Bench to Bedside

August 2016

Tour International Pediatric Research With New Global Health RAG


As the global community comes together in August to celebrate the Olympic Games, it reminds us of the unique contributions that our world neighbors have to share. A new Global Health Research Affinity Group (Global Health RAG) at The Children’s Hospital of Philadelphia is promoting this same spirit of innovative cooperation to advance international pediatric research.

A growing number of researchers at CHOP are involved in global health efforts aiming to improve clinical, public health, and other interventions in limited-resource settings. Projects are underway in at least 14 countries, including some in sub-Saharan Africa, Latin America, and Asia. Many of these low-income communities have huge populations of children who are suffering from preventable and treatable illnesses.

“The expertise and technology we have here at CHOP could play a big role in expanding care for these children,” said Elizabeth Lowenthal, MD, MSCE, research director for CHOP’s Global Health Center and leader of the Global Health RAG, who has been working in resource-limited settings for 13 years and has ongoing research in Botswana, Zimbabwe, and the Dominican Republic. “And research elsewhere can inform care here.”

For example, Dr. Lowenthal provides care as a CHOP attending physician for a few hundred children who are affected by HIV. Prior to coming to CHOP, she worked at a clinic in Botswana where she cared for thousands of children with HIV. In order to answer important HIV-related research questions that could benefit her CHOP patients, she could coordinate a multisite study throughout the U.S. But often that same question could be answered more efficiently at a single site in Botswana. Her current research there focuses on how to optimize adherence to antiretroviral therapy among perinatally HIV-infected adolescents.

Now that the Global Health RAG has launched, investigators can learn from their own backyard about the challenges unique to global health research. It will provide a forum to raise awareness about existing resources and infrastructure available within CHOP, the Penn Center for Global Health and other affiliated groups such as the Penn Center for AIDS Research (CFAR) that support international pediatric research. And it will foster collaborative efforts between interdisciplinary and multidisciplinary investigators who have common research interests.

“The Global Health Research Affinity Group will help pool the body of knowledge and share how those of us who have done this sort of work have dealt with the practical and ethical considerations that often come up,” said Dr. Lowenthal, who also is an assistant professor of Pediatrics and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania.

In Botswana, Dr. Lowenthal’s study team had to navigate one of those research challenges when they realized that adolescents weren’t being forthright when an adult research assistant asked them research questions related to their personal health behaviors, such as sexual activity and drug and alcohol use. As a solution, the investigators set up computers with software that allowed them to ask the same questions using audio computer-assisted self- interview (ACASI).

The research participants now wear headphones and answer questions pre-recorded in their language by local university students. The voices the participants hear are matched to their age and gender. About one-third of the research participants using the ACASI admitted that they were alcohol or drug users; during the face-to-face questioning, none of them did. The study team also worked with CHOP’s information systems experts to ensure that the data generated by the ACASI could be uploaded securely and anonymously to CHOP’s servers.

Another issue that required some thought and negotiation was finding a common ground that satisfied local standards in the Dominican Republic and institutional review board standards at CHOP requiring parent/guardian consent for a child’s research participation. When a child is an orphan in a low-resource setting, his or her caregiver may not be able to provide legal guardianship documentation, Dr. Lowenthal explained. She discussed this with the head of the national institutional review board in the Dominican Republic who suggested a locally-acceptable alternative in which the guardian who is not the parent would sign to state their guardianship, and someone unrelated to the study also would sign as a witness.

“These are the kind of hoops that we’ve jumped through, and now through the RAG we’ll be able to talk with other CHOP researchers who are thinking of new studies about these solutions so they don’t have to jump through those same hoops independently again and again,” Dr. Lowenthal said.

Other potential complications that global health researchers commonly encounter include financial management, data security in settings with limited internet access, onboarding foreign research staff, and reporting results to appropriate international stakeholders. The Global Health RAG will support researchers as they troubleshoot, share best practices, and find creative solutions in these areas.

A key goal for the Global Health RAG is to foster pediatric research collaborations by linking investigators who have a passion for working in resource-limited settings but previously may have been unaware of the global health projects that their colleagues are pursuing. Here is a quick look at some of the diverse and novel studies in progress by CHOP-based investigators that the Global Health RAG is helping to guide on their research journeys:

While these projects still have a ways to go, their results eventually could catalyze improvements in pediatric health worldwide. And Dr. Lowenthal is excited that Global Health RAG members will be along for the ride.

“I hope the Global Health RAG will bring us all together and give us some inspiration on how we can expand and strengthen our programs and systems within the institution to allow us to have strong collaborations on the other end,” Dr. Lowenthal said. “I’d like to hear from CHOP researchers about the amazing global health research they’re doing and what their dreams are so that we can help them to find potential collaborators and move their ideas forward.”

For more information on the Global Health RAG, contact Dr. Lowenthal or Jennifer Chapman, MPH, administrative lead for the group. And be on the lookout for an upcoming half-day CHOP Global Health Research Retreat.

