Bench to Bedside

November 2014

Teaming Up to Help Teens with ADHD and ASD Drive Safely


A new teen driver with attention-deficit/hyperactivity disorder (ADHD) jumps behind the wheel and steps on the gas, looking for freedom and adventure. Could his inexperience on the road combined with the inattention, distraction, and impulsivity that are the signature symptoms of his ADHD increase his risk of crashing?

Teen driving safety researchers suspect the answer is, “probably,” but there is a surprising lack of rigorous scientific studies focusing on teen drivers with ADHD, according to Allison Curry, PhD,  a senior scientist and director of epidemiology and biostatistics at the Center for Injury Prevention and Research (CIRP) at The Children’s Hospital of Philadelphia. Using a unique database, Dr. Curry is leading a research project to help fill this knowledge gap from an epidemiological perspective.

As the first study of its kind, the study team will provide a new methodological advancement in the field of young driver research, in order to examine the risk of adverse driving outcomes among a general population of adolescents and young adults ages 16 to 25 diagnosed with ADHD. The database combines two data-rich sources:

  1. electronic health record information for about 1,800 children with ADHD and 10,000 children without ADHD who were born from 1987 to 1995 and patients at CHOP’s Care Network in New Jersey
  2. a linked traffic safety database that contains the full licensing, citation, and crash history of every New Jersey driver from 2004 to the present

“The data are really valuable because they can help us look at teens who are typically developing and other teens who have developmental disabilities to see whether there are differences in when they get licensed and in their risk of crashing,” Dr. Curry said. “If we know what kind of crashes teens with ADHD are getting in, we can begin to develop interventions that are tailored to address the driving skill deficits common among this group of new drivers.”

Motor vehicle crashes are the leading cause of death and disability among adolescents. Inattention, distraction, and unsafe driving behaviors are major contributors to teens’ car accidents, but little is known about how ADHD influences driving and how those factors could vary with gender, age, driving experience, comorbidities, and long-term ADHD medication.

Dr. Curry has spent four years creating NJ’s traffic safety database, and it already has spurred multiple published studies on teen crash rates among the general population in N.J. Her current work includes the ADHD study — funded as a three-year grant by the Eunice Kennedy Shriver National Institute of Child Health & Human Development in August 2014 — and a pilot study of teen drivers with autism spectrum disorder (ASD) that addresses similar research questions funded by a CHOP Foerderer Grant for Excellence.  Dr. Curry hopes findings from the pilot study will provide the basis for a future NIH research project grant application.

Two-thirds of high functioning adolescents with ASD of legal driving age are either currently driving or plan to drive, according to previous research done at CHOP by Patty Huang, MD, a developmental pediatrician at The Children’s Hospital of Philadelphia. However, little is known about the ability of teens with ASD to drive safely. ASD is characterized by deficits in communication and social interaction and can be associated with impairments in body coordination and ability to regulate emotions, which could come into play while driving. The research team will use the novel database to determine rates of licensure, police-reported crashes, and moving violations among 500 to 600 adolescents with autism treated at CHOP who were born from 1987 to 1994 and live in New Jersey and then compare them to rates among all New Jersey adolescents.

“We hope these projects will help to set the scientific foundation for the development of interventions that tailor the learning-to-drive process for teens with developmental disabilities,” Dr. Curry said.

In addition to the robustness of the database, both studies stand out to Dr. Curry because they are being conducted in collaboration with two other research centers at CHOP: The Center for Autism Research and the Center for the Management of ADHD. The research teams are in the process of finding and validating the ADHD and autism cases in the CHOP electronic medical record. Concurrently, they are preparing the licensing and crash database, and by the middle of next year, Dr. Curry expects they will be ready to begin analysis.

Dr. Curry hopes their novel research methods can be used to investigate the effect of other medical conditions or events, such as children who have had concussions or seizures, on driving licensure rates and traffic outcomes.

“The large patient population at CHOP gives us the opportunity to provide a unique perspective on teen drivers,” Dr. Curry said.

Understanding how each of these conditions impacts driving could lead to the development of more personalized driving assessments and educational tools for teens. Teen driver safety research is a major focus of CIRP, and the Center offers many universal resources and tips at for navigating the learning-to-drive process.

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Prevention Bundle Reduces Urinary Tract Infections


Clinicians and researchers at The Children’s Hospital of Philadelphia are always striving to improve care, which is partly why the institution continues to rank as the No. 1 pediatric hospital in the country. So, when they determined in 2010 that the rate of catheter-associated urinary tract infections (CAUTIs) at CHOP was significantly higher than the national average, they got to work to develop a bundle of strategies aimed at improving care.

Eighty percent of urinary tract infections are associated with an indwelling urinary catheter, which is a tube inserted into the bladder through the urethra to drain urine, according to the Institute for Healthcare Improvement. Symptoms of a urinary tract infection are burning or pain in the lower abdomen, fever, burning during urination, or an increase in the frequency of urination.

