Bench to Bedside

February 2015

Spin a Good Yarn: Using Narratives to Improve Prescribing Practices


A team of investigators from The Children’s Hospital of Philadelphia’s PolicyLab recently received nearly $600,000 from the William T. Grant Foundation to lead an innovative study examining antipsychotic prescribing practices. Led by David Rubin, MD, MSCE, the co-director of PolicyLab, the researchers plan to study whether novel, narrative-informed guidelines that tell stories have a deeper impact on clinicians’ practices than standard guidelines.

As one of CHOP Research’s Centers of Emphasis, PolicyLab’s mission is to achieve optimal child health and well-being by informing program and policy changes through interdisciplinary research. At PolicyLab, the team’s experience caring for children and families informs its “evidence to action” approach to improving children’s health. Current projects include a Pennsylvania-wide evaluation of maternal and child home visiting programs, research addressing barriers to timely immunization, and a study of changes in children’s health care coverage under the Affordable Care Act.

With their current project, Dr. Rubin and colleagues — including his co-Principal Investigator, Zachary Meisel, MD, MPH, MSc, from the University of Pennsylvania’s Department of Emergency Medicine; and Kathleen Noonan, JD, the co-director of PolicyLab — plan to compare narrative-accompanied prescription guidelines with more traditional, “didactic” evidence-based prescription guidelines. Over the course of their three-year project, Dr. Rubin and his team hope to determine whether guidelines that both involve a narrative component and give clinicians a voice have any effect on antipsychotic prescribing habits.

The study comes as concerns grow about the increasing rate of antipsychotic prescriptions for children. Antipsychotics are a class of medications used to treat mental and behavioral health disorders. Traditionally, antipsychotics, which act like powerful sedatives, have been prescribed only to children with major psychotic disorders such as schizophrenia, bipolar disorder, and autism. But these medications are increasingly being prescribed off-label to treat disruptive behaviors, a practice that lacks supporting safety and efficacy data.

The use of antipsychotic medications among children has risen significantly over the past twenty years, largely because of their growing use to manage disruptive behaviors. Youth who are especially at-risk for increasing prescription of antipsychotic medications are Medicaid-enrolled children, for whom antipsychotic prescribing has grown at a rate far exceeding that for children who are privately insured.

Overall, some 25 percent of Medicaid-enrolled children receiving mental health treatment were prescribed antipsychotics by 2007, largely for less severe disorders like attention deficit hyperactivity disorder (ADHD). Particularly alarming, especially given their complex trauma histories, children in foster care are prescribed antipsychotic medications at a rate three times higher than children enrolled in Medicaid overall.

Another cause for concern is the growing practice of polypharmacy, the prescription of antipsychotic medications prescribed in combination with other mental health drugs. In a study published recently in the Journal of the American Academy of Child & Adolescent Psychology, Dr. Rubin and colleagues found that children were increasingly prescribed antipsychotic medications alongside other psychotropic medications, such as stimulants, at the same time.

The rise in antipsychotic prescriptions also points to a need for — and a lack of — non-pharmaceutical behavioral health treatment options for an at-risk population of children and youth. Only specialized behavioral health treatments can address the underlying trauma often driving disruptive behaviors.

Moreover, antipsychotic medications can cause challenging side effects. Particularly concerning have been reports of serious adverse metabolic effects, including rapid weight gain, glucose intolerance, and type 2 diabetes, which may affect children more than adults.

Clinician Narratives Wanted

The study team will conduct their study in two parts. In its first phase, they will conduct semi-structured interviews with a sampling of Pennsylvania clinicians to elicit narratives from them. They will seek to interview between 30 and 50 clinicians across a range of specialties, with the goal of identifying key themes and constructs that influence clinicians’ prescribing habits.

By synthesizing data from the clinician interviews, the investigators plan to create sample narratives that use real events but redact confidential information. A focus group will help the investigators narrow these synthesized narratives down to three “core” narratives to be tested in the second phase of the research project.