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How Reformed ‘Mean Girls’ Can Help Their Classmates


Any middle school student could tell you that gossip, rumors, and manipulation of social relationships are hallmarks of “mean girls.” That pattern of behavior is better known as relational aggression to researchers who work to understand these dynamics and intervene to help young people develop healthier relationship skills. Behavioral researchers have observed another trend that youth might find obvious:

“Relationally aggressive kids are very socially influential and perceived as quite popular,” said Stephen Leff, PhD, co-director of the Violence Prevention Initiative (VPI) at The Children’s Hospital of Philadelphia, and professor of Clinical Psychology in Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

Dr. Leff led a team that has demonstrated it is possible to turn that influence into a positive force for pro-social behavior not only among relationally aggressive girls themselves, but among their classmates and teachers.

Implementation of the Friend to Friend Intervention

The new study is a broader look at the classroom impact of their behavioral intervention, called Friend to Friend (F2F), that is targeted to ethnic minority girls in grades 3 to 5 in urban schools, after a randomized clinical trial of the program. F2F is a pull-out small group intervention for relational aggression and bullying behaviors that uses age-appropriate cartoons, videos, and roleplaying activities to engage with girls and help them slow down, act like “social detectives” in their peer interactions, and think in moments when they might otherwise react aggressively. It encourages girls to give others the benefit of the doubt and consider their choices in social settings.

Dr. Leff and colleagues at CHOP have worked for more than 15 years to develop the F2F intervention collaboratively with input from girls, parents, teachers, and other school stakeholders such as lunchroom and recess supervisors, and then to test it.

They compared classroom climate in classes where a subgroup of girls had participated in F2F with control classrooms where the eligible subgroup of girls at risk for relational aggression received an educationally-based group intervention focused on homework and study skills.

The previously reported main outcome of the randomized trial of 144 relationally aggressive girls in six schools was itself noteworthy: Girls enrolled in F2F had improved social behaviors compared to girls enrolled in the homework program, and those improvements were sustained a year later. The researchers reported that outcome last year in the journal Psychology of Violence.

Empowering Girls to Use Positive Social Influence

Next, they examined the broader impact of F2F on everyone else in the classroom who did not participate in the small-group program, including non-relationally aggressive girls, boys, and teachers.

“Part of the model was not only working with at-risk children in small groups, but also doing it in the context of their environment, classrooms and teachers, so they’d have opportunities to show how they were being more positive,” Dr. Leff said.

For example, about halfway through the 20 session small-group F2F program, the relationally aggressive girls in F2F co-teach 10 sessions in their own classrooms to share the program’s lessons with their classmates. This helps participating girls reinforce their new skills while extending the intervention to the whole class and also potentially changing classmates’ perceptions of the girls’ reputations.

“In the past, the girls might have been excluding people, and that’s how they used their influence,” said study co-author Brooke Paskewich, PsyD, program manager for VPI. “If they demonstrate how they use their influence to include people and encourage people to do positive things instead of negative ones, they hold on to popularity and influence while doing something positive.”

In the study, the students in each class rated their classmates on a variety of behavioral measures, both positive social behaviors and aggressive and disruptive ones, before and after the intervention. Teachers also completed pre- and post-surveys describing the type of relationships they had with each student.

In classes of girls who received the F2F intervention, boys and girls uninvolved in the small-group sessions received higher peer ratings in friendship and nice behaviors and improved closeness with their teachers than those in the classes whose relationally aggressive girls received a homework intervention. Boys in the F2F classes also received lower scores on negative behaviors including rumor spreading, exclusion, and fighting, and lower teacher conflict scores.

In short: Even though the program was targeted to those girls at the highest risk, it showed benefits for the entire classroom environment. The team reported these results in the journal Behavior Modification.

What Everyone Can Do to Curb ‘Mean Girl’ Behaviors

Drs. Leff and Paskewich recommend that, even for aggressive girls who are not enrolled in a formal program like F2F, teachers and parents can help build pro-social skills by looking for positive teachable moments and reinforcing social behaviors when they catch kids behaving well.

“We know that kids who are aggressive, especially aggressive girls, have tons of potential and a lot of resilience,” Dr. Leff said. “When they do something right, give them positive attention and reinforce it. When appropriate, look for opportunities for leadership, such as mentoring younger girls, or talking about when they resolved a situation in a positive way.”

Read more about the F2F intervention and its broader impacts in a post by Dr. Leff on the CHOP Center for Injury Research and Prevention blog.

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His and Hers: Orexins’ Role in Sex Bias in Psychiatric Disease


Stress is interwoven with today’s nonstop society, and it can leave many of us feeling frayed at the edges. Women, especially, seem to experience higher rates of psychiatric disorders that are stress related, such as depression, anxiety, and post-traumatic stress disorder (PTSD), than men. Scientists at The Children’s Hospital of Philadelphia, with the support of a new grant from the National Institute of Mental Health (NIMH), are exploring the idea that these sex differences could be related to our brain’s orexin system, which is a key interface for arousal, sleep, vigilance, and feeding.

