Oct 08 2014

Experts’ Research Leads to Rare Disease Clinical Trial

rare diseaseAs rare pediatric diseases go, Fibrodysplasia Ossificans Progressiva (FOP) is about as rare and debilitating as they come. Affecting roughly one in two million people around the world, FOP is a condition in which extraskeletal bone is formed when “muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone,” according to the NIH’s Genetics Home Reference page. FOP is caused by a congenital mutation in a gene called ALK2.

Over time, this ectopic bone — also known as heterotopic ossification (HO) — becomes pervasive and widespread and eventually restricts FOP patients’ ability to move, speak, and feed themselves, and can lead to near-total paralysis and early death. In addition, there is a non-genetic form of HO that is not as severe as FOP and can occur in individuals of any age.

Like so many rare diseases, there are few treatment options for fibrodysplasia ossificans progressiva because its rarity means it has been studied by fewer research groups and has attracted less research money than more common conditions. In the U.S., a disease is considered rare if it affects fewer than 200,000 people, so FOP — of which there are roughly 300 cases in the U.S. — is one of the very rarest rare diseases.

Fibrodysplasia Ossificans Progressiva “is an extremely serious disease,” said CHOP’s Maurizio Pacifici, PhD, who often hears from families desperate to find a treatment for FOP.

Dr. Pacifici is among a group of CHOP Orthopaedics’ Investigators — including Masahiro Iwamoto, DDS, PhD and Motomi Enomoto-Iwamoto, DDS, PhD — who have been working to better understand, and ultimately treat, FOP. Their many years of work may soon pay off, because a drug they identified as a possible FOP treatment is now being tested into a phase II clinical trial to treat FOP.

FOP is marked by “flare-ups”—localized swelling and inflammation—that signal the development of ossification in the affected area. Currently, the only approved treatment for FOP is to give patients steroids when they experience flare-ups. The steroids reduce inflammation and swelling, but are not able to prevent ossification and can also have considerable side effects. Because FOP patients are prone to getting multiple flare-ups, at times with little respite between episodes, their steroid treatments’ side effects can be compounded, Dr. Pacifici pointed out.

This has spurred the search for a safer, more effective treatment for FOP and HO. Unlike FOP, HO is not confined to a small community of patients with a genetic mutation, and “can happen to any of us,” Dr. Pacifici pointed out. The condition can be brought on by any number of causes — trauma, invasive surgeries, and burns, as well as prolonged immobilization. Because severe trauma is such a strong inducer of HO, it was seen in some 65 percent of seriously wounded soldiers during the peak of recent wars.

Supported in large part by Department of Defense funding, Dr. Pacifici and colleagues have been looking at ways to arrest HO (and by extension, FOP) for several years. In 2011 their investigations led to a paper in Nature Medicine showing that drugs called retinoic acid receptor agonists inhibited chondrogenesis, or the development of cartilage, which is the first step in the formation of ectopic bone during HO and FOP. Moreover, the drugs all “seem to have minimal side effects,” the authors noted.

One of the drugs the CHOP researchers identified was Palovarotene. Originally developed by the pharmaceutical company Roche to treat emphysema, Palovarotene was shelved when trials showed the drug was effective but not as effective as expected. Following the publication of the Nature Medicine paper, the Montreal-based startup Clementia Pharmaceuticals acquired the rights to develop Palovarotene to treat FOP in close collaboration with the CHOP Investigators. Fast forward to today: in July, Clementia launched a phase II trial Palovarotene to treat fibrodysplasia ossificans progressiva.

“It is rare to go from basic science, and we really started with completely basic science, to a clinical trial, …it took us a long, long time to do it,” Dr. Pacifici noted. Palovarotene may turn to be an effective treatment for FOP in the pediatric and young adult population as well as HO in wounded soldiers and other affected individuals.

To read more of this remarkable story of how research was taken from a lab at CHOP to a clinical trial, see this month’s issue of Bench to Bedside.

Permanent link to this article: http://www.research.chop.edu/blog/experts-research-leads-rare-disease-clinical-trial/

Oct 06 2014

Genetic Study Gives Clues to Cognitive Abilities

cognitive abilitiesAs students with bulging backpacks return to school this fall, each one also brings a unique skill set to the classroom. One child may be a math whiz, while their buddy in the next desk is an avid reader. A large genetic study conducted by experts at The Children’s Hospital of Philadelphia and University of Pennsylvania’s Perelman School of Medicine may lead to new ways to evaluate these complex traits in children’s intelligence.