Because they are so common and costly, CAUTIs have received national attention as a high-priority, preventable hospital-acquired condition. Yet, most of the research on CAUTI epidemiology and evidence-based prevention guidelines focused on adults, until an observational study was published in the September issue of Pediatrics by the multidisciplinary “Prevent CAUTI” team at CHOP that established a plan to reduce the infection in a pediatric setting.

“We had a huge ‘aha moment’ when we compared ourselves to data in the literature and we had more than two times the CAUTI rate for comparable institutions,” said Katherine Finn Davis, PhD, RN, CPNP, a nurse researcher for CHOP’s Center for Pediatric Nursing Research and Evidence-Based Practice. “That was unacceptable, of course, and we decided that we must do something immediately.”

In July 2010, the team initiated a bundle that focused on placing indwelling urinary catheters only when indicated, using sterile techniques at all points of care, and reviewing catheter necessity daily. A crucial part of the intervention was institution-wide training on proper urinary catheter insertion technique and maintenance practices.

Using an online tutorial and simulation training, four leaders of the quality improvement project who Dr. Davis described as “passionate about CAUTI prevention” — Ann Colebaugh, RN, MSN, CPN; Benjamin Eithun, RN, MSN, CRNP; Natalie Plachter, CRNP; and Allison Thompson, MSN, RD, RN, CCRN, CRNP — trained 200 physicians, advanced practice providers, registered nurses, and radiology technicians in hospital areas with the highest rates of urinary catheter placement and utilization. Once the trainees mastered the insertion checklist, they became qualified observers who were responsible for promoting ongoing education by ensuring that other clinicians on their units completed the online tutorial and then followed the evidence-based practices.

Next, the Prevent CAUTI team rolled out the educational module to other hospital areas that had patients with urinary catheters, including the general medical and surgical units. In all, about 1,500 clinicians over a three-month period received training on the CAUTI prevention bundle.

“It was an incredible example of multidisciplinary work,” Dr. Davis said. “People from different aspects of the clinical world drew on their strengths and worked together toward a common goal to get our rate down.”

The Prevent CAUTI team also conducted a retrospective, observational analysis that compared CHOP’s hospital-wide CAUTI rates before and after implementation of the quality improvement project. Using data from July 2009 to June 2012, they found that the multifaceted intervention was associated with a 50 percent reduction in the hospital’s monthly CAUTI rate.

“That reduction was impressive,” Dr. Davis said. “After analysis, we also determined that the children getting catheters were still the right kids — everyone had an indication. The usage rate of catheters did not decrease during that time period, but we were using them appropriately.”

In addition to understanding better which children are at risk for CAUTIs, Dr. Davis said the study is important because it is one of the first to provide information to healthcare institutions on how to prevent CAUTIs from a pediatric perspective. Other pediatric institutions can assess their CAUTI rates and then use CHOP’s tools, such as taking the insertion checklist to the bedside, to implement similar CAUTI prevention bundles.

In an effort to sustain CHOP’s success and reduce the rate of CAUTIs even further, the Prevent CAUTI team conducts bedside reviews to reinforce standardized care and performs “just in time” training if they identify a lapse that puts the patient at risk. They also continue to identify groups throughout the hospital that benefit from CAUTI prevention training, such as hospital staff who handle the urinary reservoir bag during patient transport. They should check the position of the collection bag and ensure that it is always below the level of the patient’s bladder, Dr. Davis said.

“We want to get our CAUTI rate to zero,” Dr. Davis said. “We’re not there yet, but for any infection that is preventable, we want to get there.”

Other members of the CHOP Prevent CAUTI team who contributed to the Pediatrics paper include Sarah B. Klieger, MPH; Dennis J. Meredith, DVM, CIC, of CHOP’s Department of Infection Prevention and Control; and Julia Shaklee Sammons, MD, MSCE, and Susan E. Coffin, MD, MPH, both of CHOP’s Division of Infectious Diseases and Department of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania.

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Grant to Explore Eradicating HIV from Hiding Places in the Brain


Exploring new methods to eradicate HIV that lingers in brain cells despite conventional antiviral treatment is the focus of a new study by investigators at Children’s Hospital and Temple University. They are the joint recipients of a $4.3 million, four-year NeuroAIDS grant from the National Institute of Mental Health.

The grant funds three research projects, each targeting different biological pathways crucial to the persistence of the human immunodeficiency virus that causes AIDS. Investigators from CHOP’s section of immunology and Temple’s department of neuroscience are collaborating on these cell and animal studies to explore methods to enhance the immune system’s ability to attack HIV infection.

“This program represents a fresh look into a longstanding problem in HIV treatment — reservoirs of HIV within immune cells,” said Steven D. Douglas, MD, chief of the section of immunology at CHOP and a professor of pediatrics at the University of Pennsylvania. “While current antiretroviral treatments can reduce the virus to undetectable levels, HIV persists latently inside cells. If drug treatment is interrupted, the virus comes surging back.”

Dr. Douglas and Jay Rappaport, PhD, professor of neuroscience and neurovirology at Temple University School of Medicine, are co-principal investigators of the new grant.

“All three projects seek to bypass vulnerabilities in the body’s immune system that are exploited by HIV,” said Dr. Rappaport. “By using biological tools to reinforce immune function, we aim to enable the immune system to eliminate HIV infection.”