Narratives have been shown to promote behavior change on the part of patients, helping clinicians improve assessments of falls in older patients, promote well-being after stroke, and in the research of CHOP’s Roy Wade Jr., MD, MPH, use children’s feedback to inform responses to childhood adversity. But what remains less clear is the impact narratives can have on clinicians.

However, as Dr. Meisel points out in a blog post written for PolicyLab, “a powerful story will stick.”

“We know that stories can help patients – there are some excellent studies showing that stories which maximize concepts such as homophily (where the audience identifies with the storyteller) can move patients to engage in healthier behavior, including controlling their blood pressure and getting a cancer screening,” he writes. In addition, “stories can help researchers and clinicians translate evidence to policymakers in salient and coherent ways.”

Dr. Meisel has done other work on narrative implementation for physicians. “If you ask them, physicians will tell you that they want to learn new information in a probabilistic way,” Dr. Meisel said. “But when you compare narratives to bare-bones data presentations (which we have done in other work looking at guideline adoption), the stories do better. From a cognitive perspective, it makes sense. After all, doctors are people too.”

In the study’s second phase, which Drs. Rubin and Meisel hope to begin by the middle of 2016, the researchers will test the effectiveness of the narrative-influenced guidelines. They plan to target roughly 3000 to 4000 psychiatrists, pediatricians, and family practitioners across Pennsylvania, who they will break into three groups. One group, a control, will only receive standard recommendations, while the “low-dose” and “high-dose” arms of the study will receive one and three narratives, respectively. Medicaid claim data will be used to ascertain how effective each arm was.

“We are concerned about the rate at which children — particularly those in foster care — are prescribed powerful antipsychotic medications, and are interested in learning whether prescribing guidelines accompanied by narratives have more of an effect on clinicians than traditional guidelines,” said Dr. Rubin. “We are grateful to the William T Grant Foundation for giving us the opportunity to impact this issue.”

To read more about this project, see the William T. Grant Foundation’s page on the study. To learn more about the many groundbreaking studies currently underway at PolicyLab, see the Center’s site.

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Project Increases Flu Vaccination in Pediatric Patients With Cancer


While influenza vaccination is important for all children, it is critical that pediatric patients with cancer get a flu shot because their weakened immune systems leave them especially vulnerable to severe infections. A quality improvement project at The Children’s Hospital of Philadelphia used simple strategies and cues for families and clinicians to ensure that these children did not leave outpatient clinics or inpatient units without any protection from the insidious virus.

Influenza hospitalizes and kills more people in the U.S. than any other vaccine-preventable disease. Because strains of influenza virus that circulate can differ from one season to the next, new influenza vaccine is available each September. The Centers for Disease Control and Prevention recommend that all children at least 6 months old should get the flu vaccine each year, as soon as it is available in their community. Healthy children can opt for a nasal spray version of the vaccine, but children who have cancer and are immunocompromised receive the flu shot, which does not contain live virus.

“Historically at CHOP, about 53 to 56 percent of patients with cancer were getting the flu vaccine,” said Jason L. Freedman, MD, MSCE, an attending physician in the Division of Oncology at CHOP. “Some parents fear: My child has cancer, why would I give them a vaccine on top of this? They may not realize that the ramifications of being unvaccinated are much worse. If you’re immunosuppressed and can’t fight the virus, it could be fatal.”

Dr. Freedman and colleagues decided to improve the Division of Oncology’s track record for flu vaccinations by implementing a multifaceted quality improvement initiative. Between September 2012 and March 2013, they focused on five overlapping interventions that took advantage of multiple opportunities during outpatient visits to identify patients who needed an annual flu shot and communicate the importance of early vaccination.

