Oct 22 2014

Investigators Study Orexins’ Role in Resilience to Stress

orexinChronic stress, whether it is from illness, interpersonal relationships, or other social stressors, can have a significant influence on the brain and body. Yet, only some individuals develop illness in response to chronic stress, such as anxiety, depression, and post-traumatic stress disorder (PTSD).

Why do some of us get stressed out while others seem to roll with life’s punches? That is the big question in the field of stress neurobiology, and to get closer to the answer, researchers at The Children’s Hospital of Philadelphia are exploring peptides called orexins as potential mediators of resilience or vulnerability to the effects of stress.

“If we could understand better the brain mechanisms that lead to vulnerability to stress, then we could either prevent the effects of stress from happening or help treat individuals who are sick and even try to identify them before they get sick,” said Seema Bhatnagar, PhD, an associate professor in the CHOP Research Institute’s Division of Stress Neurobiology.

Scientists first described orexins about 17 years ago and found that these neurochemicals are important for arousal, sleep, vigilance, and feeding. Orexins are made in the hypothalamus, but they have widespread projections to other areas of the brain. Growing evidence suggests that orexins play a role in people’s ability to be alert and respond to stressful stimulus.

In a new research project recently funded by The National Institute of Mental Health, Dr. Bhatnagar’s study team will use a model of repeated social defeat in young adult male rats in which two distinct subpopulations emerge with different coping strategies. When exposed for a week to a larger, more aggressive rat that is territorial, some animals that show anxiety and depressive-type behaviors will give up quickly and assume a defeat posture. Others are more active in resisting the defeat and appear more resilient. Based on the researchers’ preliminary data, it appears that the resilient population exhibits lower orexin expression.

“If we’re correct that orexins are important in vulnerability and resilience, you could imagine developing drugs that inhibit orexin release could be used in a situation of chronic stress or trauma to decrease arousal and maybe prevent the effects of stress from happening,” Dr. Bhatnagar said.

The study team will use an emerging technology called DREADDs (designer receptors exclusively activated or inhibited by designer drugs) to modulate orexin release. These viral vectors have mutated receptors that are either stimulatory or inhibitory, and they are injected into the brain where they enter orexin cells. The researchers can target the viral vectors through a drug administered peripherally to stimulate or inhibit the population of orexin cells. They will observe if this shifts the animals’ phenotype during periods of stress. Can vulnerable animals become more resilient and vice versa? In other experiments, the investigators also will look at which key brain regions are facilitating the effects that they are seeing in the resilient and vulnerable animals.

While many other neurochemicals are being studied for their potential role in mediating stress resilience or vulnerability, the CHOP researchers’ exploratory research is novel because it is the first to center on orexins. The early data they gathered on orexins came from a study supported by the Defense Advanced Research Projects Agency, which focused on preclinical studies examining neural substrates of arousal and on clinical studies with military service members with PTSD through collaborations with the Philadelphia VA Medical Center. Dr. Bhatnagar also is a co-primary investigator of National Institutes of Health-funded study on adolescent stress that eventually could provide insights into the specific involvement of orexins.

“There’s very clear literature that stress in early life has long-lasting impact for producing depression and anxiety,” Dr. Bhatnagar said. “We don’t know if the orexin system is important in mediating resilience or vulnerability to early life stress as it develops across the lifespan. We hope to gather enough data to expand our research to look at the pediatric and adolescent periods.”

Permanent link to this article: http://www.research.chop.edu/blog/investigators-study-orexins-role-resilience-stress/

Oct 20 2014

T-Cell Therapy Leads to Remission in 90 Percent of Leukemia Patients

leukemia

90 percent of leukemia patients treated with a groundbreaking form of cellular therapy achieved complete responses.

A landmark new study published in the New England Journal of Medicine shows that 90 percent of leukemia patients treated with a groundbreaking form of cellular therapy achieved complete responses.

Led by The Children’s Hospital of Philadelphia’s Stephan M. Grupp, MD, PhD, the study is the latest to validate Dr. Grupp and colleagues’ work with CTL019 therapy, in which patients’ immune cells are engineered to multiply and fight against acute lymphoblastic leukemia (ALL) and other B cell cancers. The cells are designed to proliferate in patients’ bodies, continuing to fight and protect against cancer. Children’s Hospital’s Shannon Maude, MD, PhD, and the University of Pennsylvania’s Noelle Frey, MD, were the study’s co-first authors.