The study drew on the largest data set ever used in a single sample across multiple cognitive traits grouped within five broad domains: executive function, memory, complex cognition, social cognition, and reading ability. Previous estimates of the heritability of cognitive traits relied on much smaller twin and family studies; however, the authors note that their current research represents a first step in discerning the overall genetic architecture of cognitive abilities.

The researchers performed genotypes of all participants, administered a battery of neurocognitive tests, and assessed participants in structured psychiatric interviews. They used a powerful gene software tool called genomewide complex trait analysis (GCTA) to analyze a subset of 3,689 individuals aged 8 to 21, all of European ancestry, drawn from the Philadelphia Neurodevelopmental Cohort, a general-population sample of close to 10,000 individuals who received care within CHOP’s pediatric network for a broad range of health needs.

The GCTA analyzes common SNPs (single-nucleotide polymorphisms, changes of a single base in DNA) to estimate how much these common gene variants contribute to differences in cognitive abilities within the total sample.

“When we computed the contribution of common variants to these cognitive abilities, we found that some of the contributions were substantial,” said one of the study’s two co-senior leaders, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia.

For instance, common SNPs accounted for roughly 40 percent of the population differences in nonverbal reasoning, and 30 percent of the differences in language reasoning, with the balance of the differences attributable to rare variants and environmental factors. On the other hand, common gene variants together contributed to only 3 percent of the differences in spatial memory — the ability to navigate in a geographical location. The researcher also identified significant overlaps between trait domains. Reading ability, which was 43 percent attributable to common variants, was often inherited together with language reasoning abilities.

“Intuitively, it makes sense that skills in reading and language reasoning are related,” said Dr. Hakonarson, who added that those traits might be investigated together in future genetic and neurobiological studies.

Upcoming research also will focus on analyzing age-dependent differences to investigate how genetic influences vary as children mature. Other, larger studies should focus on non-European populations. Ultimately,  Dr. Hakonarson added, if the current findings are replicated and extended, researchers may be able to generate a genetic profile reflecting a normal distribution of cognitive abilities.

“Uncovering the genetic architecture of these diverse cognitive abilities may offer new insights into cognitive development and may ultimately allow investigators to identify useful biomarkers for diagnosing and predicting risks of neuropsychiatric conditions,” Dr. Hakonarson said.

The study appeared online July 15 in Molecular Psychiatry. Dr. Hakonarson’s co-senior author is psychiatrist Raquel Gur, MD, PhD, director of Neuropsychiatry in the Perelman School of Medicine at the University of Pennsylvania. The study team represents a collaboration among the CHOP and Penn investigators with colleagues at the Broad Institute, Harvard Medical School, and Massachusetts General Hospital who developed GCTA.

Permanent link to this article: http://www.research.chop.edu/blog/genetic-study-gives-clues-cognitive-abilities/

Oct 03 2014

Research Tool Based on Common Crash Scenarios for Teens

crashPer mile driven, teens have three times the fatal crash risk than adults, according to the Centers for Disease Control and Prevention. In addition, for those who survive serious car crashes, the disability and long-term psychosocial problems that follow can interfere with teens’ ability to reach their full potential.

“Keeping teens safe on the road helps to improve their health and the health of other road users, including passengers and pedestrians,” said Catherine McDonald, PhD, RN, an assistant professor of nursing in the Family and Community Health Department at the University of Pennsylvania School of Nursing who is affiliated with the Center for Injury Research and Prevention (CIRP) at The Children’s Hospital of Philadelphia Research Institute. She initially became interested in better understanding why teen drivers crash in her previous role as a nurse in a variety of settings — pediatric intensive care, pediatric emergency department, and schools.

teen driver safety“I treated many patients who suffered injuries as a result of a crash, but it was devastating when students in my school were killed in crashes,” Dr. McDonald said. “I hope that my research will translate into designing effective strategies to prevent similar tragedies.”

Working toward this goal, she worked with Dr. Flaura K. Winston and other team members at CIRP to form the foundation for a one-of-a-kind Simulated Driving Assessment (SDA) tool that measures teens’ performance in complex driving situations. The SDA is based on crash types that she and her team identified from the most frequent teen driver serious crash types in the National Motor Vehicle Crash Causation Survey (NMVCCS).