They started by boosting family education. Informational handouts and posters in physician waiting rooms encouraged patients to ask their physicians about flu vaccination. The next critical piece was working with the CHOP health informatics team to generate from the electronic health record a color-coded daily list of outpatients due for vaccination. As patients had their vital signs taken, the triage staff and nurses would ask, “Did you get the flu vaccine?” Patients who still needed flu shots received bright yellow colored wristbands as an alert to clinicians to order the vaccine. The study team provided education for clinicians during staff meetings on how to order the vaccine correctly and document any refusals or contraindications.

“On the inpatient side, we also saw discharge as an opportunity for vaccination,” Dr. Freedman said. “We built in an order for the flu vaccine into their admission order set. So when clinicians are admitting a child for chemo, there is already a prompt to order the flu vaccine for when they go home, which was a huge area of missed opportunity.”

The interventions were implemented in tandem, so while the research team is unable to pinpoint which interventions made the most difference, overall they increased the complete flu immunization rate by 20.1 percent to 64.5 percent. The proportion of patients receiving at least 1 dose of vaccination went up by 22.9 percent to 77.7 percent. In 2013, the oncology team continued to reinforce the process changes that they implemented during the study period, and they were able to sustain those rates, Dr. Freedman said.

“We augmented the opportunity for vaccination,” Dr. Freedman said. “The key to the success of this initiative is it was multifaceted and multidisciplinary. It has become part of our culture in clinic, and everyone has a sense of comradery about catching someone falling through the cracks.”

Other pediatric healthcare institutions could easily adapt this project to their settings with little expense or upkeep, Dr. Freedman pointed out. He also anticipates that similar approaches could be used within future quality improvement efforts to increase vigilance in other areas of pediatric cancer care, such as facilitating adherence to medication.

“This study shows that putting together new process changes, while it requires attention, education, and people who are invested, is feasible, doable, and affordable,” Dr. Freedman said.

The results of this study appeared online Jan. 12 in Pediatrics.

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President Obama Announces $215 Million Precision Medicine Initiative


Saying precision medicine — in which patients receive highly personalized treatments — offers “one of the greatest opportunities for new medical breakthroughs that we have ever seen,” President Obama recently announced the launch of the Precision Medicine Initiative (PMI). First mentioned in the 2015 State of the Union Address, the Initiative seeks to spur advances in precision medicine by supporting genomic research, developing a network of patient volunteers, and partnering with academia and industry.

The PMI launch was attended by Chief Executive Officer of The Children’s Hospital of Philadelphia, Steven M. Altschuler, MD, as well as 9-year-old CHOP patient Emily Whitehead, whose leukemia was successfully treated with a breakthrough form of cell therapy treatment developed at CHOP.

The PMI is the second healthcare-related initiative launched during President Obama’s second term. In April of 2013, he announced the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. By mapping the brain’s connections in detail, that Initiative — which was launched with funding from DARPA, the NIH, and the NSF — aims to help researchers accelerate the development of technologies to inform treatments for conditions like epilepsy.

For its part, the PMI will be led by four government agencies: the NIH, the National Cancer Institute (NCI), the FDA, and the White House Office of the National Coordinator for Health Information Technology.

Francis S. Collins, MD, PhD, director of the NIH, and Harold Varmus, MD, director of the NCI, co-authored a New England Journal of Medicine (NEJM) article detailing the Initiative. “The proposed initiative has two main components: a near-term focus on cancers and a longer-term aim to generate knowledge applicable to the whole range of health and disease,” Drs. Collins and Varmus write.

Specifically, an immediate goal of the PMI is “to significantly expand efforts in cancer genomics to create prevention and treatment successes for more cancers,” according to the NIH’s website. The NIH will also develop a “national cohort study of a million or more Americans” who by sharing genomic data and specimens will aid research into diseases’ underpinnings.

“With sufficient resources and a strong, sustained commitment of time, energy, and ingenuity from the scientific, medical, and patient communities, the full potential of precision medicine can ultimately be realized to give everyone the best chance at good health,” note Drs. Collins and Varmus in their NEJM piece.

