Apr 27 2015

Minimal Improvement in Infants’ Neurodevelopment After Cardiac Surgery

neurodevelopmentCardiac specialists have concentrated for many years on helping high-risk infants with complex congenital heart disease (CHD) to survive surgery. As advances in surgical and perioperative care have improved their success rates dramatically, researchers, clinicians, and families now are able to turn their attention to these children’s long-term outcomes.

The most common complication for children who undergo CHD surgery in infancy is neurodevelopmental disability. Previous research has shown that they have lower abilities with reasoning, learning, executive function, inattention and impulsive behavior, language skills, and social skills compared to the general pediatric population.

The International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators looked at trends over a 14-year interval in neurodevelopmental outcomes for survivors of CHD surgery. Twenty-six institutions from six countries — the U.S., Canada, Austria, New Zealand, Japan, and Switzerland — submitted study participant data for the pooled analysis project. The study team evaluated 1,770 children born between 1996 and 2009 who underwent CHD surgery, which is the largest cohort reported to date.

The investigators assessed the study participants’ scores at age 14.5 months on the Bayley Scales Version 2, a standard series of measurements that examine multiple facets of child development. They reported that these scores were significantly lower than expected compared with the general population.

“We showed that over the last 15 years, despite all the improvements in care, we have really made very little progress in improving the long-term neurodevelopmental outcomes for these kids,” said J. William Gaynor, MD, first author of a Pediatrics article that reported the ICCON investigators’ results. “Once you’re past the excitement and stress of the operation, this is what parents really care about: Is my child going to need special education? Is my child going to have attention-deficit/hyperactivity disorder? Is she going to be able to have a job? Is he going to be able to have a family? That’s what we’re trying to answer.”

The ICCON investigators will continue their worldwide collaboration to study factors that may explain the lack of greater improvement in early neurodevelopmental outcomes over the study period. The study team already is gathering data to determine if there is any relationship between intraoperative management strategies and neurodevelopmental outcomes. Another possibility is that brain development in children with CHD is immature prior to birth.

“The data here is suggestive that if you’re going to make these kids better, we’ve got to make their brains better before they’re even born,” said Dr. Gaynor, who is an attending cardiothoracic surgeon at The Children’s Hospital of Philadelphia and associate professor of surgery at the University of Pennsylvania School of Medicine. “Our goal is that when you meet these kids, if you didn’t see the scar on their chests, you would not know that they had heart surgery because they’re completely like every other kid in every other way. We’re not there yet, but this is the type of research that we need to get us there.”

The pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation.

Permanent link to this article: http://blog.research.chop.edu/minimal-improvement-in-infants-neurodevelopment-after-cardiac-surgery/

Apr 24 2015

Scientists Explore Gene Silencing as Novel Approach to Dystonia

dystoniaMany 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. 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? 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.

Permanent link to this article: http://blog.research.chop.edu/scientists-explore-gene-silencing-novel-approach-dystonia/

Apr 23 2015

Center for Injury Research and Prevention Engineering Students Honored

Center for Injury Research and PreventionTwo undergraduate engineers from the Center for Injury Research and Prevention (CIRP) were recently honored during CHOP Research Poster Day. Held February 25, 2015 Poster Day was the 25th anniversary of the event, and 40 researchers’ work was selected by a faculty panel to receive awards. Among a collection of hematologists, oncologists, and neonatologists, the research Richard Hanna and Todd Hullfish presented — focused on child restraint systems and side air bags, respectively — stood apart.

Currently in his final year at Drexel University, Richard Hanna has been working toward a Master of Science in Biomedical Engineering. Since coming to CIRP in June 2014 through CIRP’s National Science Foundation (NSF)-funded Injury Science Research Experiences for Undergraduates program, he has assisted with data analysis and co-authored a paper to be presented at the SAE World Congress and Exhibition in April.

Todd Hullfish, meanwhile, has been studying toward a Bachelor of Science in Mechanical Engineering and has been at CIRP since September 2013. At CIRP Hullfish has analyzed motor vehicle crashes, worked on an IV monitoring system, and developed computer models of crash scenarios. Hullfish came to CHOP through Drexel University’s Co-op program, in which Drexel students gain experience in their future fields at employers across the United States and internationally.