During the first two years of the grant, the project teams will concentrate on basic biology to determine which pre-clinical approaches show the most promise for advancing into studies using animal models in the third and fourth years. The goal of the animal studies is to demonstrate proof-of-concept for strategies that could set the stage for subsequent human trials of innovative HIV treatments.

Project 1, led by Dr. Rappaport, focuses on the metabolism of ATP, the chemical that serves as energy currency in cells. Because HIV infection stimulates enzymes that degrade ATP and weaken immune responses, the research team will explore drug candidates that inhibit those enzymes.

Project 2, led by Tracy Fischer-Smith, PhD, assistant professor of neuroscience and neurovirology at Temple, concentrates on signaling proteins that drive immune polarization, in which cells called macrophages shift from protective roles to immune-suppressive activities. The team’s goal is to counteract those proteins’ signals and restore infection-fighting functions to immune cells.

Project 3, led by Dr. Douglas, investigates substance P, a neuropeptide with a key role in promoting inflammation during HIV infection. By manipulating NK-1R, a cell receptor that binds to substance P, the research team aims to disrupt HIV’s entry into cell reservoirs and to block the viral replication that accounts for HIV’s devastating effects.

“HIV infection disrupts immune cells by swinging a biological pendulum off balance into immune-suppressive activities that drive the disease,” said Dr. Fischer-Smith. “All three projects aim to modulate the immune system, inhibiting processes that are dangerously up-regulated, and restoring a healthy balance.”

This work is in collaboration with the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP, and Temple’s Comprehensive NeuroAIDS Center — two NIH-supported centers concentrating on mental health and HIV.

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Next Generation of Innovators Get Start at CHOP


High school students from Philadelphia are getting out from behind their desks to explore basic science careers in The Children’s Hospital of Philadelphia Research Institute’s state-of-the-art laboratories and work beside top-notch faculty.

It is crucial that more students are inspired and energized to become the next generation of innovators because the pipeline of young investigators in the United States has slowed to a trickle. Only 16 percent of American high school seniors are interested in a science, technology, engineering, and mathematics (STEM) career; yet job openings in STEM are expected to be among the fastest growing occupational clusters through 2020.

That is why the Research Institute’s senior leadership, Office of Responsible Research Training, Office of Research Safety, and faculty members are thrilled to have partnerships with two local schools that give bright students the opportunity to take the beaker caps off their ambitions.

“It can be an exciting and formative experience,” said Jodi Leckrone, MEd, assistant director of the Office of Responsible Research Training. “They can ask people, ‘How did you get to be a lab tech? How did you get to be a postdoc?’ And then they can start to formulate their own plan to pursue those kinds of goals.”

With beaming smiles and contagious enthusiasm, two sets of high school juniors began their work-study programs in September. Six students are from Science Leadership Academy, a partnership between the School District of Philadelphia and The Franklin Institute that provides a college-preparatory curriculum focused on science, technology, mathematics, and entrepreneurship. SLA students come to CHOP weekly for two to four hours. Each student is paired with a faculty member, and this year the hosts include Ian Krantz, MD; Motomi Enomoto-Iwamoto, DDS, PhD; Francis McGowan, MD; Eric Marsh, MD, PhD; Beverly Emanuel, PhD; and Sharon Diskin, PhD.

The other students are from Cristo Rey Philadelphia High School, an independent, Catholic college-preparatory school open to all faiths and dedicated to students from families with limited economic means. This is the first year that the Research Institute has partnered with Cristo Rey, and Robert Fabiszewski, director of the school’s work-study program, is grateful for the placements that will prepare students to realize their full potential.

“I believe this program fuels students’ passion for science and their drive toward accomplishing their dreams,” Fabiszewski said. “The sky is the limit. It’s very exciting!”

Fabiszewski selected four young women with an aptitude in science and medicine to job-share a full-time position in the neurosurgery laboratory of Adam Resnick, PhD, and Phillip (Jay) Storm, MD. Each student works in the lab one day a week and logs her work in a notebook so that the next day her classmate can pick up where she left off.  They work closely and contribute scientifically to projects focused on targeting pediatric brain tumors, in partnership with staff, technicians, graduate students, and postdocs.

“For us, the power for scientific research to be transformative extends far beyond the discovery process,” Dr. Resnick said. “Having these four students join our laboratory for an entire school year provides a unique opportunity for lasting synergy between education and research.”

Before they get to work, the students participate in an orientation and learn the basics about laboratory safety. In their first few weeks, they observe lab skills and set individual goals. By December, they will be immersed in an actual research assignment under the supervision of their faculty mentor, in accordance with the Research Institute’s Minors in Research Laboratories policy.

“Students see what a real-life lab environment is like and what the different job roles are, how they come up with project ideas, how their project idea fits within a larger question on improving health,” Leckrone said.

At the end of their work-study experience, SLA students from the 2013-2014 school year gave a short slide presentation about what they learned to their principals, advisers, faculty mentors, lab mates, and the research training staff. For example, students who completed the program described their work on cardiac stem cells, cellular and molecular mechanisms of cartilage tumors, and brain development in Cornelia de Lange Syndrome.