CHOP T Cell Treatment Success Highlighted

The proposed 2016 Budget includes $215 million to support the PMI. However, the Initiative’s ultimate funding level is subject to Congress’ approval, and so far the Republican response to the Budget, which the White House delivered February 2, has been typically hostile.

“Today President Obama laid out a plan for more taxes, more spending, and more of the Washington gridlock that has failed middle-class families,” said Speaker of the House John Boehner (R-Ohio). “It may be Groundhog Day, but the American people can’t afford a repeat of the same old top-down policies of the past.”

But in a sign that there might be bipartisan support for the PMI, Congressman Fred Upton (R-Mich.), chairman of the House Energy and Commerce Committee, said in a statement that the PMI “is a natural fit in the discussion about how to accelerate and improve the discovery, development, and delivery of new cures and treatments.”

Patients who have benefited from advanced, targeted forms of medicine were in attendance for President Obama’s announcement. In addition to CHOP’s Dr. Altschuler and Emily Whitehead — who traveled to Washington, DC at the White House’s invitation — several other patients were in the room, including the famous basketball player Kareem Abdul-Jabbar. In 2011 Abdul-Jabbar, a leukemia patient whose disease is currently in remission, received the Double Helix Medal from Cold Spring Harbor Laboratory for his efforts to advance biomedical research.

And shortly after the Precision Medicine Initiative was announced, Emily’s story was highlighted in a White House blog post about Americans whose lives have been changed by precision medicine.

When then 7-year-old Emily first came to CHOP, her acute lymphoblastic leukemia (ALL) had relapsed for the second time and was resistant to chemotherapy. However, after Emily became the first child to be treated with T cells that had been engineered to multiply and fight against ALL, she experienced a dramatic recovery. More than two years later, Emily is healthy and cancer-free.

“If you didn’t know what happened to her, and you saw her now, you would have no idea what she has been through,” said Emily’s mother Kari Whitehead in the White House post.

“I am thrilled that President Obama recognizes the promise of our nation’s research efforts by making this investment,” said Dr. Altschuler. The Precision Medicine Initiative announcement “signifies his commitment to bringing this issue to the forefront of our national agenda.”

To read more about the Precision Medicine Initiative, see the NIH’s site about the project.

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Research Collaborative Aims to Advance Understanding of Preterm Birth


What causes preterm birth and how to prevent it remains a perplexing riddle in medical science. One in nine babies in the U.S. is born prematurely, according to the March of Dimes, and this rate has barely budged despite years of investigation.

Finding the solutions will require the ingenuity of researchers and physicians at The Children’s Hospital of Philadelphia who are part of a transdisciplinary team established by the new March of Dimes Prematurity Research Center at the Perelman School of Medicine at the University of Pennsylvania. They will apply sophisticated technology and methodology in molecular biology and genomics to help better understand the basis for preterm birth and eventually diminish the leading cause of newborn death in the U.S.

Babies born before 37 weeks are considered to be premature, and because their bodies and organ systems have not matured completely, they often need help breathing, eating, fighting infection, and staying warm. They can have long-term health problems, including cerebral palsy, cognitive impairments, and sensory disorders.

The March of Dimes announced in November that it will invest $10 million over the next five years to create the Prematurity Research Center, which is one of four launched by the foundation since 2011. The new center involves more than 40 investigators who will focus on three research themes that aim to generate important new discoveries regarding preterm birth: bioenergetics and genetics, cervical remodeling, and placental dysfunction.

“This kind of cooperation and collaboration is on a different scale than has ever been developed for preterm birth,” said Rebecca A. Simmons, MD, the project leader for the bioenergetics and genetics theme and an attending neonatologist at CHOP and the Hospital of the University of Pennsylvania. “It’s not only collaborative across our campus and many different departments within the Penn/CHOP system, but we also collaborate between centers, which is a very unique structure.”

The other transdisciplinary prematurity research centers include Stanford University School of Medicine in California; a partnership of Ohio research centers in Cincinnati, Columbus, and Cleveland; and Washington University in St. Louis.