Data from NMVCCS indicated that when teens crashed, the most common types were left turns, rear-end events, and situations where they ran off the road. With these data, the SDA’s creators gathered rich descriptions of the scenarios involved in the crashes to construct roadway, traffic, and weather configurations that they programmed into a driving simulator. The SDA uses established safety metrics from the literature to assess the performance of a participant. So far, testing of the SDA has shown some promising support for its validity.

“We think we’ve opened up an exciting area of research and a new way of thinking about driving assessment,” Dr. McDonald said. “Not only does the SDA assess performance in a driver, but it also has the potential to be used in the future as a screening tool for clinicians to identify teens’ skills or deficits, or it could be used as a way to measure future interventions that we build to improve driver training.”

With multiple risk factors contributing to crashes, such as inexperience behind the wheel, weather and traffic conditions, and risk-taking tendencies of teens, Dr. McDonald also believes that the SDA could address these different domains of teen driving.

It won’t take long for the SDA to get some traction as a robust research tool for use by the scientific community. Dr. McDonald plans to use the SDA in a project funded by the National Institute of Nursing Research. The feasibility study will focus on the effects of a web-based intervention for risky driving behaviors.

Permanent link to this article: http://www.research.chop.edu/blog/research-tool-based-common-crash-scenarios-teens/

Oct 01 2014

Safety of Severe Asthma Care Outside the ICU Assessed

asthmaClinicians at The Children’s Hospital of Philadelphia have extensive experience in treating children with acute asthma flares, partly due to the tremendous volume of patients with this respiratory condition who come from the urban community nearby. Asthma is one of the leading, serious, chronic illnesses among children in the U.S., and Philadelphia ranks among the top 5 worst asthma cities.

During an asthma exacerbation, a child’s lungs and airways overreact to a certain trigger. The airways’ lining swells, and muscles surrounding the airways constrict. As these air passages narrow and become clogged with mucus, the child’s breathing becomes difficult, as if trying to get air through a pinched straw.

About 2,700 patients are admitted for asthma in a given year at The Children’s Hospital of Philadelphia, accounting for 17 percent of the total admissions. When a child with a severe asthma flare arrives at the emergency room, clinicians initiate one hour of continuous aerosolized albuterol (CAA), a quick-acting beta-agonist bronchodilator, in addition to other therapies, to relieve the patient’s shortness of breath.

If the flare is very severe, clinicians will continue continuous medication delivery when the patient is admitted to the hospital, which in many hospitals occurs in the intensive care unit. Because asthma is such a prevalent pediatric condition, often a patient with severe asthma occupies an intensive care unit (ICU) bed that is in high demand.

Chén Kenyon, MD, an attending physician in the Division of General Pediatrics at CHOP, and colleagues, wanted to find out if these patients are treated safely and effectively with CAA in the non-ICU, inpatient setting, which may free up limited ICU beds for other high acuity patients and offer significant cost-savings. Unfortunately, no published scientific data existed to support this practice, so to begin to answer the question, they conducted a retrospective cohort analysis of electronic medical record data using the CHOP Data Warehouse.

“Using this unique resource, we are able to provide much more granularity than prior studies,” Dr. Kenyon said. “We can pinpoint physician orders and see at what point a particular therapy was ordered and when it was stopped.”

A clinical pathway in place for 18 years at CHOP helps clinicians to streamline and standardize asthma care. It includes a component that allows for CAA to be administered in the non-ICU, inpatient setting for patients with severe asthma who are assessed hourly by trained respiratory therapists and nurses. The researchers combed through physician orders for CAA of 1,300 children ages 2 to 18 treated under this protocol from July 2011 to June 2013. They compared the cohort to 1,700 patients who received intermittent albuterol only and assessed the two groups’ characteristics and rate of adverse outcomes. Results from the study appeared online Sept. 29 in Pediatrics.

“There seemed to be no difference in the prevalence of low potassium or cardiac arrhythmia, two side effects associated with beta-agonists in rare situations,” Dr. Kenyon said. “While patients who received continuous aerosolized albuterol had a higher rate of transfers to the ICU, there was no difference in the rate of intubation. Zero patients in the continuous aerosolized albuterol group were intubated. These findings support the safety – and efficacy – of continuous aerosolized albuterol delivery in the non-ICU setting.”