The most common form of leukemia found in children, ALL is largely curable, with a roughly 85 percent cure rate. However, the remaining 15 percent of ALL cases resist standard therapy. In conjunction with the University of Pennsylvania’s Carl H. June, MD, last year Dr. Grupp reported the results of early work that showed the promise of their immune therapy approach. In that study, also published in the New England Journal of Medicine, they showed two children with acute lymphoblastic leukemia achieved a complete response after being treated with an innovative cell therapy.

One of those patients was then 7-year-old Emily Whitehead, who was the subject of a media frenzy when the experimental therapy led to her dramatic recovery after she relapsed following conventional treatment. Since receiving the CTL019 therapy, Emily remains healthy and cancer-free.

In the recent New England Journal of Medicine paper, 30 children and adults were treated at Children’s Hospital and UPenn with CTL019 therapy. Of those, 27 patients — 90 percent — experienced complete remissions, or a complete lack of detectable disease. Sustained remissions were seen in 67 percent of patients, and CTL019 cell proliferation was seen in 68 percent of patients.

Aside from the high percentage of complete remissions seen, the study’s findings are remarkable because many of the patients who took part had already experienced relapses or had treatment-refractory acute lymphoblastic leukemia. “Relapsed ALL is a considerable therapeutic challenge, particularly in patients who do not have a second complete remission or have a relapse after stem-cell transplantation,” the authors note. According to the study, of the 27 patients who had complete remissions, 19 remained in remission, some for as long as two years.

Advocacy organizations were quick to praise the CHOP-Penn team’s work. The Leukemia & Lymphoma Society (LLS), which has funded Dr. Grupp since 1992, called the work an “important advance.”

“This study comes almost exactly 70 years after Robert Roesler de Villiers, the son of the founders of LLS, died from ALL,” said the Leukemia & Lymphoma Society’s Louis J. DeGennaro, PhD. “At the time, the chance of surviving ALL was less than five percent of patients. Today nearly 90 percent of pediatric patients with ALL survive more than five years, and the findings announced today suggest that we may see even more patients surviving this blood cancer.”

“The patients who participated in these trials had relapsed as many as four times, including 60 percent whose cancers came back even after stem cell transplants,” said Dr. Grupp. “The durable responses we have observed with CTL019 therapy are unprecedented.”

To read more about CTL019 therapy, see The Children’s Hospital of Philadelphia’s page about the trial.

 

Permanent link to this article: http://www.research.chop.edu/blog/hope-springs-t-cell-therapy-leads-remission-90-percent-leukemia-patients/

Oct 17 2014

Intervention Aims to Promote Effective Practice for ADHD

ADHDApproximately 7,800 children with attention-deficit/hyperactivity disorder (ADHD) visit primary care practices across The Children’s Hospital of Philadelphia Care Network. Treating such a large patient population that is coping with a multifaceted, chronic condition can be demanding for busy primary care physicians (PCPs). That is why a study team at CHOP is launching an outcomes improvement project in the fall to promote PCPs’ use of clinical practice guidelines for managing ADHD consistently and efficiently.

ADHD is the most common neurobehavioral disorder among children, occurring in about 8 percent of youth. Yet each child experiences symptoms of inattention, impulsivity, and hyperactivity differently, so delivering treatment that is responsive to individuals’ specific needs, goals, and family preferences can be time-consuming and complex.

The major features of treatment for children with ADHD include parental support and education in behavioral training, appropriate school placement, and medication. Subsequently, the ADHD care team goes beyond the pediatrician office’s walls and extends to families, teachers, guidance counselors, coaches, social workers, and other healthcare providers including psychologists, psychiatrists, and neurologists.

“ADHD is somewhat more difficult to manage than some other conditions in the sense that many of the problems show up at school and home, so it takes care coordination across different settings,” said Alexander G. Fiks, MD, MSCE, associate medical director of the Pediatric Research Consortium (PeRC), and associate director for Outpatient Research Activities, Center for Pediatric Clinical Effectiveness (CPCE) at CHOP. “It is hard to keep engaged with multiple healthcare providers, schools, and families and easily exchange information.”

For children who are prescribed medications for ADHD, Dr. Fiks added, it may take a few months to achieve optimal success, and the guidelines recommend that medication efficacy should be systematically monitored at regular intervals. It can be cumbersome to schedule and accomplish those follow-ups from an organizational standpoint.

Even with these challenges, keeping ADHD management on track is crucial, said Dr. Fiks, who is also an Assistant Professor of Pediatrics at the University of Pennsylvania, because early detection and intervention can reduce the severity of symptoms, decrease the interference with school functioning, enhance the child’ self-esteem and social relationships, and improve the quality of life experienced by children or adolescents with ADHD and their families.