Orexins are neuropeptides that are made in the hypothalamus. Neurons use neuropeptides to communicate with each other, and orexins are particularly chatty — they project to multiple brain areas. One of the places that receives dense inputs from orexins is the thalamus, which is the brain region that Seema Bhatnagar, PhD, an associate professor in the CHOP Research Institute’s Division of Stress Neurobiology, enjoys studying the most. The thalamus is a busy central hub that relays sensory information to limbic and cortical brain regions that are important in regulating emotion and memory.

Previous research by Dr. Bhatnagar using rodent models suggested that orexins play a role in the ability to be alert and respond to a stress stimulus. Intrigued by this connection, she worked with Laura Grafe, PhD, a postdoctoral fellow in her lab who was interested in sex differences in responses to stress, to find out if orexins function differently in female and male rats. This is of much relevance to humans because of the pronounced sex differences in psychiatric diseases that are related to stressful life experiences.

“Typically, women have depression and some anxiety-type disorders at twice the rate as men,” said Dr. Bhatnagar, who also is an associate professor of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania. “We’ve been interested in identifying the mechanisms by which these sex differences occur in the impact of stress.”

In a series of experiments comparing adult female and male rats, Dr. Grafe demonstrated that under baseline conditions, female rats have higher levels of orexins that are more activated in the brain and also greater orexin concentrations in cerebrospinal fluid. She also showed that when the rats were exposed to repeated mild cognitive stress, female rats showed a baseline increase in stress hormones (glucocorticoids), their cognitive performance was impaired, and they did not habituate to the stressor as much as males.

Habituation is an adaptive process by which animals and humans learn that they do not need to fully respond to mild stressors that are not life-threatening. In people with PTSD, habituation is disrupted; they continue to be responsive to things that they know are not harmful but that they associate with previous trauma.

The study team’s next step was to demonstrate if the higher orexins in females were responsible for some of the changes that they observed when the animals were under stress. They tested this using a technique called designer receptors exclusively activated or inhibited by designer drugs (DREADDs), which are viral injections that allowed them to block the activity of orexin cells in the rats’ brains.

“If you block orexins in female rats, we found that you can prevent the baseline increase in glucocorticoids,” Dr. Bhatnagar said. “You also prevent the cognitive impairments. You don’t make them habituate any better, but some aspects are improved. This suggests that the orexins are involved in the sex differences in behaviors that are changed by stress. Of course we are interested in determining whether these effects can translate to humans, and that is something we are working on.”

The investigators’ future work will take a closer look at orexins’ electrophysiological and morphological properties to see if they are related in any way to sex differences and also at how orexins’ target regions and receptors in the brain may change under stress. And since orexins are integral to sleep and wakefulness, they are curious to see if higher orexins could influence females’ sleep parameters.

“Not a lot is known about sex differences and the amount and types of sleep that men get compared to women,” Dr. Bhatnagar said. “For example, females seem to be more easily aroused from sleep. We’re going to start looking at electroencephalogram recordings in female rats compared to males to get a basic idea of what sleep is like for the different sexes, how that may change under stress and how orexins may influence sex differences in sleep parameters.”

Another big unknown: When do these sex differences start in life? The study team will conduct experiments to see if orexins are promoted by ovarian hormones that start increasing in circulation during puberty.

As the investigators start to piece together the answers, they aim to gain a better understanding of the neurobiology underlying sex differences in stress response, which could one day lead to sex-specific approaches to treating stress-related psychiatric illnesses.

Dr. Grafe’s work also is supported by a postdoctoral fellowship from NIMH.

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Competing in ‘Olympics’ Helped Teens Retain CPR Skills


After the starting signal, instead of immediately bolting into a sprint, the runner crouched to the ground. So did all the other runners in the other lanes. With intense focus, the competitors attached their specially designed race batons to the simulated victims resting at the starting line, and they performed 30 chest compressions. Only then did each runner dash at top speed and hand off the baton (which resembled an automated external defibrillator, or AED), to a teammate who stood ready to revive the next simulated manikin victim 100 yards down the track.

You did not see this AED Relay race during the Olympic Games in Rio, nor in any future elite international athletic competition. But a great deal of training went into these so-called CPR/AED Olympics, which were held at the historic Franklin Field at the University of Pennsylvania.

New research from The Children’s Hospital of Philadelphia suggests that training for and competing in this event gave the participants a lasting edge in improvement in their ability and readiness to resuscitate a victim of sudden cardiac arrest. The researchers believe that further study and expansion of such successful educational elements could support a broader effort to improve cardiac arrest survival throughout the community.