The researchers also determined that certain factors identified initially in the emergency room predicted which patients would go on to deteriorate clinically and require prolonged therapy. These included comorbid pneumonia and administration of intravenous magnesium or subcutaneous terbutaline in the emergency room. Being acquainted with these characteristics may help clinicians in hospitals without a pediatric intensive care unit (PICU) in terms of recognition of patients at higher risk for clinical deterioration who may benefit from relocation to an institution that does have a PICU, Dr. Kenyon said.

While this retrospective study sets the stage for other hospitals to evaluate how CAA could fit within the context of their asthma protocols, Dr. Kenyon emphasized that CHOP’s success in CAA delivery outside the ICU is, at least in part, due to the support structure and care processes in place. For example, in addition to the standard nurse to patient ratio of 1 to 4 and robust expert respiratory therapy support, a critical assessment team assists front-line providers in the care of patients with severe asthma who have early signs of clinical deterioration.

“This is a first step,” Dr. Kenyon said. “There is still work to be done to figure out who the ideal cohort is for continuous therapy and what resources are necessary to make this practice safe and effective in a non-ICU setting outside of CHOP. But this study provides initial evidence for the safety and effectiveness for institutions that already are providing continuous aerosolized albuterol on their non-ICU units.”

Future studies could aim to reproduce a similar study on a multicenter level, Dr. Kenyon suggested. Researchers could perform further analysis of the data to reveal any potential cost savings that may be associated with centering CAA delivery for severe asthma cases outside the ICU. More evidence also is needed to determine the appropriate length of CAA administration, and if other modes of therapy could help to enhance patients’ recovery so that they spend less time in the hospital.

Permanent link to this article: http://www.research.chop.edu/blog/safety-severe-asthma-care-outside-icu-assessed/

Sep 29 2014

Antibiotic Use in Infancy May Play Role in Obesity

obesityWhile it is easy to blame the childhood obesity epidemic on too many french fries and video games, it is likely that multiple factors such as genetics and environment also contribute to excessive weight gain. A retrospective study based on data from The Children’s Hospital of Philadelphia’s electronic health records identified another significant risk factor that may influence how tendencies toward obesity develop during infancy.

Childhood obesity has more than doubled in children over the past 30 years, according to the Centers for Disease Control and Prevention. Many will remain obese into adulthood and be susceptible to heart disease, type 2 diabetes, stroke, several types of cancer, and osteoarthritis. Medical researchers at CHOP want to identify ways to intervene as early as possible, in order to avert the lifetime of medical, developmental, and social problems associated with obesity.

They were intrigued by the emerging idea that the microbial population that begins to colonize in infants’ intestines shortly after birth, known as the microbiome, plays an important role in establishing energy metabolism. Previous studies have shown that antibiotic exposure influences the microbiome’s diversity and composition.

“As pediatricians, we’re interested in whether there is anything happening early in life that resets this ‘thermostat’ and has a long-term effect on how your body regulates its weight,” said L. Charles Bailey, MD, PhD, lead author of the study that appeared online Sept. 29 in JAMA Pediatrics. “The thought is that the microbiome may be critically dependent on what is going on during infancy.”

Dr. Bailey and colleagues observed an increased risk of obesity with greater antibiotic use, particularly for children with four or more exposures to broad-spectrum antibiotics in early childhood. The study team analyzed electronic health records from 2001 to 2013 of 64,580 children with annual visits at ages 0 to 23 months, as well as one or more visits at ages 24 to 59 months within the network of primary care practices affiliated with CHOP. They assessed the relationships between antibiotic prescription and related diagnoses before age 24 months and the development of obesity in the following three years.

“What this study is showing is that we can detect a connection between the antibiotics that you may have received as an infant and what your weight is going to look like later in childhood,” Dr. Bailey said, adding that it is important to note that the study does not directly examine cause and effect.

obesityThe investigators saw the association with broad-spectrum drugs, but they reported no significant association between obesity and narrow-spectrum drugs. For this study, they classified first-line therapy for common pediatric infections, such as penicillin and amoxicillin, as narrow-spectrum. They considered broad-spectrum antibiotics to include those recommended in current guidelines as second-line therapy.

“What we think we’re seeing here with these associations is that the more we choose to use narrow-spectrum antibiotics, the less likely it may be that we’re doing something that will affect a patient’s risk of obesity later on,” Dr. Bailey said.