Both Hanna and Hullfish have been working with the Center for Injury Research and Prevention’s Aditya Belwadi, PhD. A member of CIRP since 2011, Dr. Belwadi studies injury biomechanics and injury causation, and has published recent papers in Traffic Injury Prevention and the Annals of Advances in Automotive Medicine, among others.

Modeling Child Restraint Systems with Kinect

Richard Hanna’s award-winning project was focused on using the Microsoft Kinect for Windows motion-sensing device. Perhaps best known as an Xbox peripheral (allowing users to play games with gestures rather than a controller), Hanna used the device in a novel way: to create three-dimensional digital models of 48 child restraint systems (CRS) representing close to 300 child seats in the US market as of March 2015.

According to a 2013 CIRP report on child passenger safety, motor vehicle crashes remain the leading cause of death for children older than 4 years and resulted in 952 fatalities in 2010 for children age 15 and younger. Although the number of children restrained in CRS has risen due to awareness and legislation, unintentional misuse of these restraints remains an issue; a 2004 NHTSA survey found that 72.6 percent of child restraints observed in parking areas throughout the United States had at least one “critical” misuse.

With this study, Hanna and Dr. Belwadi sought to make it easier for vehicle manufacturers to evaluate CRS-to-vehicle fit early on in the design phase, rather than an after-thought process once the CRS has been purchased. Currently, there is no standard method of quantifying child restraint systems’ geometry and volume, and the Kinect presents a simple, economic alternative to methods currently used by manufacturers.

Dr. Belwadi recently wrote about CIRP’s use of the Kinect in a post on the CIRP blog, noting “results from this research can ultimately help to improve testing conditions for vehicle and restraint safety devices.”

Finite Element Modeling of Side Air Bag Effectiveness

Todd Hullfish’s project, meanwhile, explores the effectiveness of side air bags and their interaction with pediatric passengers, a little studied topic. While various types of side air bags have become standard in many vehicles, the degree to which they protect passengers is up for debate. To get a better sense of how side air bags affect children seated next to them, Hullfish used Finite Element Modeling to model computer simulations of side impact crashes with accurate anthropometric test devices (ATD), or crash test dummies.

What then is Finite Element Modeling? Last summer Hullfish wrote a post for CIRP’s blog about FEM, which he defined as “a method of computation that represents complex geometry with simple shapes, such as triangles and squares in what is referred to as a ‘mesh’.”

The researchers use of a computational model allowed them to examine in detail side air bags’ deployment and effectiveness. The researchers next plan on testing pediatric models, in a variety of CRS designs. Their work could help vehicle manufacturers and CRS companies design more effective systems for child passengers.

Going forward, Hanna has said he is interested in working in the medical device or automotive biomechanics industries, while Hullfish — who doesn’t graduate from Drexel until 2016 — is considering graduate school.

“I’m extremely proud of Rich and Todd’s accomplishments. For engineers to be recognized among the world-class clinicians at CHOP is truly remarkable,” said Dr. Belwadi.

For more information about research at CIRP, check out the Center for Injury Research and Prevention website and CIRP’s Research in Action blog. To read more about Richard Hanna and Todd Hullfish’s work, see the March 2015 edition of CHOP Research’s Bench to Bedside.

Permanent link to this article: http://blog.research.chop.edu/center-for-injury-research-and-prevention-engineering-students-honored/

Apr 22 2015

Investigation Bolsters Use of Variant Protein in Hemophilia Gene Therapy

hemophilia_gene_therapyUsing gene therapy to produce a mutant human protein with unusually high blood-clotting power, scientists have successfully treated animals with the bleeding disorder hemophilia, without triggering an unwanted immune response. In addition, the “turbocharged” clotting factor protein eliminated pre-existing antibodies that often weaken conventional treatments for people with hemophilia.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said the study’s leader, Valder R. Arruda, MD, PhD, a hematology researcher at The Children’s Hospital of Philadelphia (CHOP) and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Dr. Arruda and colleagues published their results in the recent print edition of Blood.

Hemophilia is an inherited bleeding disorder that famously affected European royal families descended from Queen Victoria. Most commonly occurring in two types, hemophilia A and hemophilia B, the disease impairs the blood’s ability to clot, sometimes fatally. When not fatal, severe hemophilia causes painful, often disabling internal bleeding and joint damage. Doctors treat hemophilia with frequent intravenous infusions of blood clotting proteins called clotting factors, but these treatments are expensive and time-consuming. Moreover, some patients develop inhibiting antibodies that negate the effectiveness of the infusions.