SLA student Amy Chen had a phenomenal experience working with Dr. McGowan last year, even though she was challenged to step out of her comfort zone.

“Every day, there was always a word that I didn’t understand,” Amy said. “I’d have to research the word in order to understand the next step of the project.”

The most amazing part, she recalled, was getting a chance to see thin slices of heart tissue from animals and humans. Spending time in the laboratory helped Amy decide that she wants to study biology and attend medical school to become a pediatric cardiology surgeon.

“I know that I will be one step ahead of my peers because of this program at CHOP,” Amy said. “One of the most important things that I achieved is building a relationship with my mentor.”

Colleen Ambron, MBA, training coordinator for the Offices of Postdoctoral Affairs & Research Safety, facilitates the SLA students’ work-study program. She encourages dedicated students like Amy to take advantage of the professional network at CHOP and establish connections with research leaders who can point them in the right direction for higher education. Perhaps former work-study students will continue working in the labs once they are in college, or maybe they will come back in between going to medical school and then onto their fellowships.

“I love working with the students,” Ambron said. “They’re really excited when they first come here, and they think, ‘Wow, this is CHOP.’ It’s an eye-opening experience for them. They are a great group of kids, and we get so many ‘thank you’s’ for giving them this opportunity.”

As interest in the high school work-study program continues to grow, Ambron and Leckrone welcome faculty who are willing to host students to contact them: and

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New Center for Childhood Cancer Research Director Named


Stephen P. Hunger, MD, a nationally prominent specialist in children’s cancer, has been named the new director of the Center for Childhood Cancer Research and chief of the Division of Oncology. Dr. Hunger, who started Nov. 1, joins a premier, comprehensive program, staffed by internationally recognized experts in pediatric cancer who rely on the most current advances in research and treatment. In U.S. News & World Report’s most recent rankings of pediatric care specialties, CHOP’s cancer care ranked second in the nation.

“We are delighted to welcome this internationally renowned pediatric oncologist to CHOP to lead our pediatric cancer program, advancing the treatment of children, adolescents, and young adults with cancer and overseeing pediatric oncology research,” said CHOP’s Physician-in Chief and Chair of the Department of Pediatrics, Joseph St. Geme, MD. “Dr. Hunger has an impressive background as a clinician, investigator, teacher, and leader in pediatric oncology and will undoubtedly have a major impact at CHOP.”

Dr. Hunger comes to CHOP from Children’s Hospital Colorado, where he was most recently director of the Center for Cancer and Blood Disorders and holder of the Ergen Family Chair in Pediatric Cancer. He also was a professor of Pediatrics at the University of Colorado School of Medicine and the chief of the Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation.

He has a particular research interest in acute lymphoblastic leukemia (ALL), the most common childhood cancer. Recent papers include a Journal of Clinical Oncology pharmacokinetic study in ALL patients, an Annals of the New York Academy of Sciences paper on the development of asparaginase as an ALL treatment, and a Frontiers in Oncology review of current concepts in Philadelphia chromosome-positive ALL.

A leading member of the Children’s Oncology Group (COG), the national cooperative organization of pediatric cancer centers, Dr. Hunger has sat on numerous COG study committees, and has served as chair of the organization’s ALL Committee since 2008. He also has served on NIH study sections and committees of the National Cancer Institute, the American Society of Hematology, the American Society of Clinical Oncology, and numerous other foundations and groups.

Dr. Hunger has received research grants from the National Institutes of Health, the St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society, among others. He has published scores of scientific articles, reviews and book chapters, and has made invited presentations throughout the world on pediatric oncology.

“I am tremendously excited by this opportunity to join one of the premier pediatric cancer programs in the world and to help CHOP develop more and better therapies toward our eventual goal of curing all pediatric cancers,” said Dr. Hunger.

To learn more about cancer care and research at The Children’s Hospital of Philadelphia, see the Center for Childhood Cancer Research site and the Cancer Center website.

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Study Shows Rise in Preventive Pediatric Dental Care


A study conducted by PolicyLab researchers shows the proportion of US-born, Medicaid-enrolled children in Pennsylvania who utilized preventive dental care rose significantly for children ages 5-10 years from 2005-2010, with marked gains among Latino children. The study, published recently in the American Journal of Public Health, found that while overall preventive dental care utilization increased from 2005 to 2010, utilization remained less than 60 percent overall. Latino children in non-immigrant families demonstrated the largest gains over time, with 63 percent of children ages 5-10 years receiving preventive dental care in 2010 compared to 35 percent in 2005.

“We know that dental caries, also known as tooth decay, is the most common chronic pediatric disease in the US,” said Katherine Yun, MD, MHS, the study’s lead author and an attending pediatrician and faculty member at PolicyLab. “We also know that it disproportionally affects poor and minority children, and children in immigrant families.”

Preventive dental care includes routine prophylactic cleaning and the application of fluoride by a dentist. The researchers used state Medicaid claims (2005-2010), birth records (2000-2010), and data from the 2010 American Community Survey. Children who were born in Pennsylvania and enrolled in Medicaid for at least 10 months of any calendar year were eligible for the study.