One of the study’s advantages is that the researchers capitalized on CHOP’s wealth of information captured during regular medical care for a large group of patients without compromising individuals’ privacy. While the study did not assess children’s activity levels, dietary habits, family structure, or socioeconomics, the researchers’ conclusions were similar to those from a previous study that evaluated those factors and also found a connection between antibiotics in early childhood and higher risk of obesity.

Future investigations are needed involving multiple large pediatric health systems that will take a broader look at several populations and how adopting guidelines that accentuate the use of narrow-spectrum antibiotics might affect patients’ risk of obesity, Dr. Bailey said.  In addition to supporting this type of research locally, CHOP is also a key contributor to networks such as PEDSnet that link many children’s hospitals to make more effective clinical research possible.

Researchers also are looking at ways the microbial communities living in infants’ intestines are swayed by dietary and environmental factors. The Children’s Hospital of Philadelphia’s Healthy Weight Program has a study underway that is following the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain. As part of the study, they will track any babies who are prescribed antibiotics, in order to identify fluctuations in their microbial profiles.

Such research projects will add up to help give clinicians practical guidance on how to address the complexities of obesity.

“Treating obesity is going to be a matter of finding the collection of things that together have a major effect, even though each alone has only a small effect,” Dr. Bailey said. “Part of what we are exploring in this study is one of those factors that we can possibly modify in the way we take care of kids and make it better.”

Christopher Forrest, MD, PhD; Peixin Zhang, PhD; Thomas M. Richards, MS; Alice Livshits, BS; and Patricia DeRusso, MD, MS, contributed to the article published in JAMA Pediatrics. The American Beverage Foundation for a Healthy America provided an unrestricted donation to support this Healthy Weight Program research study.

Permanent link to this article: http://www.research.chop.edu/blog/antibiotic-use-infancy-may-play-role-obesity/

Sep 26 2014

Basic Research Invests in Our Future

We just had to share this great video explaining how supporting basic research can lead to unforeseen breakthroughs in the future. Winner of the second annual Federation of American Societies for Experimental Biology (FASEB) “Stand up for Science” competition, the video was produced by a group of young Bay Area researchers, and is a call to support basic research funding.

“Basic research is an investment in our future. It broadens our understanding of the world we live, and the potential benefits are limitless,” the video states.

While the NIH’s funding may seem impressive—in the 2015 budget the agency is allotted $30.2 billion, a slight increase over 2014—that number is somewhat misleading. Adjusted for inflation, the 2015 budget would be $100 million lower than the 2002 funding level for the NIH. Therefore messages like the one in this video, which does a great job of explaining why scientific research needs your support, are more important than ever. Enjoy!

Permanent link to this article: http://www.research.chop.edu/blog/basic-research-invests-future/

Sep 24 2014

Investigators Take Clinical Look at Teen Driver Safety

teen driver safetyCrashes remain the leading cause of young adult death (ages 16 to 24) with four times the number of deaths from cancer and 38 times the number of deaths from the flu. In fact, a teen’s highest lifetime risk of crashing occurs immediately following the learner phase when beginning to drive without adult supervision.

A team of researchers at The Children’s Hospital of Philadelphia Research Institute’s Center for Injury Research and Prevention (CIRP), led by Flaura Koplin Winston, MD, PhD, is taking a new tactic by addressing novice drivers’ performance and risk management from a clinical standpoint.

“As a primary care pediatrician at Karabots, I see my role as helping families to anticipate and manage health issues and ensure their children can realize their full potential,” said Dr. Winston, scientific director and founder of CIRP. “When my research showed that motor vehicle crashes accounted for one-third of all teen deaths, I looked for protocols to include driving management in my practice, but I couldn’t find them. I could not even find a valid way to assess driving performance and risk.

“This is when I knew that CHOP could take a lead on bringing our science to bear in evidence-based, evaluated ways to help families manage this exciting but dangerous phase of an adolescent’s life,” Dr. Winston continued. “Each teen approaches the driving task with assets as well as challenges, and once we figure out what they are, then we can put into place a personalized care management plan.  Driving has a relatively small margin for error, and I want to do what I can to ensure that adolescents safely navigate the transition from childhood to adulthood — from the car seat to the driver’s seat.”