The study team’s project aims to give PCPs the tools they need to initiate and sustain appropriate treatments and achieve successful long-term outcomes. In preparation for the project, a set of practice supports will be built into a web-based portal linked to CHOP’s electronic health record to promote shared decision-making. Practitioners also will be offered the option of obtaining American Board of Pediatrics Maintence of Certification Part IV credit through their participation.

Overall, the intervention will include an integrated approach featuring:

  • education about ADHD management
  • communication training
  • collaborative consultation
  • performance feedback.

The investigators will conduct a randomized controlled clinical trial to evaluate the effectiveness of the intervention over eight months to increase the use of evidence-based practices among PCPs for children with ADHD. They will contact providers in CHOP’s 31 primary care practices to inform them of the study, which focuses on patients in the age range from 5 to 12 years.

Providers in the control group will be given brief education about how to use the portal, while the experimental group will receive detailed guidance about the portal along with the multiple components of the integrated approach. The study team already has formed an advisory board that consists of parents, clinicians, and teachers from throughout the communities that CHOP’s Care Network serves.

“We predict that if clinicians have more knowledge and backup support, then they will feel more confident in the recommendations that they have for families,” Dr. Fiks said. “Introducing the EHR technology as a way to facilitate information exchange also will make ongoing communication easier. And by giving feedback, clinicians will see their strengths and weaknesses, in order to help improve the care that they deliver.”

The project is a collaborative effort that taps the talents of several CHOP experts including co-principal investigator Thomas J. Power, PhD, director of the Center for Management of ADHD; co-investigator Nathan J. Blum, MD, acting associate chief of the Division of Child Development, Rehabilitation Medicine and Metabolic Disease and professor of Pediatrics at the Pereleman School of Medicine at the University of Pennsylvania; co-investigator James Guevara, MD, MPH, attending physician and associate professor of Pediatrics at Penn; collaborator Robert Grundmeier, MD, attending physician; and other team members from the Center for Biomedical Informatics, PolicyLab, CPCE, and PERC. It is funded by an unrestricted, independent research grant from Pfizer.Approximately 7,800 children with attention-deficit/hyperactivity disorder (ADHD) visit primary care practices across The Children’s Hospital of Philadelphia Care Network. Treating such a large patient population that is coping with a multifaceted, chronic condition can be demanding for busy primary care physicians (PCPs). That is why a study team at CHOP is launching an outcomes improvement project in the fall to promote PCPs’ use of clinical practice guidelines for managing ADHD consistently and efficiently.

ADHD is the most common neurobehavioral disorder among children, occurring in about 8 percent of youth. Yet each child experiences symptoms of inattention, impulsivity, and hyperactivity differently, so delivering treatment that is responsive to individuals’ specific needs, goals, and family preferences can be time-consuming and complex.

The major features of treatment for children with ADHD include parental support and education in behavioral training, appropriate school placement, and medication. Subsequently, the ADHD care team goes beyond the pediatrician office’s walls and extends to families, teachers, guidance counselors, coaches, social workers, and other healthcare providers including psychologists, psychiatrists, and neurologists.

“ADHD is somewhat more difficult to manage than some other conditions in the sense that many of the problems show up at school and home, so it takes care coordination across different settings,” said Alexander G. Fiks, MD, MSCE, associate medical director of the Pediatric Research Consortium (PeRC), and associate director for Outpatient Research Activities, Center for Pediatric Clinical Effectiveness (CPCE) at CHOP. “It is hard to keep engaged with multiple healthcare providers, schools, and families and easily exchange information.”

For children who are prescribed medications for ADHD, Dr. Fiks added, it may take a few months to achieve optimal success, and the guidelines recommend that medication efficacy should be systematically monitored at regular intervals. It can be cumbersome to schedule and accomplish those follow-ups from an organizational standpoint.

Even with these challenges, keeping ADHD management on track is crucial, Dr. Fiks said, because early detection and intervention can reduce the severity of symptoms, decrease the interference with school functioning, enhance the child’ self-esteem and social relationships, and improve the quality of life experienced by children or adolescents with ADHD and their families.

The study team’s project aims to give PCPs the tools they need to initiate and sustain appropriate treatments and achieve successful long-term outcomes. In preparation for the project, a set of practice supports will be built into a web-based portal linked to CHOP’s electronic health record to promote shared decision-making. Practitioners also will be offered the option of obtaining American Board of Pediatrics Maintence of Certification Part IV credit through their participation.