At CHOP, the March of Dimes is particularly interested in researchers’ expertise in mitochondrial biology and biochemistry. Mitochondria are organelles often described as the body’s cellular power plants because they systematically extract energy from nutrient molecules (substrates) that is necessary to perform cells’ most basic and critical functions. Along with Marni Falk, MD, director of the Mitochondrial-Genetic Disease Clinic at CHOP, and Neal Sondheimer, MD, PhD, an attending physician at CHOP, Dr. Simmons will investigate how impaired cellular metabolism could result in power shortages in the reproductive tract that contribute to preterm labor.

“Reproductive tissues — the placenta, the uterus, the cervix — require a huge among of energy,” Dr. Simmons said. “But if for some reason the mitochondria aren’t able to utilize substrates normally, those reproductive tissues may not function properly.”

The study team will look at reproductive tissues from mice and humans with preterm birth to identify any patterns of mitochondrial dysfunction and then see if these disturbances interfere with the tissues’ ability to maintain bioenergetics and metabolic stability during pregnancy.

The Prematurity Research Center’s second theme ties into this hypothesis by exploring how the microbiome may influence cervical remodeling, which is a dynamic process during delivery that transforms the cervix from a rigid structure into a pliable passageway for a baby. The microbiome is a community of bacteria that normally inhabit the vagina and cervix. Preliminary studies suggest that the microbiome is different in women who experience preterm birth. The researchers will explore if abnormal bacteria cause mitochondrial distress and inflammation that accelerates cervical remodeling.

Michal Elovitz, MD, associate professor of Obstetrics and Gynecology and director of the Maternal and Child Health Research Program at the University of Pennsylvania, will lead the theme two projects. Samuel Parry, MD, associate professor of Obstetrics and Gynecology and chief of the Division of Maternal-Fetal Medicine at the University of Pennsylvania, is the project leader for theme three, which also will focus on mitochondrial deficiencies and an unhealthy microbiome as possible factors that disrupt metabolic processes in the placenta and lead to early labor.

“If we do find changes in the microbiome, those are targets for therapeutics that can be developed,” Dr. Simmons said. “We’ll look for strategies to either change the composition of the microbiome or change how the microbiome is functioning.”

Some of the answers to the medical mystery of preterm birth also may lie within complex gene-environment interactions that new research approaches could help to unravel. The study teams will explore the evolving field of epigenetics, which is the study of mechanisms that change how genes are expressed without altering the underlying DNA sequence.

They expect to gain insights into the multiple pregnancy-related risk factors — biological, behavioral, social, physical, and environmental — that could cause epigenetic modifications. For example, Dr. Simmons will explore in theme one how any abnormalities in the genes and biochemical pathways that regulate mitochondrial metabolic function could have a role in preterm birth.

“We think that if we can identify novel metabolic pathways, we can certainly design future interventions,” Dr. Simmons said.

As the Prematurity Research Center moves from the discovery phase to targeting and developing therapeutics, the researchers hope that their findings along the way will spark additional preterm birth studies. The Center will offer a series of pilot grants to investigators to encourage them to tackle this important health challenge. Dr. Simmons expects the first request for grant proposals to be issued in February.

Deborah A. Driscoll, MD, the Luigi Mastroianni Jr. Professor and Chair of the Department of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, is the director of the Prematurity Research Center, and Dr. Simmons, the Hallam Hurt Professor of Pediatrics, and Dr. Parry are the principal investigators.

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Scientists Explore Gene Silencing as Novel Approach to Dystonia


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

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

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

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

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

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

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

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

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

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

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

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Brain Imaging Links Language Delay to Chromosome Deletion in Children


According to a team of radiologists and psychologists led by a CHOP expert, children born with a DNA abnormality on chromosome 16 already linked to neurodevelopmental problems show measurable delays in processing sound and language.

By strengthening the case that the deleted gene disrupts a key biological pathway, the research may lay the foundation for future medical treatments for specific subtypes of autism, along with cognitive and language disabilities.