For more than two decades, research teams have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. However, this approach has been frustrated by the body’s immune response against vectors — the non-disease-causing viruses used to carry the DNA. Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent: higher amounts of vectors caused more powerful immune responses.

Dr. Arruda and colleagues therefore investigated gene therapy that used lower dosages of vector produce a more potent clotting factor — a variant protein called FIX-Padua.

In 2009, Dr. Arruda was part of a team that discovered this variant protein in a young Italian man who had thrombosis, excessive clotting that can dangerously obstruct blood vessels. A mutation produced the mutant clotting factor (named FIX-Padua after the patient’s city of residence), the first mutation in the factor IX gene found to cause thrombosis. All previously discovered FIX mutations lead to hemophilia, the opposite of thrombosis.

FIX-Padua is hyperfunctional — it clots blood 8 to 12 times more strongly than normal, wild-type factor IX. Therefore in the current study, the researchers needed to strike a balance: to relieve severe hemophilia by using a dose strong enough to allow clotting, but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans,” said Dr. Arruda, “by adapting this variant protein found in one patient to benefit other patients with the opposite disease.”

The recent Blood investigation tested the safety of FIX-Padua in animals, all with naturally occurring types of hemophilia B very similar to that found in people. The researchers found the gene therapy injections changed their hemophilia from severe to mild, with no bleeding episodes for up to two years. The animals did not develop inhibitory antibodies, nor was there evidence of thrombosis.

Another set of preclinical safety studies supported the safety and efficacy of gene therapy using FIX-Padua. However, Dr. Arruda noted additional work is needed to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B — at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

To read more about this encouraging work, see the full press release about the Blood study.

Permanent link to this article: http://blog.research.chop.edu/investigation-bolsters-use-of-variant-protein-in-hemophilia-gene-therapy/

Apr 21 2015

Restoring Cellular Energy Could Lead to Mitochondrial Disease Treatments

mitochondrial diseaseRooted in malfunctions in the power plants that energize our cells, mitochondrial disorders are notoriously complex, with few effective treatments. Now, novel findings published recently in the journal Mitochondrion may hold great promise for children and adults with mitochondrial disorders. By using existing human drugs to improve metabolism and restore shortened lifespans in microscopic worms, scientists have set the stage for human clinical trials of possible innovative therapies for mitochondrial disease.

Mitochondria are present in nearly every cell, but when they don’t work properly, they impair many systems in the body by short-circuiting normal energy flow. While primary mitochondrial disorders are individually rare, hundreds of them exist, collectively affecting at least one in 5,000 individuals. Abnormal mitochondrial functions also play important roles in common conditions such as type 2 diabetes, epilepsy, Alzheimer’s disease, and even aging.

“This work carries strong promise for identifying effective therapies for mitochondrial diseases,” said The Children’s Hospital of Philadelphia’s Marni J. Falk, MD, director of CHOP’s Mitochondrial-Genetic Disease Clinic and leader of the Mitochondrion study. “The drugs we used in this study improve cellular signaling in ways that could directly benefit patients.”

The researchers’ investigation focuses on the respiratory chain, a set of five enzyme complexes that together are a crucial site of energy production inside mitochondria. In respiratory chain (RC) defects, cells fail to properly produce energy. The most common site of RC dysfunction is complex I, a group of proteins that normally generates a key metabolic product, nicotinamide adenine dinucleotide (NAD+).

NAD+ normally regulates hundreds of other chemical reactions within the cell. When genetic mutations disrupt complex I proteins and the metabolic conversion of NADH to NAD+, patients may suffer severe energy shortages in the heart, brain, eyes, muscles, and many other parts of the body.

In their Mitochondrion paper, Dr. Falk and colleagues studied microscopic worms, called Caenorhabditis elegans, with mutations that disrupt their mitochondria and make them a useful laboratory model for investigating mitochondrial disease. The researchers tested a series of drugs currently used to treat patients with diabetes or lipid disorders. One drug, nicotinic acid, is a form of niacin (vitamin B3) that has been used for decades to treat patients who have high triglycerides in their blood.

