control participants in terms of differences in the streets, buildings, and natural surroundings.

“Our goal was to say, at this particular time, on this particular day, what were the surroundings like for a kid who died versus a kid who didn’t suffer an injury, and what can we learn in terms of place-based factors that put adolescents at risk for homicide?” Dr. Culyba said.

Within two weeks after each homicide event, field researchers photographed the immediate surroundings where the homicides took place to create 360-degree, high-resolution panoramic images. They also photographed the locations where the control participants reported being on the same day and time. Trained coders examined the images to identify 60 visible, environmental elements, such as displays of graffiti or homes with broken windows.

Environmental Elements’ Potential Role in Shaping Crime

While the researchers acknowledge that homicides stem from a complex interplay of factors at individual, family, community, and socioeconomic levels, results of this study contributed new evidence about the potential role of physical surroundings in shaping violence. In examining features of the natural surroundings of participants, the presence of a park or a maintained vacant lot were both associated with significantly lower odds of homicide.

Indicators of frequent pedestrian activity, such as street lights, illuminated walk/don’t walk signs, and public transportation stops, were significantly associated with lower homicide. In contrast, stop signs were associated with higher odds of adolescent homicide, perhaps because they are markers of less travelled intersections in residential neighborhoods and present more prospects to covertly commit severe crime.

“Initially, we were somewhat surprised to find such strong associations with street infrastructure, which you typically think about around pedestrian injury and motor vehicle safety but not so much around homicide,” said Charles Branas, PhD, the study’s senior author and director of the Penn Injury Science Center. “One new theory that resonated with a lot of the things we found points to the importance of busy streets in promoting outdoor activity, interaction, and cohesion in communities, which could potentially deter street violence.”

More Research Needed to See Impact of Place-based Interventions

While this new study shows associations between certain neighborhood elements and teen homicide, Dr. Culyba pointed out that the findings do not demonstrate cause and effect. However, they do importantly highlight potential targets for future intervention studies. Future experimental research is needed to make actual changes to city spaces and see if those changes make a difference in urban violence. For example, if volunteers remediate vacant lots by mowing the lawn and creating a manicured community garden, will it promote safety for adolescents who live nearby?

“Adolescence is a time of tremendous cognitive development,” Dr. Culyba said.  “For many urban teens, assessing and lessening the risks they face — how to get to school safely, how to hang out and play basketball without facing violence — poses a huge challenge. Place-based interventions may be particularly important for them.”

Already, other research has recognized the impact of vacant lot greening on reducing less severe crimes, and has also demonstrated that mixed urban residential neighborhoods with good walkability can promote physical activity and improve mental health.

“It’s encouraging that some of our findings are in line with the idea that you may be able to better design or change city spaces and have an impact on multiple health indicators at the same time,” Dr. Culyba said. “Now our job is to figure out exactly which are the best design strategies.”

The study team included several of Dr. Culyba’s colleagues who also are interested in factors that shape the risk of urban youth violence. Dr. Branas and Sara Jacoby, PhD, MPH, are in the department of Biostatistics and Epidemiology at UPenn; Therese Richmond, PhD, CRNP, is in the School of Nursing at the University of Pennsylvania; and Joel Fein, MD, MPH, is director of Advocacy and Health Policy for the Division of Emergency Medicine at CHOP, co-director of the CHOP Violence Prevention Initiative, and a professor of Pediatrics and Emergency Medicine at UPenn. Dr. Culyba also is an adolescent medicine consultant to CHOP’s Violence Intervention Program, and is a PhD candidate at UPenn.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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