Overall, the intervention will include an integrated approach featuring:

  • education about ADHD management
  • communication training
  • collaborative consultation
  • performance feedback.

The investigators will conduct a randomized controlled clinical trial to evaluate the effectiveness of the intervention over eight months to increase the use of evidence-based practices among PCPs for children with ADHD. They will contact providers in CHOP’s 31 primary care practices to inform them of the study, which focuses on patients in the age range from 5 to 12 years.

Providers in the control group will be given brief education about how to use the portal, while the experimental group will receive detailed guidance about the portal along with the multiple components of the integrated approach. The study team already has formed an advisory board that consists of parents, clinicians, and teachers from throughout the communities that CHOP’s Care Network serves.

“We predict that if clinicians have more knowledge and backup support, then they will feel more confident in the recommendations that they have for families,” Dr. Fiks said. “Introducing the EHR technology as a way to facilitate information exchange also will make ongoing communication easier. And by giving feedback, clinicians will see their strengths and weaknesses, in order to help improve the care that they deliver.”

The project is a collaborative effort that taps the talents of several CHOP experts including co-principal investigator Thomas J. Power, PhD, director of the Center for Management of ADHD; co-investigator Nathan J. Blum, MD, acting associate chief of the Division of Child Development, Rehabilitation Medicine and Metabolic Disease; co-investigator James Guevara, MD, MPH, attending physician; collaborator Robert Grundmeier, MD, attending physician; and other team members from the Center for Biomedical Informatics, PolicyLab, CPCE, and PERC. It is funded by an unrestricted, independent research grant from Pfizer.

Permanent link to this article: http://www.research.chop.edu/blog/intervention-aims-promote-effective-practice-adhd/

Oct 15 2014

Simulated Driving Assessment Fuels Teen Driver Research

simulated drivingDrivers who turn the key of the driving simulator at The Children’s Hospital of Philadelphia Research Institute’s Center for Injury Research and Prevention (CIRP) quickly become immersed. Small details like active steering and brakes, an actual vehicle instrument panel and seat, the change in the cup holder, and a working radio with knobs create an authentic feel of being on the road. Pushing the gas pedal sets dynamic traffic situations in motion on the three high-fidelity screens. What a driving experience!

Helen Loeb, PhD, a biomechanical research engineer at CIRP, joined the research team one year ago and has the led the effort refining the programming that displays dynamic, realistic traffic scenarios and collects research and clinical grade data. The simulator offers the CIRP@CHOP team an opportunity to safely and reproducibly place drivers in situations that are the most challenging for teen drivers to negotiate — a major advance over relying solely on road tests. Weather, time of day, road friction, and traffic density are also programmed into the simulations, providing a wide variety of driving conditions to efficiently collect a broad representation of a teen’s real-world driving behaviors during a single drive.

simulated driving“If you’re on the road showing your kid how to drive, hazards appear just by chance,” Dr. Loeb said. “Here, we can create difficult traffic situations and expose teens to them in a safe environment.”

A CIRP team, led by Drs. Flaura Winston and Catherine McDonald, dedicated to teen driver safety research  is utilizing the driving simulator in a unique way to create a clinical-grade assessment of teens’ driving deficits with respect to skill and safety. The process of designing the Simulated Driving Assessment (SDA) tool began four years ago with funding from a Pennsylvania Department of Health grant. Two years ago, research statistician Venk Kandadai, MPH, became the project manager.

“When you think of an assessment for asthma, you have spirometry,” Kandadai said. “For cardiovascular disease, clinicians use electrocardiograms and stress tests. What we’ve built is a generalizable assessment that can essentially diagnose poor driving performance that is directly linked to the most serious crash scenarios for teens.”

Dr. Loeb has created a toolkit called DriveLab along with the SDA that reduces the immense amount of simulation and video data collected from participant drivers to produce easy-to-interpret results. Every action by the driver is recorded by the computer software in tandem with a portable eye-tracking system and a digital video that captures the driving scene, the participant’s hands on the wheel, and feet.

One of the studies conducted to validate the SDA as a research tool involved 21 teens ages 16 and 17 who had been licensed drivers for fewer than three months and 17 experienced adults 25 to 50 years of age who had been driving for at least five years with no history of police-reported crashes. They participated in 35- to 40-minute sessions of simulated driving. The study team compared the teens’ performance to experienced adult drivers who underwent the same simulations.