The C. elegans worms had mutations that directly impaired their complex I function and shortened their lifespans. Nicotinic acid restored the worms’ lifespans to that of normal animals. It also restored the levels of NADH, enabling it to play its crucial role of initiating the transport of electrons in the RC that is necessary to produce cellular energy, as well as regulating many other cellular processes.

The team showed that other available human drugs also improved key metabolite levels in C. elegans. “In contrast to research that aims to repair defective mitochondria, we are bypassing the damaged mitochondria and focusing instead on how cells respond to mitochondrial problems,” said Dr. Falk.

Dr. Falk and colleagues are now planning a pilot clinical trial in children to determine whether the effects seen in the animals will translate to meaningful clinical benefits in patients. Ultimately, she expects the complexity of mitochondrial biology will dictate that effective treatments will require combination therapies specific to restoring signaling pathways that are commonly disrupted in major subtypes of mitochondrial disease.

“We’re enthusiastic that we have reached a major threshold on the path toward bringing important new therapies to a very challenging group of diseases,” Dr. Falk added.

To read more about this study, see the full press release.

Permanent link to this article: http://blog.research.chop.edu/restoring-cellular-energy-could-lead-to-mitochondrial-disease-treatments/

Apr 20 2015

Genomic Sequencing Helps Scientists Trace High-risk Leukemia Relapse

leukemiaThe ability to sequence all the genetic abnormalities in a tumor cell was unimaginable when Stephen Hunger, MD, was a pediatric oncology fellow. Twenty-five years later, he and a team of researchers from throughout the country used highly sensitive deep sequencing techniques to see how genetic changes in acute lymphoblastic leukemia (ALL) cells evolve from diagnosis to remission and relapse.

ALL, a fast-growing form of cancer that affects immature white blood cells, accounts for 30 percent of all pediatric cancers. While most patients respond well to current chemotherapy, 15 percent will relapse, and ALL remains a leading cause of pediatric cancer death. Once relapse occurs, it is much, much harder to cure patients.

In order to better understand high-risk pediatric ALL, Dr. Hunger, chief of the Division of Oncology and the director of the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia, and his co-investigators wanted to trace the founder mutations that appear in every leukemia cell and see how other mutations persist, expand, or are eradicated between the time of initial diagnosis and relapse. They focused on 20 trios of samples from patients: ALL cells from the time of initial diagnosis, blood samples obtained while patients were in remission, and leukemia samples obtained at the time of relapse.

The researchers performed whole exome sequencing, which identifies all the coding regions of genes, and they also performed whole genome sequencing, which identifies the noncoding regions as well. They also performed “deep sequencing” to confirm the presence of mutations and determine their frequency in samples. This sophisticated analysis gave the researchers high coverage of every piece of the leukemia cells’ genetic material.

“In many cases, we were reading the same sequences 500 to 1,000 times,” Dr. Hunger said. “It is very useful because it allows us to get exact fractions of how often specific changes are present in the whole population of leukemia cells.”

The study’s results published in Nature Communications will help scientists to decipher the process of how ALL and other cancers relapse. These insights are only “the tip of the iceberg” of what is to come from the Therapeutically Applicable Research to Generate Effective Therapies (TARGET) study, said Dr. Hunger, who is the principal investigator of the TARGET ALL Project. TARGET is collaborative effort of a large, diverse consortium of investigators devoted to determining the genetic changes that drive the initiation and progression of hard-to-treat childhood cancers.

When the study team looked at leukemia cells from the time of initial diagnosis, they recognized the founder cells that all have specific abnormalities that kick-start the ALL disease process. The researchers also identified two to five subclones, which are descendants of the founder clone that have additional mutations present. Typically, one subclone was dominant in 90 to 95 percent of cells.

“One of the most striking things we found is that in almost every case, the clone that was most dominant at diagnosis was not present at relapse,” Dr. Hunger said, which suggests that those cells were effectively extinguished with current chemotherapy.

However, some rare subclones were able to survive, populate, and create the relapse. At the time of initial diagnosis, these subclones were often detected in only 1 or 2 percent of cells.

“One of the key points is that in every case, it was clearly the same leukemia that persisted because these founder mutations were present both at diagnosis and relapse,” Dr. Hunger said. “So it’s not like you developed a new leukemia. It also tells us that we have to look at the rare changes that are present at diagnosis because those are the cells that are likely to come back and acquire more changes.”

