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/

Apr 13 2015

We Can Prevent Crashes: Driving Safety Expert Dr. Flaura Winston Visits Ireland

driver safety“The fact is for teen drivers, in the United States for example, one third of the reason why adolescents die is road traffic injury. So if you have something that’s that big of an epidemic, why aren’t we doing more?”

So said CHOP Research’s Flaura Winston, MD, PhD, speaking to Ireland’s national broadcaster RTE Radio. Doing her part to prevent teen accidents, Dr. Winston visited the Emerald Isle recently for a series of meetings on driving safety at the Royal College of Physicians of Ireland (RCPI).

Dr. Winston took part in two meetings at the RCPI, the first a conference on driving safety and attention-deficit/hyperactivity disorder (ADHD), alcohol, drug use, and psychiatric issues. She then led a panel of experts in a public discussion of preventing accidents among young drivers. And last but certainly not least, she took the time to contribute to RTE Radio’s “Drivetime” afternoon show.

“The thing that’s important with teens is they don’t need to be scared away with crashes,” Dr. Winston said on “Drivetime.” “What they need is skill. What they need is experience.”

Founder and scientific director of the Center for Injury Research and Prevention, Dr. Winston is an internationally recognized car safety expert who has published extensively on teen driving and driving safety. Recent studies include an Evidence-Based Mental Health investigation of the effect ADHD medication has on driving, and an Injury Prevention study of a simulated driving assessment tool.

At the RCPI, Dr. Winston gave a keynote speech to healthcare professionals on ADHD and driving, then gave a public talk on preventing teen crashes, effective use of child restraints, and medical trauma associated with crashes. She also found time to talk to RTE’s “Drivetime” about a range of teen driving-related topics.

After telling the program’s host Mary Wilson that many people assume crashes are simply part teen drivers’ experience, she noted “we can prevent these crashes.” For example, Dr. Winston said, while 20 percent of teen drivers have accidents, 80 percent don’t. So what, she asked, can we learn from those who don’t get into accidents?

For example, “driver education begins when the child is in a forward-facing car seat,” Dr. Winston said, as children pick up their parents’ driving behavior. And whether they turn out to be safe drivers is also dependent on how much time parents put into teens’ “supervised practice period,” Dr. Winston noted.

“Think about how much time you spend teaching your child to play football,” Dr. Winston said. “Think about how time you spend with your time with your child in their music lessons, or their math lessons. And then think about how time you’re spending and the variety in which you’re doing your practice driving.”

After all, she pointed out, safe driving is “a complex skill.”

To listen to Dr. Winston’s entire interview, check out RTE Radio (start at 01:42:10).

Permanent link to this article: http://blog.research.chop.edu/we-can-prevent-crashes-driving-safety-expert-dr-flaura-winston-visits-ireland/

Apr 03 2015

PolicyLab Paper Finds Millions of Children Still Impacted by Recession


“Economists say the recession is over, but five years later, it’s still impacting millions of children,” said First Focus President Bruce Lesley.

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.”

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.

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 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.

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. “A true recovery would reverse the trends of growing poverty and widening income gaps,” they write.

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

Permanent link to this article: http://blog.research.chop.edu/policylab-paper-finds-millions-children-still-impacted-recession/

Apr 02 2015

Researchers Suggest NTRK3 Gene Mutation Contributes to Heart Defects

heart defectDuring pregnancy, a series of intricate processes takes place for the heart to form correctly. Cells develop, proliferate, migrate, and die frequently, as the heart tissue transforms from a primary heart tube to four cardiac chambers. Scientists suspect that if there is a genetic mishap, those steps may not occur at the right time or place, resulting in congenital heart defects (CHDs).

One in 125 babies in the U.S. is not born with a perfect heart. CHDs are the most common major birth defects, and they range from simple to complex. For example, a heart defect called ventricular septal defect (VSD) involves an opening in the dividing wall between the two lower chambers of the heart. The hole allows an extra volume of blood to be pumped into the lungs, creating increased pressure, stress, and congestion.

Researchers at The Children’s Hospital of Philadelphia are searching for genes that could be linked to the presence of heart defects, and they recently reported on mutations in the gene NTRK3 that may be involved in the development of VSDs. NTRK3 regulates cell survival and encodes a protein called neurotrophic tyrosine kinase receptor C (TrkC).

“Finding the potential variations that are involved in heart defects in children is like finding a needle in a haystack, but you’re looking at a field of hundreds of haystacks,” said Petra Werner, DVM, PhD, a senior research associate in the laboratory of Elizabeth Goldmuntz, MD, professor of pediatrics in the Division of Cardiology at CHOP. “We picked NTRK3 as a candidate gene because deletion of this gene in mice will result in heart defects, and we had identified a patient with a VSD that had a large deletion encompassing NTRK3.”