“This study shows an important connection between gene differences and differences in neurophysiology,” said the study’s leader, Timothy P.L. Roberts, PhD, vice chair of Radiology Research at The Children’s Hospital of Philadelphia and a researcher at CHOP’s Center for Autism Research. “It may also help to bridge a largely unexplored gap between genetics and behavior.”

Dr. Roberts, who holds the Oberkircher Family Endowed Chair in Pediatric Radiology at CHOP, led the study published recently in Cerebral Cortex, collaborating with a group led by Elliott H. Sherr, MD, PhD, of the University of California, San Francisco (UCSF).

The researchers examined children with copy number variants — either deletions or duplications­ of DNA — at the genetic site 16p11.2. Previous researchers had found that this location on chromosome 16 was associated with a subset of autism spectrum disorders (ASDs) and with language impairments and developmental delays. The researchers used magnetoencephalography (MEG), which detects magnetic fields in the brain, just as electroencephalography (EEG) detects electrical fields. As each child heard a series of tones, the MEG machine analyzed changing magnetic fields in the child’s brain, measuring an auditory processing delay called the M100 response latency.

The researchers analyzed 115 children: 43 with the 16p11.2 deletion, 23 with the 16p11.2 duplication, and 49 healthy controls. The children came from CHOP and UCSF. Only a fraction of the children had ASD diagnoses: 11 of the 43 with the deletion, and 2 of the 23 with the duplication.

In children with the deletion, the researchers found a significant delay: 23 milliseconds (ms), a figure that Dr. Roberts called “stunningly high” compared to the healthy children. There was no such delay among children with the duplication, who actually had a non-significant tendency to process sounds faster than the control subjects.

The 23-ms delay, about one-fortieth of a second, was twice as high as the 11-ms M100 delay that Dr. Roberts found in a 2010 MEG study of children with ASDs. In that study, Dr. Roberts remarked that 11 milliseconds is a brief interval, but that it meant that a child hearing the word ‘elephant’ would still be processing the ‘el’ sound while other children moved on, with delays cascading as a conversation progresses.

While the 2010 study focused on children diagnosed with ASDs, Dr. Roberts added, the current study took a “genetics first” approach, analyzing children known to have genetic variants with or without ASD diagnoses. “We have approached the problem from both ends,” he said. The previous study found a link between the brain and behavior, while this new study found a link between genetics and the brain.”

Although not all of the children with CNVs had autism, all of them had some neurological or learning disabilities, he noted. Because the severity of neurodevelopmental symptoms did not correlate with the length of the auditory processing delay, the M100 delay may not become a clear-cut diagnostic biomarker in neurological disorders, but it may be a clue to an important common pathway in neurobiology.

“We don’t yet know the significance of the 23-millisecond delay, but we have established its origin in genetics,” Dr. Roberts said. “It seems to be a proxy for something of biological significance.” He pointed out that this finding meshes with a current research strategy articulated by the National Institutes of Health — focusing on research domains criteria in neurological diseases. Because ASDs and mental disorders are very diverse and heterogeneous, involving many different genes, a research domains approach seeks to discover genes that may overlap differing disorders but operate on common biological pathways and processes.

Further studies will investigate other genes previously implicated in ASDs and other psychiatric disorders, to determine whether they also involve M100 response delays. “Our goal is to unify diverse genes along a few common pathways, some of which may be treatable with specific therapies,” said Roberts.

He added that his laboratory is planning a very small pilot study of children with ASDs who have the M100 response latency. Using a drug that acts on synaptic transmissions (signals across nerve cells), he will analyze whether this drug reduces the M100 auditory delays.

This research is at an early stage, Dr. Roberts stressed, adding that the biological mechanisms underlying the chromosome deletion and auditory delays remain undiscovered. “We don’t know, for instance, whether the abnormality that leads to the delay happens at the synapses or in the brain’s white matter, which acts as highway for carrying brain signals. Our next studies may help answer that question.”