When the researchers examined blood samples taken at the end of the first month of treatment, in some cases they identified a low frequency of mutations that also appeared at the relapse stage. These findings raise the question of whether it would be valuable for scientists to perform highly sensitive genomic analysis following the first few weeks of chemotherapy to provide early detection of mutations that might drive relapse.

To help shed light on this answer, the study team already is performing deep sequencing of hundreds of pediatric ALL cases that relapsed and comparing them to those that never relapsed. They will search for any differences in the genetic basis of the leukemia cells from the two groups.

“Those sorts of studies will help us learn whether there are particular mutations that help to predict who will and won’t be cured,” Dr. Hunger said.

Another interesting finding from the current study, Dr. Hunger pointed out, is that certain mutations emerged at relapse and caused resistance to common chemotherapy drugs, yet those mutations were never found at any level when the patient was first diagnosed.

“Could we test patients during treatment to see if those mutations are starting to be detected, and if they were, could we change treatment to use different drugs that these mutations don’t cause resistance to?” Dr. Hunger suggested as a future research question.

Pediatric ALL was the first disease to be piloted for the TARGET initiative, which launched in 2006. The project expanded to include research efforts focused on acute myeloid leukemia, neuroblastoma, osteosarcoma, and Wilms’ Tumor. The TARGET ALL team includes investigators from the Children’s Oncology Group , the National Cancer Institute, University of New Mexico Cancer Center, and St. Jude Children’s Research Hospital.

Permanent link to this article: http://blog.research.chop.edu/genomic-sequencing-helps-scientists-trace-high-risk-leukemia-relapse/

Apr 17 2015

Severe Pediatric Sepsis Remains Highly Prevalent Public Health Problem

SPROUT_BLOGSevere pediatric sepsis is a formidable challenge for critical care specialists who unfortunately see children in pediatric intensive care units (PICUs) die from body-wide inflammation and subsequent organ damage that can occur when the immune system responds to infection. Until recently, researchers had not defined the true scope of severe pediatric sepsis worldwide.

Julie Fitzgerald, MD, PhD, a pediatric intensivist, and Scott Weiss, MD, MSCE, an attending physician in Pediatric Critical Care at The Children’s Hospital of Philadelphia, led an international, multicenter prospective point prevalence study called Sepsis, Prevalence, Outcomes, and Therapies (SPROUT) to identify patients admitted to PICUs for severe sepsis and characterize the therapies that they received and their outcomes.

Previous studies that attempted to look at the epidemiology of severe pediatric sepsis used administrative databases based on billing codes or were conducted at single centers. Dr. Fitzgerald and Dr. Weiss received an overwhelmingly positive response three years ago when they approached fellow members of the broad, international Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) with their study design. They were eager to get a clearer and bigger picture of severe sepsis that they could rely on to provide baseline data for future interventional trials to improve survival for their patients.

“When we look at our own ICUs, while mortality has gone down, it is still a lot higher than what was being reported in these administrative studies,” said Dr. Fitzgerald, who also is an assistant professor at the Perelman School of Medicine at the University of Pennsylvania. “So, in our minds, we were trying to resolve that discrepancy. We wanted to see what other ICUs’ experiences were in terms of how much sepsis they had and what their mortality rates were. We thought it was a bigger problem than maybe was being appreciated based on those administrative studies.”

They conducted SPROUT in 128 sites from 26 countries and screened a total of 6,925 patients on five days throughout 2013 and 2014. Using consensus criteria for severe pediatric sepsis, the researchers identified 569 patients. Their average age was 3, and 25 percent did not survive, which was much higher than previous administrative studies that reported mortality rates in the 5 percent to 8 percent range.

“Another key feature was the burden of pediatric severe sepsis in ICUs worldwide,” said Dr. Weiss, who also is an assistant professor of Anesthesiology, Critical Care, and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “We found an overall prevalence of 8.2 percent, which means that your average PICU is treating at least one child with severe sepsis at any one time. So it is an incredibly common cause of pediatric critical illness, and it highlights the ongoing problem of severe sepsis.”

With these new estimates, researchers now have a better idea of how many centers and patients would be available for future interventional studies of severe pediatric sepsis. SPROUT also provided data on other outcomes measures such as multiorgan dysfunction syndrome, ventilator days, and the need for vasoactive medications. This information will facilitate better study planning, Dr. Fitzgerald said.