Coverage for preventive dental care is available for Medicaid-enrolled children through Medicaid’s Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) benefit. However, despite this coverage, wide-scale utilization of preventive dental care has lagged in many states. Increasing utilization of preventive dental care by Medicaid-enrolled children has been a public health priority in Pennsylvania.

“Dental care is an incredibly important part of EPSDT,” explained Dr. Yun. “Mouth pain can make it hard for children to pay attention in school, and unhealthy baby teeth increase the chances that children will have unhealthy adult teeth.”

The study team looked at different groups of children to see if their use of preventive dental care had increased, decreased, or plateaued from 2005 to 2010. The authors also focused on US-born children whose mothers were born outside of the U.S., as prior research has suggested that the children of immigrants have difficulty accessing preventive healthcare. They found that in Pennsylvania disadvantage was not concentrated among the US-born children of immigrants.

Latino children in immigrant families were more likely than their peers in non-immigrant families to receive preventive dental care (72 and 61 percent, respectively, in 2010). White children in immigrant families were more likely to receive preventive dental care than their peers in non-immigrant families (62 and 51 percent, respectively, in 2010). African American children in immigrant and non-immigrant families had moderate rates of preventive dental utilization and were comparable to each other (e.g. 60 and 59 percent, respectively, in 2010).

Asian children in both immigrant and non-immigrant families showed relatively high rates of preventive dental utilization at each time point and were also comparable to each other (e.g. 69 and 63 percent, respectively, in 2010).

“We now need to identify the factors responsible for increasing utilization overall and understand why some groups of children have accessed preventive dental care services more than others,” said Dr. Yun. “This is just the first step in ensuring that all children have access to preventive dental services.”

For more information about the study, see PolicyLab’s website. And to access a blog post on the study written by Dr. Yun, visit:

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Problem of Noisy Patient Monitors Trigger NHLBI-Funded Study


If you ever have visited a hospitalized patient, you probably heard a symphony of blips, chirps, and buzzes emanating from a variety of monitors. In fact, hundreds of alarms signal for every critically ill patient each day, but research shows that 85 percent to 99 percent of alarms do not require clinical intervention. For clinicians and nurses who must distinguish these simultaneous alarms — usually while performing other high-risk tasks — the symphony often  becomes white noise.

Hospital administrators, prominent healthcare organizations, and researchers have begun to sit up and listen: The barrage of unnecessary alarms could threaten the safety of the 60,000 Americans who are treated in intensive care units each day.

The ECRI Institute, an independent nonprofit that researches the best approaches to improving patient care, named clinical alarms the No. 1 health technology hazard for 2014. In addition, the Joint Commission announced alarm management as a 2014 National Patient Safety Goal. This followed an April 2013 Sentinel Event Alert in which the Joint Commission reported 80 alarm-related deaths from 2009 to 2012 and blamed alarm fatigue as the “most common contributing factor.”

Alarm fatigue is when caregivers become desensitized because too many previous alarms were insignificant, putting them at risk for missing an important alarm. While alarm fatigue is not a new problem, the number of patients connected to alarm-based physiologic monitors has increased as medical technology has advanced, multiplying the sounds that these devices generate.

Recognizing that alarm management has become a high-priority patient safety issue, Christopher Bonafide, MD, MSCE, an attending physician at The Children’s Hospital of Philadelphia wants to lead the way in alarm fatigue research nationally, with the support of a five-year career development award he recently received from the National Heart, Lung, and Blood Institute.

“No one has actually quantified alarm fatigue in the hospital before,” Dr. Bonafide said. “We want to evaluate the relationship between the number of false alarms that nurses are exposed to and their response time to critical alarms. In doing this, we hope to learn more about the science behind alarm fatigue and discover new ways to combat it.”

Dr. Bonafide has created a video research lab that uses small GoPro cameras temporarily mounted in patients’ rooms, with families’ and nurses’ permission. Every time an alarm goes off, the research team can see exactly what happens next from multiple camera angles. They synchronize the video with monitor data to allow for objective review by experts to determine the validity of alarms and measure response time.

Dr. Bonafide hypothesizes that, “Experiencing lots of false alarms leads to alarm fatigue, and this can delay responses to alarms that might represent true signs of impending cardiac or respiratory arrest. Alarms also interrupt high-risk tasks, and that can lead to dangerous medical errors. We need to do everything we can to ensure that alarms help patients, not harm them.”

Dr. Bonafide plans to use the findings of his video analysis to support future research to evaluate interventions aimed at making alarm management safer.

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New Jersey Teen Driver Decals Linked to Fewer Crashes


A new study from the Center for Injury Research and Prevention (CIRP) provides valuable evidence that New Jersey’s Graduated Driver Licensing (GDL) decal provision is associated with a sustained two-year decline in crash rates among intermediate teen drivers. The study, which linked New Jersey’s licensing and crash record databases to measure effects of the requirement, was published recently in the American Journal of Preventive Medicine. Crash involvement of an estimated 3,197 intermediate drivers was prevented in the first two years after the decal’s implementation.