In Philadelphia, sudden cardiac arrest occurs about four times every day, with 80 percent of arrests occurring at home. Often, a friend or family member is a bystander who could potentially perform lifesaving cardiopulmonary resuscitation (CPR) while waiting for an emergency medical responder to arrive — but, in reality, bystander CPR occurs too rarely. Expanding access to and the effectiveness of educational interventions could better equip more bystanders with the right skills and attitudes to act.

A Competition in a Class of its Own

The CPR/AED Olympics challenged students to put their learning about CPR and the use of AEDs into practice in a fun, competitive environment. In addition to the AED Relay, other competitions during the day-long event challenged students to perform CPR on manikins during a mock emergency scenario and to do so at the correct depth and rate during a two-minute compression challenge.

All of these competitions called for at least as much brains as brawn. And one competition in particular asked for the most: Each team was scored on the planning and creativity of its own new educational program designed to teach other students the CPR and AED skills they had learned.

Planning for the CPR/AED Olympics and the study of its outcomes were led by Victoria Vetter, MD, MPH, a pediatric cardiologist and medical director of the Youth Heart Watch Program at CHOP and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. The project overall is called the SPORTS study.

Dr. Vetter and colleagues from CHOP and Penn devised the SPORTS study as a unique partnership with the Philadelphia School District to improve existing CPR/AED education in high schools’ health class curriculum. The one-year program in 2011 was funded by a grant from the American Heart Association and the Laerdal Medical Foundation, a provider of training, educational, and therapy products for lifesaving and emergency medical care. The CHOP Youth Heart Watch Program had previously partnered with the schools to help them secure AEDs for all Philadelphia public high schools and middle schools.

Fifteen schools enrolled in the study. In two health classes in each school, members of the CHOP research team tested students’ cognitive and psychomotor skills in performing CPR and using AEDs, as well as their attitudes and willingness to perform CPR, before and after they learned these skills. One health class in each participating school was a control class receiving standard teaching, while one intervention class was asked to develop an original, creative CPR education program and invited to train to compete against other schools in the CPR Olympics at the end of the school year. Retention testing was performed a year later.

“We asked the kids to figure out what type of lesson would be good for their own community, in their own school, so they could take it and run with it,” said Noreen Dugan, RN, BSN, CCRC, clinical research project manager for the Youth Heart Watch Program at CHOP and a co-author of the study.

The students not only ran, but leapt at the creative educational challenge. They wrote and performed original music in genres from rap to ballad. They shot music videos with ballet and CPR dramatizations. They even considered low-cost solutions to help more students practice CPR skills in budget-strained schools. In particular, students in one school proposed using a field hockey ball to practice compressions because the ball has a similar resistance to a human chest and is already widely available in many schools, unlike expensive CPR training manikins. The Youth Heart Watch Program subsequently adapted that idea by creating a simple heart-shaped ball as an inexpensive training tool.

“We didn’t know what to expect from these kids,” Dr. Vetter said. “Here was this group at CHOP saying, ‘We want to hear what your thoughts are. We want you to come up with something and tell us what you’ve done.’ And they really stepped up. As pediatricians who invest our careers in watching children develop, that was very rewarding.”

Measuring a Lasting Impact on Skills, Working Toward Increasing Survival

“Participating in this competition and the educational program creation process resulted in a remarkable retention of resuscitation skills in the students who were in the intervention class,” Dr. Vetter said.

These findings were recently published in the journal Resuscitation.

All of the students in the participating schools improved their skills and willingness to perform CPR after learning about it in health class, both in the control classes and in the intervention groups. When the CHOP team returned to six schools a full year later for follow-up testing, they found that students who had participated in the CPR Olympics and developed educational programs a year earlier retained the psychomotor skills for performing CPR exceptionally well, at a rate of 88 percent. That represented a drop of less than one percentage point from their scores immediately after completing the class. In contrast, scores from students in the control classes dropped to 79 percent after a year, despite initially being slightly higher than scores in the intervention classes.

The high level of skill retention as an outcome of the program is a unique finding.

“We are hoping this will develop into a nationwide program that will promote CPR and AED education and awareness,” Dr. Vetter said. “It’s a program that has scientific grounding and also has educational input and impact.”

Representatives from the Youth Heart Watch Program at CHOP, the Center for Resuscitation Science at Penn, and other partners, have joined forces as part of a group called the Philadelphia Regional CPR Awareness Coalition. The group’s CPR Ready campaign aims to triple the rate of bystander CPR in the Philadelphia region while addressing racial and ethnic disparities in cardiac arrest survival. Tripling bystander CPR rates would have an estimated overall impact of doubling survival rates from sudden cardiac arrest. Educational interventions like the CPR Olympics could be a valuable component of that plan.