CIRP experts have spent many hours dissecting the factors behind why teens crash and what skills new drivers are missing. They compiled research and evidence-based practice about the major constructs around safe driving behavior. Team members also mined a massive database called the National Motor Vehicle Crash Causation Survey, and they identified the most common crash scenarios involving teen drivers.

teen driver safety

“Each teen approaches the driving task with assets as well as challenges, and once we figure out what they are, then we can put into place a personalized care management plan.” – Dr. Flaura Koplin Winston

Their work has led to the innovative concept of developing a systematic method for diagnosing driving skill level as a crucial step in personalized driving management plans. The first phase of their work is nearly complete: The team has built and validated an initial version of a Simulated Driving Assessment (SDA) tool that uses a high fidelity driving simulator located at CIRP to achieve realistic reproductions of driving experiences and conditions.

Study participants are exposed to a series of “drives” that involve variations of three main crash scenarios during a 35- to 40-minute session. The researchers collect and analyze data on numerous aspects of the drivers’ performance — from steering and braking reaction times to eye movement and headway time — and can produce an automated report.

“Some teens may have trouble with attention; some may have trouble with hand-eye coordination; some may not have the cognitive skills needed to drive safely; and due to inexperience, most have skill deficits,” Dr. Winston said. “By diagnosing driving, we want to tease out what driving deficits a teen might have before he or she crashes.”

Having a mechanism in place that gives clinicians and parents a better sense of whether or not teens are ready for independent driving is especially important in states like Pennsylvania that have laws requiring physicians to medically certify that a patient is fit to drive. If a teen has some type of medical condition that could impair his or her ability to safely operate a motor vehicle, physicians are mandated to report it to the Pennsylvania Department of Transportation.

As the CIRP team gains more experience at determining which teens could benefit the most from the SDA, Dr. Winston’s future dream is to establish a driving clinic at CHOP. Physicians could refer patients to the clinic for screening, and based on the driving diagnosis, young drivers would receive recommendations or training to help improve their performance on the road. Already, the CIRP team has published findings that show novice drivers benefit from web-based training programs that expand the diversity of the teens’ driving practice.

“CHOP is at the forefront of teen driver safety research, and it is an amazing place to take these leaps because of our interdisciplinary nature,” Dr. Winston said. “Generous funding from the Pennsylvania Department of Health allowed us to get the driving simulator and put us in a unique position to address the leading cause of death for teens.”

The CIRP team is encouraged by interest from other potential partners who support this urgently needed line of research and are looking for sponsorship to making a driving clinic at CHOP a reality.

Permanent link to this article: http://www.research.chop.edu/blog/investigators-take-clinical-look-teen-driver-safety/

Sep 22 2014

Healthy Weight Program Launches Study on Microbiome

microbiomeTrillions of naturally occurring bacteria and other microbes coexist in the human gut and are part of how we process food and harness energy. Known as the microbiome, this complex collection’s potential role in early weight gain and obesity has become a fascinating area of scientific exploration.

Approximately 10 percent of children in the U.S. are already obese by age 2. These rates are especially concerning because research suggests that infants with rapid growth during the first two years of life may be more likely to be obese later in childhood and into adulthood. Excessive weight gain in childhood is associated with elevated blood pressure, musculoskeletal complaints, and asthma.

An interdisciplinary study team from The Children’s Hospital of Philadelphia and University of Pennsylvania has begun an observational cohort study that will focus on the role of the gut microbiome in the development of obesity early in life. It is a unique research opportunity because babies are born with close to sterile conditions, but they are quickly colonized with the microbes that they are exposed to in their environment.

“We are enrolling moms during their third trimester and trying to characterize their vaginal and gut microbiota, look at the transmission to infants, and follow the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain,” said Babette S. Zemel, PhD, principal investigator of the Infant Growth and Microbiome (I-gram) study. “We are focusing on low-income African American families because they have the highest rates of obesity in adulthood in the U.S. We want to try to tackle this problem early if we can.”

Not only will the researchers consider the microbiome in this long-term study, but they also will have the opportunity to simultaneously investigate a number of other risk factors associated with obesity. For example, epidemiological evidence suggests that children born by cesarean section have higher rates of obesity than those who are born vaginally. This points to the hypothesis that infants who miss out on early transmission of maternal microbiota could be more susceptible to excess weight gain in childhood.