In May 2010, New Jersey implemented Kyleigh’s Law, requiring all youth 16 to 20 years of age holding a learner’s permit or intermediate license to display a reflective decal on the front and back license plates of vehicles they are operating. On any given day there are more than 170,000 intermediate drivers on New Jersey’s roadways. The decal was intended to facilitate police enforcement of GDL restrictions and, ultimately, reduce teen crash rates.

While many other countries have had decals for decades, New Jersey is the first state to implement them in the U.S. And CHOP researchers are the first in any country to evaluate the long-term changes in crash rates after a decal provision went into effect.

“Decal provisions now have the support of science. The provision may encourage safer driving behaviors, both among teens and other drivers sharing the road with them,” said the study’s lead author, Allison Curry, PhD, MPH, CIRP’s director of Epidemiology and Biostatistics.

Dr. Curry and the CIRP team — including biostatistician Michael R. Elliott, PhD, and Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research — linked New Jersey’s licensing and motor vehicle crash databases from January 2006 through June 2012 to compare monthly rates of police-reported crashes for intermediate drivers in the four years before the decal’s implementation and in the two years after. After accounting for age, gender, and other criteria, the investigators found in the first two years after the new decal requirement took effect the crash rate for young intermediate drivers declined 9.5 percent, as compared to the previous four years before decal implementation.

More dramatic effects were observed for single-vehicle crashes involving older intermediate drivers, with rates decreasing 13 percent per year for 18-year-olds and nearly 17 percent for 19-year-olds. In the previous four years before the decal was put into practice, the rate of single-vehicle crashes did not significantly decrease in either group.

A previous CHOP study on the decal’s first year of implementation found a 14 percent increase in the rate of GDL-related citations issued to intermediate drivers, but the increase seemed to be concentrated in the few months after implementation.

“There is definitely more we need to learn, in particular with respect to the specific mechanisms by which the decals reduced crashes,” noted Dr. Curry. “The end result, however, is that many fewer teens crashed.”

To learn more about the Center for Injury Research and Prevention work on teen driver safety and other topics, visit the CIRP website.

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Obese Teens With Sleep Apnea Show Impaired Neurobehavioral Functioning


Navigating the tumultuous teenage years can be exhausting, and new research shows that they can be particularly challenging for overweight adolescents with obstructive sleep apnea syndrome (OSAS), a sleep disorder that affects an estimated 2 percent of youths. Obesity and OSAS often exist simultaneously, and both conditions have been associated with neurobehavioral changes such as problems with regulating emotions, school performance, attention, and alertness.

As child obesity rates have tripled among school-aged children and adolescents over the past 30 years, it appears that teens are on the fast track for increasing their risk of developing OSAS. It is a trend that Melissa Xanthopoulos, PhD, sees firsthand as a child and adolescent psychologist at The Children’s Hospital of Philadelphia and as an investigator for its Sleep Center and Healthy Weight Program.

At the clinical level, Dr. Xanthopoulos and colleagues observed a pattern among some young patients with obesity who were struggling to follow their treatment recommendations and also reporting difficulties in school. The research team wondered if an interaction between obesity and sleep could somehow be impeding their success.

“It is an important research question because during this critical period of adolescence, the brain’s frontal lobe, which is in charge of executive functioning, is making a lot of changes,” Dr. Xanthopoulos said. “Executive functioning involves higher order cognitive processing such as planning, monitoring, and initiating tasks.”

If a teen’s brain is busy reorganizing during this sensitive time, what happens when it is repeatedly disrupted by the many pauses in breathing during sleep — called apneas and hypopneas — and ensuing abrupt dips in blood oxygen saturation that are the hallmarks of nightly episodes of OSAS?

Research performed with adults who have OSAS suggests that they experience cognitive changes, Dr. Xanthopoulos said, but she found that the obesity and sleep research literature involving teens was lacking in this area. In order to build evidence for the adolescent period, the study team looked at three groups of teens ages 12 to 16 years old: obese teens with OSAS, obese teens without OSAS, and lean teens without OSAS. The investigators hypothesized that obese teens with OSAS would exhibit more neurobehavioral functioning deficits.

They analyzed self-reports from the teens and their parents that focused on several dimensions of neurobehavioral abnormalities that have been associated with sleep disorders including executive function, attention, sleepiness, and behavior and mood. The results showed that executive function, in particular, was impacted in this age group of participants who had obesity and OSAS.

The study team also used sophisticated statistical methods to examine how participants’ BMI z-scores, which is a measure of relative weight adjusted for a child’s age and sex, related to their obstructive apnea hypopnea index (AHI), which is an average that represents the combined number of apneas and hypopneas that occur per hour of sleep. Their analysis revealed that the AHI level had a significant influence on the relationship between BMI-z scores and executive functioning, attention, and behavior.

Dr. Xanthopoulos and her co-investigators want to spread the word about this study’s outcomes with their colleagues and raise patients’ awareness about the potential risks of OSAS and obesity. When a teen with obesity is exhibiting attention problems, difficulty in school, and signs of depression, she encourages healthcare providers to ask, “Does this patient snore?” and then to consider recommending a sleep study.