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Study Results Offer Reassurance on Anesthesia Safety for Young Children


A young child gives a groggy wave to his parents as he is wheeled into the operating room suite. They are confident that he is in the good hands of the surgical and anesthesiology teams, but a worry still lingers. Will the anesthetic agents used during the procedure have long-term effects on their child’s developing brain? Results from a large, comprehensive study that looked at the neurodevelopmental risks of a single anesthesia exposure in early childhood may offer them some reassurance.

About 2 million children younger than 5 undergo general anesthesia or deep sedation each year for surgical procedures such as tonsillectomy and hernia repair, and diagnostic procedures such as imaging studies. Unlike some adult surgeries, most pediatric procedures cannot be delayed for a significant length of time. These necessary medical procedures would not be possible while a child is awake, yet many questions remain about pediatric anesthesia and risks of brain abnormalities if the exposure occurs before a certain developmental age.

“It is potentially a significant public health issue that is important to look at,” said Francis McGowan, MD, endowed chair and director of Pediatric Anesthesiology Research at The Children’s Hospital of Philadelphia, who helped to design and conduct the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study along with Lynne Maxwell, MD, senior anesthesiologist at CHOP.

Many researchers previously have examined the possible association between early-life anesthesia exposure and neurodevelopmental outcomes in animals, accumulating more than 500 studies focused on this topic. Some of the results suggest that when very young animals are given various drugs used for anesthesia, the animals developed learning and memory problems and changes in their brain related to brain cell death and other abnormalities. However, scientists do not have convincing evidence that similar outcomes occur in human infants.

“The animal studies are compelling, but issues remain related to species differences, the dose and duration of the animal anesthetic exposure that was necessary to produce injury, whether there is a developmental window of vulnerability, and how long it’s open if there is one,” Dr. McGowan said.

Another important distinction, Dr. Maxwell pointed out, is that the study animals exposed to anesthesia are not experiencing any pain. Scientists do not know if the painful stimulus during surgery either increases or decreases risks of harm from the anesthetic agents. They also are uncertain if the dosages given to animals in the studies are comparable to dosages administered to children.

As basic scientists have been struggling with these unknowns, epidemiologists have tried to give a larger view by analyzing patient datasets to determine if children who received general anesthesia were more likely to have developed deficits in brain development when compared to children who have not had such exposure. Their efforts have produced mixed results, and some of the clinical studies did not account for certain factors known to influence cognitive development, such as socioeconomic status and parental education. The researchers also were not able to sort out details about why the children had surgery or specifics about their general health.

Meanwhile, the lack of definitive research findings has been unsettling for the pediatric anesthesia and surgical communities as well as for parents.

“Increasingly, parents will call because their children are scheduled for surgery, and they’ll ask what should be done to minimize the chance of having problems,” Dr. Maxwell said.

The PANDA study team, which was comprised of neuropsychology, neurodevelopment, and anesthesia experts from five institutions, recognized the imperative need to rigorously evaluate the neurodevelopmental effects of anesthesia exposure in early childhood. They designed the study to include healthy children who were exposed to the same type of anesthetic agents for a duration of 120 minutes or less when they underwent inguinal hernia surgery before age 36 months. They chose this age range because it includes the crucial period of rapid brain development in young children.

The investigators compared this group to a cohort of their healthy siblings with no anesthesia exposure. Since the 105 sibling pairs lived in the same households and were within three years of age of each other, the investigators were confident that they shared the same socioeconomic and parental education status. Most of the study participants were boys, since this type of hernia repair is less frequently needed for girls.

Using a comprehensive battery of neurodevelopmental tests performed later in childhood, the PANDA researchers showed that there was no difference in IQ scores between the two groups. The results also indicated no difference in mean scores of memory, attention, visuospatial function, executive function, language, motor and processing speed, or behavior.

“An important aspect of this study is the age of neurodevelopmental testing in these children was between 8 and 15,” Dr. McGowan said. “That is when these tests are most reliable. If something was going to appear as a problematic signal, these children were at an age when you could be relatively confident of the results.”

While the PANDA study results are encouraging, Dr. McGowan and Dr. Maxwell said this does not provide a definitive determination that all young children are unlikely to have cognitive problems following exposure to anesthesia. More clinical research needs to be done to see if certain subgroups of the pediatric population, such as those exposed to repeated or prolonged durations of anesthesia, could be especially vulnerable. And since most of the PANDA study participants were boys, future studies need to take a closer look at the effect of anesthesia on cognitive function in girls. In the laboratory, basic scientists need to better understand the mechanisms of neuronal injury in young animals exposed to anesthesia and then determine if those mechanisms apply to humans.

“CHOP is actively engaged in research projects that cover the whole spectrum — from animal studies to translational research to clinical epidemiology to testing novel anesthetic agents — in order to address these important questions,” Dr. McGowan said.

Findings from the PANDA study appeared online in the Journal of the American Medical Association. Study sites included CHOP; Columbia University Medical Center, New York; Boston Children’s Hospital; and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville. Dr. McGowan also is a professor of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Maxwell is a professor in the same department.