In an article published in the December issue of Human Mutation, Dr. Werner and colleagues described how they screened 467 patients with related heart defects for NTRK3 mutations. They identified four of those patients with VSDs who had a missense mutation, which means an amino acid substitution occurred in the TrkC protein made by the gene that may modify how it works.

Next, the study team conducted experiments to see if the mutated TrkC lost any function. As a receptor, TrkC sits on cells’ membranes and waits for a signal from its ligand, a protein called neurotrophin-3 (NT-3). The results showed that one of the mutations significantly reduced TrkC’s ability to respond to the ligand, and subsequently TrkC failed to activate essential downstream signaling pathways.

In addition, the investigators found that cells expressing mutant TrkC showed altered cell growth. Usually, when NT-3 is present and binds to TrkC, it is a survival signal for the cell to differentiate and migrate. When the NT-3 ligand is absent, the cell begins to die, a process known as apoptosis. The experiments showed that cells with some of the mutant TrkC kept growing, even when they lacked NT-3.

“These results suggest that these mutations might permit increased cell growth under developmental conditions where morphologic changes require cell death,” the investigators wrote in the Human Mutation article.

Dr. Werner and her colleagues hypothesize that if TrkC’s function is impaired and allows the wrong heart cells to differentiate and migrate, then flaws could occur during the rapid remodeling of embryonic heart development.

“They may end up in the wrong location in the heart and be missed in other locations, resulting in malformations or holes,” Dr. Werner said. “But much more research must be done before we fully understand all of TrkC’s functions.”

Permanent link to this article: http://blog.research.chop.edu/researchers-suggest-ntrk3-gene-mutation-contributes-to-heart-defects/

Mar 31 2015

Driven by Patients: CHOP’s Cutting-Edge Fetal Surgery to be Featured on PBS

fetal surgery

Tune into WHYY at 8 p.m. on March 31st, April, 7st & 14th!

Mark your calendars! Starting tonight, the work of The Children’s Hospital of Philadelphia’s N. Scott Adzick, MD, an internationally recognized fetal surgery pioneer, will be featured in the new documentary series Twice Born. Airing March 31 to April 14 on PBS, Twice Born will highlight stories from Children’s Hospital’s groundbreaking Center for Fetal Diagnosis and Treatment.

Children’s Hospital’s surgeon-in-chief, Dr. Adzick is the founder of the Center for Fetal Diagnosis and Treatment, one of the world’s leading fetal care centers. The Center offers everything from testing to fetal surgery to postnatal care, and since its inception in 1995, Center surgeons have performed more than 1,200 fetal surgeries. Its experts treat a wide range of conditions, including congenital diaphragmatic hernia, conjoined twins, spina bifida, and twin-twin transfusion syndrome.

“This can’t be done many places in the world, this not amateur hour, this is very serious stuff,” said Dr. Adzick in a preview of the series.

Twice Born will tell the stories of parents of babies with birth defects who came to CHOP for care. Including rare operating room footage and interviews with CHOP clinicians, the series “serves up both arresting human drama and astonishing medical science,” according to the show’s website.

“We’re driven by patient needs,” said Dr. Adzick. “We’re driven by trying to find solutions to those unsolved problems. It’s a miracle and a privilege to take care of patients, of babies. Babies are the future! What could be more compelling than a baby?”

In other news, Dr. Adzick was recently awarded the Philadelphia Academy of Surgery’s 2015 Samuel D. Gross Prize. Given “every five years for the best original research in surgery by an American citizen,” the prize is named after prominent nineteenth century surgeon Samuel D. Gross, MD. A surgical pioneer and founder of the Academy, Dr. Gross published numerous books on surgery and anatomy, but is perhaps best known for being the subject of the famous Thomas Eakins painting, The Gross Clinic.

The award recognizes some of Dr. Adzick’s many accomplishments. In particular, in 2011 Dr. Adzick led a landmark study in the New England Journal of Medicine that showed fetal surgery can significantly improve the outcomes for children diagnosed in utero with spina bifida. More recently, he has contributed to investigation of ex utero intrapartum treatment, congenital diaphragmatic hernia, and a study of extracorporeal membrane oxygenation, or ECMO.

For more information about Twice Born, see the trailer below. And be sure to check your local PBS station for Twice Born showtimes!

Permanent link to this article: http://blog.research.chop.edu/driven-by-patients-chops-cutting-edge-fetal-surgery-to-be-featured-on-pbs/

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