To read more, see the Cerebral Cortex study.

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Five Years After Recession, Millions of Children Live in Poverty


A new report from The Children’s Hospital of Philadelphia’s PolicyLab and the advocacy organization First Focus found poverty, food insecurity, and housing instability are more prevalent than they were before the Great Recession. Moreover, according to the report, approximately 1.9 million more children live in poverty now than before the recession.

“Economists say the recession is over, but five years later, it’s still impacting millions of children,” said First Focus’ President Bruce Lesley. “Where national leaders made smart policy choices, kids fared better — where they didn’t, kids are still struggling.”

A bipartisan organization dedicated “to making children and families the priority in federal policy and budget decisions,” the Washington, DC-based First Focus works to raise awareness of problems children face, develop policy solutions, and organizes advocate action designed to affect policymakers. PolicyLab, one of CHOP Research’s Centers of Emphasis, conducts interdisciplinary research to inform and influence policy changes.

PolicyLab’s Rachel Meadows, MPA, was the lead author of the report, “The Effect of the Great Recession on Child Well-Being.” First Focus commissioned this new paper from PolicyLab, which is a follow-up to a 2010 study of the same issues.

Defined as the period from December 2007 through June 2009, the Great Recession saw high unemployment, frequent foreclosures, and the downfall of several larger investment banks, such as Lehman Brothers. According to a Bureau of Labor Statistics report, during the Recession the unemployment rate rose to nearly 10 percent, consumer spending fell, and in February 2009 alone more than 325,000 workers were laid off.

Now, more than five years after the end of the recession, approximately one third of American children still live in food insecure households, according to the PolicyLab report. More than 22 million children remain dependent on programs like the Supplemental Nutrition Assistance Program (SNAP), which offers help to low-income families. And while many children lost their housing during the worst of the Great Recession’s foreclosures, roughly 30 percent of children live in “cost burdened” households, in which a disproportionate percent of the family’s income is spent on housing.

The report did find some silver linings. Anti-poverty safety nets such as SNAP, tax credits, unemployment insurance, and the Temporary Assistance for Needy Families program have helped lift millions of children out of poverty. Moreover, thanks to the Children’s Health Insurance Program (CHIP), which provides low-cost insurance to needy families, the number of children with health insurance increased despite the recession.

As of 2013, there were roughly eight million children enrolled in CHIP nationwide. However, CHIP’s funding has not been extended beyond 2015. And the safety net programs that proved so vital during the Great Recession face an uncertain future.

“Our research shows that investing in social safety net programs when times are good can have payoffs for ‘rainy days,’” said PolicyLab co-Director David Rubin, MD, MSCE. “We also know that millions of children are still struggling, and so we risk stalling or even reversing recovery by making budget and program cuts too soon.”

A recent decline in federal spending on children, combined with a reduction in American Recovery and Reinvestment Act (or stimulus) spending, combined with budget cuts across federal, state, and local governments means that many safety net programs may not be strong enough to weather another crisis.

“If the United States were to enter another economic downturn, it is not at all clear that the safety net programs, if suddenly needed again, would as effectively shield vulnerable children and families as they did during the Great Recession,” the report states.

In a blog post that accompanied the report’s release, Dr. Rubin and Kathleen Noonan, JD, the co-director of PolicyLab, note the report points to a need to confront income inequality. “Looking ahead, we must confront the growth in income inequality that has occurred in the last few decades, with more Americans living closer to the poverty line than ever before,” they write. “A true recovery would reverse the trends of growing poverty and widening income gaps.”

“If you look across the different aspects of a child’s life, this report makes one thing clear: whether it’s health, hunger, housing or abuse and neglect, there are more kids in harm’s way today than before the recession,” said First Focus’ Lesley. “The question for Congress is this: what are you going to do about it?”

To read more, see the full report, “The Effect of the Great Recession on Child Well-Being.”