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Children May Be Overtreated for Joint Pain Resulting from Infection


After a couple of weeks of relatively minor illnesses — an ear infection, which was treated, followed by a bout of diarrhea — a child’s new complaint about pain in her joints and difficulty walking has her parents worried enough to take her to the emergency room. When the doctor learns the child is having pain in her hip, he treats her aggressively on suspicion of septic arthritis, an infection in the joint that can be debilitating if left untreated for too long. The girl’s hip is punctured and drained, and she takes a full new round of antibiotics to knock out the infection.

But a different diagnosis requiring less aggressive treatment might have been more appropriate for the child in this scenario: reactive arthritis. According to a recent study published in JAMA Pediatrics, clinicians are underdiagnosing reactive arthritis associated with the bacterial infection Clostridium difficile in children. The study is noteworthy as the first epidemiological study of C. difficile-associated reactive arthritis. Prior research on this condition in both children and adults has consisted of case reports and series.

The researchers advise clinicians to remain attuned to signs of this rare but possible complication to help reduce misdiagnosis of septic arthritis and unwarranted excess treatment.

“In our study, in pediatric patients, involvement of the hip seemed to be more common in patients with C. difficile-associated reactive arthritis,” said the study’s senior author, Julia Sammons, MD, MSCE, hospital epidemiologist and medical director of the Department of Infection Prevention and Control at The Children’s Hospital of Philadelphia and assistant professor of Clinical Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

The choice to treat a child’s hip pain aggressively is understandable because septic arthritis is a serious clinical concern that should receive prompt treatment, Dr. Sammons said. However, in many cases like in the scenario above, children also have other symptoms that are better explained by reactive arthritis, which would warrant less intensive intervention.

One such sign is recent prior illness with diarrhea following antibiotic medications. This is a classic indicator of C. diffficile infection, a cause of gastrointestinal illness which tends to take hold opportunistically after people take antibiotics for other infections.

Another sign is pain in multiple joints. Reactive arthritis, an inflammatory response that can be triggered by infection as well as several other causes, commonly affects multiple joints, or migrates to affect different joints at different times. In contrast, septic arthritis is most often isolated to a single joint.

In nearly half of cases, Dr. Sammons and her colleagues found, clinicians treating children with these symptoms still suspected and even treated for septic arthritis, when perhaps a more cautious and watchful suspicion of C. difficile-associated reactive arthritis was needed.

Dr. Sammons and colleagues identified this trend by examining electronic health records from CHOP, Nemours A.I. DuPont Hospital for Children in Delaware, and Nemours Children’s Hospital in Florida to find cases in which children had confirmed cases of C. difficile infection and who had musculoskeletal symptoms within a period of weeks after their C. difficile infection. Reviewing those records in detail, they identified 26 cases in which the symptoms were consistent with reactive arthritis and there was no other documented possible cause for joint pain. They compared these cases to matched control cases of children with C. difficile infections but no musculoskeletal complaints.

In 12 of the 26 cases that the researchers presumed to be reactive arthritis, the clinicians treating the child suspected septic arthritis, despite symptoms suggestive of reactive arthritis such as pain in multiple joints and/or recent post-antibiotic diarrhea. In only nine of the 26 cases cases (35 percent) did the clinician treating the child actually attribute the symptoms as a side effect of C. difficile.

Since they comprehensively reviewed population-based data from multiple children’s hospitals, the researchers were able to describe common features of presumed cases, noting that most children had pain, swelling, and limited movement in multiple joints. A majority also reported joint pain that migrated to different joints. Compared to the control cases of patients who did not have musculoskeletal pain, the children with presumed cases of reactive arthritis were less likely to have underlying chronic health conditions.

The study data indicated that 1 to 2 percent of children infected with C. difficile may experience an associated case of reactive arthritis. The rate of the complication increased over the study period, consistent with a rise in C. difficile infection itself.

“This is an underdiagnosed but potentially morbid condition,” Dr. Sammons said. “Part of the takeaway message to clinicians is to consider the diagnosis of C. difficile-associated reactive arthritis in patients with a recent history of post-antibiotic diarrhea, particularly if they have multiple or migratory joint involvement, and in these patients to consider observation and supportive management rather than more aggressive intervention.”

Dr. Sammons credits the collaborative environment at CHOP and Penn for building the partnership needed to conduct this study. The first author, Daniel Horton, MD, MSCE, now a postdoctoral research fellow at Rutgers, was a former CHOP resident who approached Dr. Sammons with the idea for this study while pursuing a master’s degree in clinical epidemiology at Penn and a fellowship in rheumatology at A.I. DuPont.

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Positive Parenting Program Improves Bad Behavior in Preschool-Age Children


As a parent herself, Joanne Wood, MD, MSHP, knows that parenting is stressful. As a pediatrician-researcher who has worked with high-risk populations including children in foster care, she has seen how the challenges of parenting, combined with behavioral problems that are extremely common in young children, can sometimes add up to a negative cycle that can spiral into serious consequences.