“SPROUT highlights the incredible collaborative spirit of the pediatric critical care community worldwide and the willingness and desire of investigators, even from relatively small sites from across the world, to participate in efforts to better understand the burden of the disease that we’re caring for and to ultimately put into place efforts to improve the care that we provide,” Dr. Weiss said.

The SPROUT study investigators’ work is especially noteworthy because they received no financial compensation for their participation. Dr. Weiss and Dr. Fitzgerald gratefully acknowledged the funding and divisional support from CHOP’s Robert Berg, MD, division chief Critical Care Medicine, and Vinay Nadkarni, MD, endowed chair of Critical Care Medicine. CHOP’s Center for Pediatric Clinical Effectiveness also provided grant support to help develop the research database to launch the study. They also thanked Jenny Bush, clinical research study coordinator.

The senior author on the study, Neal Thomas, MD, is a leader in the PALISI network and an established clinical scientist in pediatric critical care at Hershey-Penn State. He has been supported by the CHOP Division of Critical Care Medicine to mentor junior faculty at CHOP, including Drs. Weiss and Fitzgerald.

Results from the SPROUT study appeared online in the American Journal of Respiratory and Critical Care Medicine.

Permanent link to this article: http://blog.research.chop.edu/severe-pediatric-sepsis-remains-highly-prevalent-public-health-problem/

Apr 16 2015

Simulation of Peer Review Sheds Light on Bias in Grant Funding

grant fundingIn an ideal world, the very best grant proposals that are the most likely to advance scientific discovery would win financial support from the National Institutes of Health (NIH). But the reality is that science is not immune to human bias. Race, ethnicity, gender, career stage, institution of origin, and other factors can accumulate as competing biases that may influence — consciously or unconsciously — how peer reviewers score submissions.

While this is no surprise to the research community, investigators may be taken aback by the results of a simulation study published in the journal Research Policy by T. Eugene Day, D.Sc., of the Office of Safety and Medical Operations at The Children’s Hospital of Philadelphia. He assessed how much bias is needed before grant funding decisions are swayed.

In his role as principal health systems specialist, Day uses simulation tools to examine clinical delivery systems and make predictions about which potential quality or safety interventions are most likely to have a positive change at CHOP. For example, he was the principal investigator for a recently published study that demonstrated how his team used simulation to test plans to improve scheduling of elective procedures in pediatric cardiac care.

During his free time, Day designed a thought experiment based on a simulation model of a simplified grant review process. He formulated the idea after a social media conversation with colleagues about how slight advantages could play a big role in determining who is lucky enough to submit a successful grant application when federal research dollars are scarce.

Day created two fictional classes of investigators for the simulation — preferred and non-preferred — and he assigned each class 1,000 grant applications that had been given intrinsic quality ratings. He ensured that the quality of the grant applications from each group was statistically identical. Then, in order to mimic the peer review process, he generated three reviewers who were imperfect at determining the intrinsic quality of the grants.

“Just like in the real world, no three reviewers on a NIH grant ever agree on exactly how good it is,” Day said. “The same was true in the simulation. I based the distribution of that randomness from my own grant score history.”

After validating the model, Day conducted a sensitivity analysis. He introduced small biases in one or all three reviewers against the non-preferred investigators and then increased the level of bias until he found statistically significant differences in the scores and in the actual awards, despite the fact that the quality of the grants was the same.

“What I found was that it takes an alarmingly small bias to make a significant difference,” Day said. “With only about 2 percent of the score being bias, we saw statistically significant differences in the scores of grants. That did not translate to the number of funded awards at that level. But with 3 percent, we saw statistically significant differences in the actual funds distributed. Very small biases can make these rather dramatic impacts on who gets funded.”

Another provocative aspect that his simulation revealed is that while the more privileged investigators received funding and the underprivileged investigators were left behind, the average quality of the funded grants was lower than it would have been without bias.

“So not only do these biases influence who gets funded, but they may degrade the overall quality of science,” Day said.

In addition, Day pointed out that bias can be difficult to detect because it is overshadowed by the random variation in how good reviewers are at determining the quality of the grants. In other words, the signal is a lot smaller than the noise. A first step to honing in on bias would be to promote more transparency in the grant review process, Day said, specifically by publishing the variation in individual reviewers’ scores.