The next step, Dr. Xanthopoulos said, is figuring out which treatment method these patients need in order to be healthy physically, mentally, and emotionally. Typically, the treatment for adults and teens with OSAS is continuous positive airway pressure (CPAP), which delivers a steady stream of pressurized air through a mask that patients wear during sleep to keep their airways open and restore normal oxygen levels.

“CPAP is not something a teenager usually wants to hear about, but it might help them feel better and be better able to engage in weight loss behaviors such as making healthy choices and increasing physical activity,” Dr. Xanthopoulos said. “If you treat obesity, oftentimes sleep apnea is reduced or goes away. But, losing weight is very hard, especially for a teenager who is super sleepy and potentially has these neurobehavioral deficits.”

Dr. Xanthopoulos suggested that more research is needed to determine if OSAS treatment could potentially reverse neurobehavioral concerns for teens with obesity and OSAS, and also to see if the therapy could help them engage in weight loss interventions more effectively.

The study appeared online ahead of print in the journal SLEEP. It is a sub-study of a larger research project led by Sleep Center Director Carole L. Marcus, MBBCh, that is focused on the pathophysiology of childhood OSAS and is funded by the National Heart, Lung, and Blood Institute. The sub-study also involved Paul R. Gallagher, MA, of the Clinical and Translational Research Center coordinated by CHOP and the Perelman School of Medicine at the University of Pennsylvania; Robert I. Berkowitz, MD, a CHOP psychiatrist who is director of the Weight and Eating Disorders Research Program and also an associate professor of psychiatry at UPenn; Jerilynn Radcliffe, PhD, a CHOP psychologist and professor of clinical psychology at UPenn; and Ruth Bradford, research coordinator for CHOP’s Sleep Center.

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Medical Emergency Teams Improve Safety, Cut Costs


Hospital administrators are always looking for ways to improve the equation of how to advance quality of care at a lower cost. A cost-benefit analysis performed by a research team at The Children’s Hospital of Philadelphia describes one winning combination that can improve the safety of hospitalized children, while at the same time achieving financial savings.

Finding ways to better identify and respond to children who are getting sicker out on the pediatric wards has been a research focus of Christopher P. Bonafide, MD, MSCE, of the Division of General Pediatrics at the Children’s Hospital of Philadelphia, so he is a big METs fan (but we are not talking about baseball).

METs are medical emergency teams that involve critical care experts who are designated to be deployed to a unit when a patient is starting to show signs of clinical deterioration (CD), in order to head off cardiac arrests and other serious events that could require a transfer to the intensive care unit and life-sustaining interventions.

“Prior to implementation of medical emergency teams, you would call a Code Blue,” Dr. Bonafide said. “That’s when you’ve already missed all the warning signs, and the patient essentially is starting to die in front of you.”

Research has demonstrated that METs are effective in preventing CD events, but until Dr. Bonafide and his colleagues published a recent paper in Pediatrics, no studies had evaluated their financial benefits. First, the research team identified the cost of CDs, and then they analyzed various MET compositions and staffing models, in order to determine the annual reduction in CD events needed to offset MET costs.

“When you’re taking people who are doing critical care and moving them out onto the units to respond to patients, questions can come up: Is that the best use of their time? Is that providing a high value service?” Dr. Bonafide said.  “It’s nice to see that some of what we’re already doing and know improves patient safety, we also can justify financially.”

In order to calculate the costs of CDs, the study team compared unplanned ICU transfers that did not require subsequent life-sustaining interventions to unplanned ICU transfers that required initiation of noninvasive or invasive mechanical ventilation and vasopressor infusion. They determined that a hospital can potentially save $100,000 every time a MET can quickly assess and stabilize a patient without the need for life-sustaining interventions.

Next, the researchers tackled some complicated math. Since there is no single way to stack a MET, they had to consider several configurations to estimate the costs of running those teams. They looked at 75th percentile salaries for a nurse, respiratory therapist, critical care fellow, and ICU attending as the folks who might make up the MET. They also took into consideration if those responders had any other concurrent responsibilities, or if they were part of a freestanding unit that is staffed 24 hours a day.

“Based on how you staff your MET, it varies a ton on what the team actually costs,” said Dr. Bonafide, who also is an assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “The correlate to that is the number of critical deterioration events that you actually have to prevent. So if you have an inexpensive team model, you actually don’t have to prevent that many events in order for the team to pay for itself.”

The MET at Children’s Hospital consists of a critical care fellow, a respiratory therapist, and a nurse who have concurrent responsibilities, which is the most common MET configuration in the U.S. Based on that model, the investigators calculated that in order to recoup MET costs, the team has to prevent between three and four critical deterioration events for the entire year.

“That really is not a difficult thing to do,” Dr. Bonafide said. “We know that we can have a significant impact on these bad outcomes by implementing medical emergency teams, so the three to four number is very attainable.”

The financial benefits could add up significantly. In a hospital that has approximately 300 unplanned transfers from ward to ICU per year, a reduction of 15 CD events per year by implementing CHOP’s MET model could result in eliminating $1,496,595 in excess costs per year for a net savings of $1,145,897 annually, the researchers wrote in the Pediatrics paper.