“Problematic behaviors from young children can prompt negative and reactive parenting that then increases the child behavior problems,” Dr. Wood said. “We know that child behavior problems are associated downstream with decreased school readiness, worse academic outcomes, increased risks of mental health issues, as well as increasing risk of harsh parenting.”

So she decided to find ways to break the cycle by helping parents in need at a primary care practice.

“Often for mental health interventions, children have to have a diagnosed condition to receive services,” said Dr. Wood, an attending physician and faculty member in PolicyLab at The Children’s Hospital of Philadelphia. “And really we want to keep kids from getting there.”

She found a promising tool to do so in a group parenting intervention called CARE, which she helped implement and evaluate during PolicyLab’s work with the city of Philadelphia helping caregivers in the foster care system develop positive parenting skills.

As she and her colleagues report in the journal Academic Pediatrics, providing a six-week version of this program to parents of preschool-age children at CHOP’s primary care facility in South Philadelphia was effective at improving ratings of child behavior and improving parent attitudes. The intervention, called PriCARE for its adaptation to a primary care setting, is now being offered to more parents in multiple classes at CHOP’s new South Philadelphia facility and at the Karabots Pediatric Care Center in West Philadelphia. The classes are funded by support from The Pew Charitable Trusts, Oscar G. & Elsa S. Mayer Family Foundation, and a private donor.

The main feature of PriCARE is its emphasis on positive parenting. Parents who attend this small-group program learn skills to focus on and reinforce desirable and prosocial behavior in children while ignoring milder misbehaviors. Providing labeled praise such as, “I like how you are sitting up in your chair,” and, “Thank you for sharing your toy,” helps parents establish a healthier, more supportive baseline relationship with their child. That healthy relationship pays dividends as parents later develop ways to address their child’s undesired behaviors.

Deliberately practicing these skills can feel a little awkward at first, Dr. Wood noted. Parents and caregivers go home from the PriCARE classes with homework assignments to try out specific behaviors during play sessions with their child. When they return the next week, they can share what worked well and where they struggled in discussions with the program’s two facilitators (both mental health therapists) and with other parents and caregivers.

The classes take place in the pediatric primary care facility in part to help reduce stigma associated with receiving a behavioral health intervention, and in part because it is a convenient location for families in their community. Child care is provided so parents can give the sessions their undivided attention. The classes combine lectures with discussions, role plays, and other interactive elements to help parents grow familiar with new parenting and stress-management skills for themselves and for their child.

The stress reduction techniques are part of a trauma-focused education component of PriCARE that also helps parents to understand that some of the behaviors they might see in their child may be a result of traumatic stressors in the community, such as violence and poverty.

“It’s not that the child is acting up because they’re bad or mean or upset at their parent, but it may be a reaction to something that they’ve been exposed to, and stress is leading to that behavior,” said Dr. Wood, who is also an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Coming from a place of understanding that possibility helps many parents take a more constructive and less punitive approach to misbehavior.

In Dr. Wood’s study of PriCARE, families were invited to participate if they had behavioral concerns about their 2- to 6-year-old child. The study team enrolled 120 families and randomized them to either receive the PriCARE intervention right away or to be on a wait list and serve as a control group before receiving the intervention later if they wished. The researchers surveyed both groups before and after the intervention group attended PriCARE sessions, focusing on parent reports of their child’s behavior and parents’ attitudes about parenting techniques.

They found that children whose parents were randomized to the intervention group had greater decreases in behavioral problems over time compared to the waiting list children, and that after attending PriCARE their parents had decreased belief in use of corporal punishment and increased empathy toward their children.

“These are things we were hoping to affect with a focus on positive parenting,” Dr. Wood said.

With the next phase of classes getting underway, Dr. Wood plans to build on this preliminary evidence base about PriCARE’s impacts by seeking more direct observational measures of children’s behavior among a subset of participants. Over the next three years, she expects to enroll 180 parent/child dyads in a follow-up study. Parents will also be welcome to enroll in PriCARE sessions without being part of a study.

Ultimately, Dr. Wood hopes this work can build a strong evidence base showing that PriCARE helps improve the trajectory for young children with behavioral problems. By intervening preventively, she wants to support parents helping their children get on the right track to help more children thrive without the need for complex and expensive behavioral health interventions.

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Childhood Cancer Advocates Find Strength in Numbers


Childhood cancer is a disease that divides. Biologically, cancer is a disease of cells dividing uncontrollably. Scientifically, genetic and molecular discoveries increasingly drive pediatric cancer researchers to divide their attention among narrower and narrower molecular subtypes of disease. And socially, families facing childhood cancer sometimes struggle against a sense of isolation if their friends and family doctors have little experience with the rare disease that now immerses their entire world.