“The first thing that we need to do is understand how big the variation is, and then next we need to work on narrowing it,” Day said. “That will allow us to identify real-world bias, which might then be addressed.”

Several efforts already are underway to maximize the fairness in NIH peer review. Last spring, Director of the NIH Center for Scientific Review (CSR) Richard Nakamura, PhD, announced an initiative to begin combing through grant proposals to remove identity cues and then testing to see if anonymization has any effect on funding disparities. The CSR, which is the gateway for NIH grant applications, also launched a challenge to produce the best ideas to detect possible bias in peer review and named the winners in September.

It is crucial for the NIH to seek solutions to overcome bias, Day said, because challenges in securing grant funding that are unrelated to submissions’ merit can have long-term consequences for investigators who are striving to pursue promising biomedical research.

“If a bias prevents you from getting that first grant, then maybe you don’t have the preliminary data that you need for the next grant,” Day said. “Maybe you don’t have the funding to continue your laboratory, and you exit science.”

Permanent link to this article: http://blog.research.chop.edu/simulation-of-peer-review-sheds-light-on-bias-in-grant-funding/

Apr 15 2015

CHOP, Drexel, Hebrew University Research Partnership Honored

research partnershipThe Philadelphia-Israel Chamber of Commerce (PICC) recently honored the joint research partnership among Drexel University, The Children’s Hospital of Philadelphia (CHOP), and the Hebrew University of Jerusalem with the 2015 Yitzhak Rabin Public Service Award. The Rabin Award honors regional businesses, academic institutions, and their leaders who exemplify the organization’s goals of broadening business and academic ties between the United States and Israel.

The agreement among the three institutions was signed in a ceremony at Jerusalem City Hall in the presence of Jerusalem Mayor Nir Barkat and Philadelphia Mayor Michael Nutter on November 11, 2013. The agreement served as a new standard for potential partnerships between US cities and foreign nations to further academic and research projects.

The research partnership — which led to a conference at CHOP in January 2014 — is designed to focus on pediatric translational research and to develop a collaborative platform for advancing pediatric medicine from the lab to the bedside. The conference provided an opportunity for investigators from the three institutions to find collaborators with whom to develop joint projects and proposals in pediatric translational research and for interested funders to learn more about the potential for discovery that this collaborative consortium holds.

Two dedicated “dream teams” of investigators were selected, each receiving $250,000 over two years in institutional funding, as administrators seek external investors interested in advancing exciting pediatric translational research with commercial viability.

One dream team is based at Drexel with Amy Throckmorton, PhD, as the principal investigator of the “Giving Kids a Chance” project that investigates a new intravascular blood pump for pediatric patients with congenital heart disease. A second dream team is located at CHOP with Robert J. Levy, MD, leading the project “Pediatric Transcatheter Valve Replacements: Preventing Device Failure due to Structural Degeneration.”

“Drexel, CHOP and the Hebrew University’s collaborative research on pediatric care is very important to strengthening and broadening the entire region’s academic, commercial, and friendship ties with Israel,” said Richard Bendit, president of the PICC. “Moreover, such joint research elevates the Greater Philadelphia’s rank as a premier center for medical research while opening myriad of new opportunities for future collaborations and further economic impact.”

To read more about the award, see the full press release.

Permanent link to this article: http://blog.research.chop.edu/chop-drexel-hebrew-university-research-partnership-honored/

Apr 14 2015

Stay in Touch With Safety During Distracted Driving Awareness Month

distracted drivingNew teen drivers may be able to recite the rules of the road, but can they learn how to handle all the distractions coming at them from inside their cars? Teen driver safety researchers at the Center for Injury Research and Prevention (CIRP) at The Children’s Hospital of Philadelphia are studying common scenarios that involve serious hazards of distracted driving and how they affect novice drivers’ performance.

Imagine that you are a teenager sliding behind the wheel, eager to hit the road after a mind-numbing last period of Social Studies. Your friends are even more thrilled to get a free ride, slamming the car doors. You exit the driveway as your BFF reaches over to turn up the volume of her favorite song. Her new boyfriend is bouncing around the backseat, and you are trying to remember if his name is Josh or Justin when “Mom” pops up on your cell phone. She wants to know how long until you will be home. Suddenly, your brain registers that there was a flashing yellow light at the intersection you just crossed, and you did not even try to slow down.