In a subset of babies, the researchers plan to observe how rapidly the infants’ microbial communities cultivate. For another subset, they intend to track any babies who are prescribed antibiotics, in order to identify fluctuations in the microbial profiles after the infants receive the medications and to see how quickly the microbes are restored.

“Fluctuations in microbial profiles could support a mechanism for the association between antibiotics and early obesity,” said Patricia DeRusso, MD, MS, director of the Healthy Weight Program at The Children’s Hospital of Philadelphia.

An additional focus of the I-gram study will be to examine the role of multiple feeding-related factors including breastfeeding, formula feeding, sucking behavior, feeding patterns, and timing of introduction of solid foods.

Looking at the potential interaction of these novel mechanisms will help to create a detailed description of what happens in the first year of life among infants born to 300 normal weight vs. obese African American, predominantly low-income mothers. The moms will give birth at the University of Pennsylvania where study collaborators will collect samples at the time of delivery. Next, infant growth experts at CHOP will measure the infants and follow their development carefully over the next 12 months. They will use a machine called a Pea Pod to periodically measure the infants’ body composition — the amount of fat and lean tissue in the body.

“The long-term implication of this study is that if we can identify early predictors of weight gain during infancy, it is an ideal opportunity to intervene in some way,” Dr. Zemel said.

Interest in the microbiome has flourished as better tools have emerged that allow scientists to analyze the microbes’ DNA and their metabolic byproducts, which are an essential part of our digestive system. Intriguing research suggests that people who are obese have a different profile of microbiota than people who are not obese. Dr. Zemel pointed out that findings from a study of twins, in which one twin was obese and the other was not, demonstrated that a fecal microbiota transplant from the obese twin into germfree mice resulted in weight gain for the rodents.

“This adds to the evidence that there is some causal link between the gut microbiome and the development of obesity,” Dr. Zemel said.

The I-gram study is one of 10 research projects in the portfolio of CHOP’s Healthy Weight Program that aim to advance understanding of the root causes of obesity and effective models for prevention and treatment, focused on early childhood intervention.  Funding was provided by an unrestricted donation from the American Beverage Foundation for a Healthy America to The Children’s Hospital of Philadelphia to support the Healthy Weight Program.

“Obesity prevention is a signature area of our research,” said Gurpreet Kalra, MS, CCRP, research program manager for the Healthy Weight Program. “Our agenda is informed by the latest Institute of Medicine’s guidelines that stressed the lack of research on obesity prevention in very young children. Identification of novel, modifiable risk factors, which is the focus of the I-gram study, is key to obesity prevention.”

The portfolio has a comprehensive focus because obesity is a complex, multifactorial disease and uses a variety of electronic health records, social media, and community partnered strategies to conduct the research.

“We are committed to long-term studies that can more conclusively prove causality and test the effectiveness of interventions,” Gurpreet said.

Most of the studies involve children and families from neighboring high-risk populations and communities where obesity rates are among the highest in the city. The multidisciplinary investigative team includes experts in anthropology, pediatric and adult gastroenterology, endocrinology, psychology, psychiatry, obstetrics and gynecology, microbiology, genetics, public health, and biostatistics.

Permanent link to this article: http://www.research.chop.edu/blog/healthy-weight-program-launches-study-microbiome/

Sep 19 2014

Gene Mutation Helps Explain How Our Body Clock is Set

sleepMost of us have failed to get enough sleep on a few occasions. Maybe it was as a college student studying for final exams, or as a new parent consoling an infant who is teething. Remember how you dragged through the next day in a bad mood and unable to focus?

Yet, a few people who are considered to be natural “short sleepers” seem to function well under the same sleep-deprived circumstances. Researchers at The Children’s Hospital of Philadelphia are investigating why some of us seem to need more sleep than others.

In a study published in the August issue of SLEEP, the study team described a new gene variant associated with short sleep and resistance to sleep deprivation in humans. Their findings support the hypothesis that genes related to circadian rhythms, in particular DEC2, can affect not only the timing of sleep, but also the magnitude of sleep homeostasis and sleep architecture.

Circadian rhythms control the biological clocks in our bodies. Homeostasis includes both short-term and long-term measures that the body uses to control and maintain an optimal internal environment.