But instead of letting cancer divide them, families, advocates, researchers, and others, are flipping that equation. An event held this summer at The Children’s Hospital of Philadelphia hosted by the Coalition Against Childhood Cancer (CAC2) was emblematic of the ways they are multiplying their efforts by coming together to defeat childhood cancer.

“It’s really helpful to have an organization that supports initiatives that promote collaboration among these different groups and provides information and educational opportunities so that people across the community have access to the same knowledge,” said Vickie Buenger, CAC2 president (pictured, left, with Peter Adamson, MD). “That’s what we do.”

Multiplying Efforts of Childhood Cancer Advocates

In the U.S., organizations focused on childhood cancer number in the hundreds, potentially as many as 1,000. Many of them are pursuing their important work in isolation, having their origins as foundations established in loving memory of a child lost to cancer or in honor of a young cancer survivor.

Within the last five years, however, approximately 130 childhood cancer organizations, independent advocates, and a handful of students, have joined forces in the CAC2. This all-volunteer nonprofit organization coalesces these stakeholders’ efforts with shared educational resources, collective support for outstanding ideas, and networking and collaborative opportunities for shared initiatives.

Representatives from dozens of these organizations convened at CHOP June 22-23 for the group’s largest and most comprehensive educational experience yet, the fourth CAC2 Summit and Annual Meeting. Members and guests heard from CHOP experts and other renowned guests from academia, government agencies, the nonprofit sector, and the pharmaceutical industry, on a variety of research, family support, and advocacy topics.

One session brought members up to date on Vice President Joe Biden’s Cancer Moonshot initiative, and another panel discussion probed psychosocial care for children with cancer and their families. CAC2 members also met for special interest breakout sessions to collaborate and share their ideas, and members toured research and clinical facilities across the CHOP campus.

A Growing Collaborative Emphasis in Childhood Cancer Research

During his opening remarks, Stephen Hunger, MD, chief of the Division of Pediatric Oncology and director of the Center for Childhood Cancer Research at CHOP, highlighted precision medicine, cancer predisposition, and immunotherapy as the biggest trends in pediatric cancer research.

Precision medicine in particular was a major area of focus for the meeting. By identifying the precise molecular mechanisms of disease and developing targeted treatments to address those mechanisms, researchers are finding newer treatments that are potentially more effective while causing fewer side effects on healthy tissue. But, too often, in these early days of precision medicine investigations, the most promising new therapies are designed to work only for narrow subgroups of rare diseases.

“It is important to find methods that work for subsets of patients, but, more importantly, we have to make it work for all patients,” Dr. Hunger said.

Two extensive panel discussions of precision medicine highlighted some of the ways that academic researchers and their partners in government and the pharmaceutical industry are working toward that goal. White House Precision Medicine Initiative (PMI) Project Manager Stephanie Devaney, PhD, spotlighted the national effort to develop targeted approaches for treatment and prevention of disease. Katherine Janeway, MD, a Boston Children’s Hospital (BCH) and Harvard investigator, highlighted several specific pediatric cancer precision medicine efforts at BCH and its affiliates. And Steven Joffe, MD, MPH, a CHOP and Penn medical ethicist and physician, led a discussion of bioethical considerations in precision medicine.

A second panel narrowed that focus in on Pediatric MATCH, a large precision medicine clinical trial to test multiple candidate drugs for multiple advanced-stage pediatric cancers according to molecular insights into the mechanisms of disease based on genetic mutations found in tumor biopsies after relapse. The trial, which is due to begin in 2017, is a collaborative effort of the multi-institution Children’s Oncology Group (COG), the National Cancer Institute (NCI), and pharmaceutical industry partners. Speakers from the NCI, Food and Drug Administration, and two pharmaceutical companies that provide investigational drugs to Pediatric MATCH (AstraZeneca and Loxo Pharmaceuticals), gave an in-depth look at this complex trial and the many biomedical, logistical, safety, regulatory, and financial challenges they are working collaboratively to overcome.

Pediatric MATCH follows a model similar to the NCI MATCH trial for adult cancers that is already underway, and in some cases it may accelerate testing of drug candidates that were not previously tested in children. The project ultimately aims to provide valuable information about multiple actionable cancer mutations affecting children with multiple rare subsets of disease, within a relatively brief multi-arm trial.

“Rare diseases or rare subsets of diseases require a nationwide infrastructure for research, and we are fortunate to have one supported by the National Cancer Institute,” said Peter Adamson, MD, a pediatric oncologist at CHOP and professor of Pediatrics at Penn who serves on the NCI’s Cancer Advisory Board and on the Blue Ribbon Panel for the National Cancer Moonshot initiative and is chair of the COG, during the CAC2 Summit’s final keynote. “For some of these studies, we are going to need a global infrastructure to get this done.”

All of the slide presentations from the CAC2 summit are available on the organization’s website.

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

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