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Researchers Honored for Using Video to Better Understand Alarm Fatigue


ECRI Institute selected an innovative study conducted by patient safety researchers at The Children’s Hospital of Philadelphia who aimed to objectively measure alarm fatigue as a finalist for its 9th Annual Health Devices Achievement Award. The award recognizes an outstanding initiative undertaken by an ECRI Institute member healthcare institution that improves patient safety, reduces costs, or otherwise facilitates better strategic management of health technology.

When healthcare workers experience alarm fatigue, they become overwhelmed, distracted by, or desensitized to the numbers of alarms that monitors activate, which can lead to delayed response times or missed alarms. Addressing alarm fatigue is one of the key factors to improving the management of clinical alarm systems, according to the Joint Commission’s National Patient Safety Goal on alarm safety.

CHOP pediatrician and patient safety researcher Christopher Bonafide, MD, MSCE, submitted the entry, “Using Video to Evaluate Physiologic Monitor Alarm Characteristics and Nurse Responses to Alarms.” It described how the study team used a video-based approach to gather data on staff response times and false alarm rates.

After obtaining permission from nurses and patients’ parents or guardians, the team mounted cameras strategically in patient rooms to capture simultaneous views of the patient room, a close-up view of the patient, a full view of monitor screens and ventilator displays, and views of the caregivers responding to the alarms. Additional software generated a time-stamped list of alarms that occurred during the video sessions.

The team performed 40 video sessions and then analyzed the data generated by 4,962 alarms. They determined that caregiver response times increased as the number of false, or nonactionable, alarms increased. In the intensive care unit, 86.7 percent of alarms in heart and lung failure patients were characterized as false. In the general wards, 99 percent of alarms were false.

An article published in the ECRI’s online journal Health Devices described how Dr. Bonafide and a multidisciplinary team of biomedical engineers, physicians, nurses, researchers, and administrators designed and conducted the study.

“Studies such as these can help drive and inform interventions to reduce alarm burden and fatigue, thereby improving system and staff performance and ultimately improving the quality of care,” the article states.

Dr. Bonafide shared his reaction to the runner-up award: “Our team was thrilled to hear that the ECRI Institute selected our project for this tremendous honor. We are committed to using the findings of this study to inform new initiatives to eliminate alarm fatigue and improve the outcomes of hospitalized children.”

The National Heart, Lung, and Blood Institute recently awarded a five-year career development award to Dr. Bonafide, who is also an assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania, to learn more about the science behind alarm fatigue and discover new ways to combat it.

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Pediatric Medical Device Innovators Receive PPDC Seed Grants


The Philadelphia Pediatric Medical Device Consortium (PPDC) announced that it will provide seed grants of $25,000 each to three companies to transform their innovative ideas into commercial devices that benefit young patients.

The PPDC brings together engineers and biomedical researchers from The Children’s Hospital of Philadelphia, Drexel University, and the University of Pennsylvania to address the shortage of medical devices designed for children. In addition to financial support, they provide clinical, business, and regulatory expertise to help overcome common hurdles of commercialization. Nineteen organizations responded to the PPDC’s first request for proposals in June 2014.

“Our request for proposals sought projects from academia and industry from around the globe,” said bioengineer Matthew R. Maltese, PhD, the PPDC’s executive director and principal investigator. Dr. Maltese also is director of Biomechanics Research in the Department of Anesthesiology and Critical Care Medicine at The Children’s Hospital of Philadelphia, as well as an adjunct assistant professor in the University of Pennsylvania’s Perelman School of Medicine. “All projects were rigorously reviewed by our clinical and industry experts, and we are excited to fund these innovators of promising medical devices for children.”

The three PPDC awards will help to advance the development of medical devices that aim to improve pediatric care for jaundice, ear infections, and prosthetic limbs:

The PPDC is one of seven regional pediatric device consortia that received funding from the U.S. Food and Drug Administration to address the unmet need for child-specific medical devices. Pediatric medical device innovators’ next opportunity to apply for a PPDC grant will be in March.

Read the full press release.

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

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