A future research challenge will be to determine what percentage of CD events are preventable, Dr. Bonafide pointed out. Another question he would like to consider is how cost-effective are METs, which takes into account how the teams’ interventions could impact not only the costs of care but also quantify the years of lives saved and patients’ quality of life.

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Researcher Delivers Key Thrombosis Lecture


The Children’s Hospital of Philadelphia’s Sriram Krishnaswamy, PhD, recently delivered this year’s Sol Sherry Distinguished Lecture in Thrombosis at the American Heart Association Scientific Sessions annual conference. A thrombosis and hemostasis researcher, Dr. Krishnaswamy investigates the biochemical underpinnings of coagulation.

Held November 15 to 19 in Chicago, the American Heart Association (AHA) conference brought together approximately 17,000 attendees from over 100 countries. The AHA’s Sol Sherry Lecture honors the late Sol Sherry, MD, who was a pioneer in the field of thrombosis research and spent nearly twenty years at Temple University in Philadelphia. Past Sol Sherry lecturers include the University of Illinois’ James Morrissey, PhD, and the University of Maryland School of Medicine’s Dudley K. Strickland, PhD.

A Professor of Pediatrics in the Division of Hematology, Dr. Krishnaswamy’s research is focused on better understanding “how protein-protein interactions involved in the assembly of the coagulation complexes on membranes modulate function and how the coagulation enzymes achieve narrow and defined specificity.” His lab is supported by a number of grants from the NIH, the most recent of which he received in August of 2014. That award supports his investigation of how platelets and vascular endothelium cells contribute to coagulation.

In addition, Dr. Krishnaswamy contributed to a recent Blood study authored by CHOP’s Lacramioara Ivanciu, PhD, and led by Rodney M. Camire, PhD.

In that study, the researchers examined the development of prothrombinase, the enzyme complex responsible for thrombin formation, which is itself an enzyme that plays a fundamental role in coagulation. They found, to their surprise, that platelets near the site of an injury “do not play the presumed preeminent role in supporting prothrombinase assembly and thrombin formation.” By shedding light on the location of prothrombinase formation, the study lays the ground for future research.

During his Sol Sherry Lecture, Dr. Krishnaswamy plans to discuss prothrombin and thrombin, following an article he wrote last year that was published in the Journal of Thrombosis and Haemostasis. A review of the process by which thrombin is produced by prothrombinase, the article goes into the mechanics of this transition while noting recent developments in the field.

“In addition to its fundamental role in coagulation, prothrombin activation embodies key structural and functional features encountered in the other proteolytic activation steps of the cascade,” Dr. Krishnaswamy writes. “Consequently, the wealth of biochemical and biophysical information that has accumulated in this system justifies its consideration as an archetypal reaction of coagulation.”

“I’m honored to have been asked by the AHA to deliver this year’s Sol Sherry lecture,” Dr. Krishnaswamy said. “Dr. Sherry was a thrombosis pioneer, and it’s an honor to follow in his footsteps.”

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CHOP, ARUP Laboratories Form Genotyping Partnership


The Children’s Hospital of Philadelphia and the Salt Lake City, Ut.-based ARUP Laboratories recently announced an agreement to provide human leukocyte antigen (HLA) testing using next-generation sequencing (NGS) methods to ARUP customers.

In February, researchers from Children’s Hospital’s Division of Genomic Diagnostics announced that they had developed a unique laboratory test to characterize the genes that encode HLA molecules. HLAs are complex, highly variable proteins on cell surfaces that are essential to immune function, and their genes are the most complex gene family known in the entire human genome, which proved a challenge for prior testing methods.

The new test may improve transplantation, and provides an advanced tool for research in immunological diseases, infectious diseases, and pharmacogenomics. With its announcement, CHOP became the first hospital in the world to offer HLA genotyping.

HLA genotyping “addresses a 60-year old problem,” said Children’s Hospital’s Dimitri S. Monos, PhD, director of CHOP’s Immunogenetics Laboratory. “Since the discovery of HLAs in the early 1950s, it has been a challenge to accurately and thoroughly characterize HLA gene sequences. We have now used NGS tools to significantly advance HLA genotyping. This is the first technology that gives results free of any current or future ambiguities.”

“Our agreement with CHOP enables ARUP to offer this innovative test to our clients to help aid decisions in bone marrow transplantation. We are very pleased to include this testing as part of our comprehensive menu of services,” said Jerry Hussong, MD, ARUP’s chief medical officer and director of laboratories.

Based in Salt Lake City, Utah, ARUP Laboratories is a nonprofit enterprise of the University of Utah’s Department of Pathology, and “offers in excess of 3,000 tests and test combinations, ranging from routine screening tests to highly esoteric molecular and genetic assays,” according to its website.

“We are pleased to be able to provide this test to ARUP Laboratories’ customers. It allows us to provide greater access to our tests,” said Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief.

To read more about genetic testing and research at The Children’s Hospital of Philadelphia, see the Division of Genetic Testing’s list of lab tests.

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

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