“We found DEC2 is not only a circadian gene, but it is also related to homeostasis,” said Renata Pellegrino, PhD, senior research associate in the Center for Applied Genomics at The Children’s Hospital of Philadelphia, who collaborated on the study with an international study team. “That is why we are so excited. This gene could explain sleep length and how we respond to sleep deprivation, or why some of us sleep for a certain number of hours a night and others don’t.”

The researchers sequenced circadian clock genes in a cohort of healthy young adult twin pairs with no chronic conditions. Out of 200 twins, they identified a DEC2 mutation in one sibling who during baseline testing slept an average of five hours per night — more than an hour shorter than his twin brother who did not carry the gene.

The study team performed a series of cognitive performance tests to see how attentive each brother was after spending 38 hours without sleep in the sleep lab. The twin with the gene mutation performed better on psychomotor vigilance compared to his brother.

During unrestricted recovery sleep for one night following the 38 hours without sleep, the twins underwent electroencephalography that showed their brains’ electroactivity throughout the major sleep phases — Stages 1, 2, 3, 4 and REM. Stage 3 is characterized by Delta waves, which are high amplitude brain waves associated with deep, restful sleep. Stage 3 sleep also is related to maintaining homeostasis after sleep deprivation or wakefulness. The twin with the DEC2 mutation made more Delta waves and stayed in Stage 3 sleep longer than his brother.

The researchers went a step further to investigate how the DEC2 mutation interacted with other circadian clock genes. They discovered that the variant appears to alter the molecular mechanisms that set the duration of sleep that individuals need.

In the future, Dr. Pellegrino and her colleagues plan to form collaborations with researchers in other countries to see how common this variant is in other populations. They also would like to discover how the genes not only affect the brain, but also other body systems.

“True short sleepers in general are very resistant to sleep deprivation,” Dr. Pellegrino said. “They are very motivated and ready to go, so maybe the mutation protects you cognitively. But is there a price for that? We still don’t know the other metabolic effects.”

The study involved a collaboration among researchers from The Children’s Hospital of Philadelphia; the University of Pennsylvania School of Medicine; the Philadelphia Veterans Affairs Medical Center; Washington State University; Universidade Federal de Sao Paulo, Brazil; and Koc University, Istanbul, Turkey. The research was supported in part by grants from the National Heart, Lung, and Blood Institute, and the Institutional Development Fund from the Center for Applied Genomics at CHOP.

Permanent link to this article: http://www.research.chop.edu/blog/gene-mutation-helps-explain-body-clock-set/

Sep 17 2014

Get Involved to Make Medical Research a National Priority

medical researchIt’s your turn to give a shout-out for scientific discovery. The Rally for Medical Research Capitol Hill Day Thursday, Sept. 18, brings together almost 300 national organizations, including The Children’s Hospital of Philadelphia, in support of making funding for the National Institutes of Health (NIH) a national priority.

Programs like those at The Children’s Hospital of Philadelphia Research Institute need a reliable stream of revenue in order to conduct the long-term scientific projects that ultimately produce breakthrough treatments and cures for diseases.

Since 2003, the NIH budget has declined by more than 22 percent, or $6.1 billion, after adjusting for inflation, according to the Association of American Medical Colleges (AAMC), a rally day sponsor. The AAMC developed a set of advocacy materials to help the medical and research communities to urge Congress to pass the FY 2015 Labor, Health and Human Services, Education, and Related Agencies (Labor-HHS) spending bill and restore funding to NIH cut by sequestration in 2013. A draft of the bill provides $30.5 billion for NIH, a $606 million (2 percent) increase over FY 2014.

What can you do? Send a letter to members of Congress through the AAMC’s legislative action center telling you representatives that NIH is critical to the advancement of science and improving the health of people around the world. You can add a personal message about your research experience, what you hope to accomplish, or what inspires your research career.

Share tweets and posts encouraging your fellow scientists, medical trainees, graduate students/post docs to call Congress to action. Here’s an example:

Federal funding for medical research is the way we protect our nation’s health. Act now: http://owl.li/BeHF9 #FinishtheJob

Support the AAMC’s Thunderclap campaign, which is a “crowdspeaking platform” that will post a message Thursday to the social media accounts of participants asking their friends and followers to also send a letter to Congress to pass the Labor-HHS bill. The AAMC hopes to generate thousands of letters in support of the federal investment in medical research. Get involved: The louder the thunder, the greater the impact.

Permanent link to this article: http://www.research.chop.edu/blog/get-involved-make-medical-research-national-priority/

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