This phenomenon called “looked but did not see” occurs when your brain is processing too many sensory inputs and your attention capacity narrows, explained CIRP researcher Yi-Ching Lee, PhD, who studies the human factors that influence safe driving dynamics. “When you’re busy driving, things come and go all the time, so how do drivers attend to multiple sources of information?” This is the question at the root of her investigations.

For teen drivers, the answer is poorly. In 2012, 10 percent of all 15- to 19-year-old drivers involved in fatal crashes were reported as distracted at the time of the crashes, according to the National Highway Transportation Safety Administration (NHTSA). Distracted driving was a factor in 14 percent of all police-reported crashes involving teen drivers in 2012, according to NHTSA.

As part of Dr. Lee’s latest work, she and colleagues at Parallel Consulting conducted a survey of about 400 drivers, ages 15 to 18, from 31 states to help understand how often teens use a cell phone while driving and to whom they talk. They discovered that more than half the teens talking on cell phones while driving reported conversing with their parents.

“We saw that parents play a significant role in the number of calls that teens receive in the car,” Dr. Lee said. “You would think that it would be friends or peers, but it’s actually the parents who are part of the problem. That was surprising.”

While some parents just wanted to check in, others bombarded their teens with repeated phone calls until they picked up. Teens said they answered the phones even though they were busy driving because they did not want their parents to get mad. A better option, Dr. Lee suggested, would be for parents to encourage their teens to find a spot to pull over to call them back.

The survey also showed that teens are more likely to text friends while driving: 35 percent of 15- to 17-year-olds reported that they text with friends while driving, while 57 percent of 18-year-olds report doing so. Yet it is apparent that parents have figured out text lingo and emojis: 8 percent of 15- to 17-year-olds text with their parents while driving, and this percentage doubled for 18-year-olds, according to the survey.

One way to deter this unsafe behavior is to use technologies that block incoming calls and texts to drivers while the car is in motion. Callers receive a standardized message such as, “I’m driving. I’ll pull over and call you back.” Dr. Lee and colleagues at the Perelman School of Medicine at the University of Pennsylvania are studying drivers’ perceptions of this type of technology, and they are preparing to conduct field trials that will track how teen and parent drivers react to different levels of restrictions when the call blocking devices are installed in the family car.

While monitoring teens and enacting legislation that restricts or bans the practice of using cell phones and text messaging while driving could be effective interventions, Dr. Lee suggested that parents could make a big difference by demonstrating good driving habits and putting their cell phones away in the car. She also encouraged society to find positive reinforcements for teens who manage their cell phone use responsibly, such as incentives from car insurance companies, and to teach teens how to deal with the temptation to stay connected and up-to-date all of the time.

“We need to make them aware of pacing and self-regulation so that they can resist the pressure of media and technology,” Dr. Lee said. “It has become so intense. People have the expectation that if I send a message, they need to respond in five minutes. When you are doing something demanding, like driving, and on top of that you have this sense of high urgency, it is really a lot. We as parents, educators, and researchers, should help them overcome that kind of burden.”

Using a driving simulator, Dr. Lee is conducting studies that are looking at how teen drivers interact with realistic traffic situations while performing multiple tasks. She and colleagues at Parallel Consulting also have developed a prototype of an educational game that gives teens some exposure to the complicated situations that can distract drivers when passengers are in the car.

The game is designed so that the passenger sees certain things that the driver does not, and they must learn how to act to help each other. For example, the driver must rely on the passenger to tell him, “Watch out, a truck is coming from the right.” Dr. Lee hopes to obtain additional funding in the future to make the prototype more robust so that it could be easily integrated into a high school or driving school setting.

Dr. Lee, who learned to drive in Taiwan and got her license at 18, has noticed that since she became a principal investigator with CIRP’s Teen Driver Safety Research Team, she tends to drive slower than most people.

“I get honks all the time,” Dr. Lee said. “But that doesn’t bother me because I know that I am safer driving the speed limit.”

April is National Distracted Driving Awareness Month. Visit http://www.distraction.gov/ to learn more about how distracted driving is a major safety issue not only for teens but for everyone.

Permanent link to this article: http://blog.research.chop.edu/stay-in-touch-with-safety-during-distracted-driving-awareness-month/

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