The SDA replicates the three most prevalent crash types among young drivers ages 16 to 19: crashing while turning left at an intersection, rear-ending a lead vehicle, and running off the right side of the road. Driving scenarios are set up in such a way that a collision will only occur when a driver makes a critical error.

“Typically, what we found is that teens tend to drive faster and follow the lead vehicle more closely than adults,” Dr. Loeb said. “I also found it fascinating that a number of teens didn’t brake as hard as adults in emergency situations. Some teens even missed the brake pedal or actually accelerated instead of braking. It seems like they panic for an instant and lose precious time. On the road, this is what makes the difference between a near miss and a bad crash. ”

Dr. Loeb, Kandadai, Dr. McDonald,  Dr. Winston and their colleagues Thomas Seacrist, MBE, Yi-Ching Lee, PhD (Simulator Program director), and Dana Bonfiglio (Simulator Program coordinator) performed statistical analyses and processed each driver’s data so that it all boiled down to a set of scores ranging from 0 to 117 errors. More errors were directly related to simulated crashes. A professional driving evaluator also independently reviewed videos of the driving simulator sessions, and his scores supported the SDA’s findings, which encouraged the research team.

CIRP’s SDA team is currently constructing an automated report card of a number of driving metrics to provide direct feedback to participants within a few minutes of completing the simulation. The researchers eventually will link video footage to the report so that drivers can replay their errors and view them from an outside perspective.

“They will see how things happen in a flash,” Dr. Loeb said. “There is no better way for them to understand than to actually experience it.”

Kandadai and Dr. Loeb anticipate that the SDA will be a widely applicable tool for scientists, clinicians, schools, and motor vehicle commissions. It also could be used to provide valuable information on other populations’ driving performance, such as adolescents with ADHD and the elderly.

Permanent link to this article: http://www.research.chop.edu/blog/simulated-driving-assessment-fuels-teen-driver-research/

Oct 13 2014

Using Genetics to Discover, Optimize Epilepsy Treatments

epilepsyA new study led by The Children’s Hospital of Philadelphia’s David Bearden, MD, and Ethan M. Goldberg, MD, PhD, supports the idea that the identification of specific genetics targets could lead to a sea change in the way epilepsy is treated. Published in the Annals of Neurology, the paper reports the case study of one young patient with migrating partial seizures of infancy (MPSI) who was successfully treated with a drug originally intended for cardiac patients.

Epilepsy affects approximately 2 million Americans. While there is no cure for epilepsy, about 70 percent of those who have the disease can have their seizures controlled with medication, according to the National Institute of Neurological Disorders and Stroke. However, MPSI is among the forms of epilepsy that present treatment challenges.

A rare, severe form of epilepsy that generally presents in the first few months of life, MPSI is characterized by frequent, treatment-resistant seizures, resulting in developmental delays and disabilities, and often leads to death in childhood. Drs. Bearden and Goldberg’s study is a close look at the effect the antiarrhythmic drug quinidine had on the patient’s seizures.

So why use a cardiac drug (and one also used to treat malaria) to treat epilepsy? Because MPSI is generally resistant to anticonvulsant drugs, the researchers decided to look elsewhere for ways to treat the disease. “MPSI is associated with mutations in a variety of genes,” the authors note, one of which is the potassium channel KCNT1. This gene, the authors point out, is activated in MPSI, and is “a known target of several cardiac drugs, including the antiarrhythmic drug quinidine, which operates as a pore blocker.” Inhibition of KCNT1 might therefore be a way to treat MPSI by normalizing potassium current through mutated KCNT1 channels, noted Dr. Goldberg, an attending physician and instructor of Neurology in CHOP’s Division of Neurology and the Department of Neurology at The Perelman School of Medicine at The University of Pennsylvania.

When the study team first saw the patient at age two, she was experiencing between five and 20 seizures a day. By the end her of seven-month treatment, the patient had been completely seizure-free for more than four months, and almost entirely seizure-free for more than 90 percent of her treatment time. Encouragingly, the patient showed developmental improvements, hitting several major milestones — saying her first words, and then her first sentences.

This “dramatic reduction in seizure frequency” seen during the patient’s treatment shows quinidine “may be at least partially effective in the treatment of MPSI associated with activating KCNT1 mutations,” the study team notes. Overall, the authors say their case “is illustrative of a new paradigm in epilepsy treatment in which rapid identification of genetic mutations could lead to targeted treatments with greater efficacy and fewer side effects than is possible with currently available antiepileptic drugs.”

To read more about Drs. Bearden and Goldberg’s study, see this month’s issue of Bench to Bedside. And to learn more about epilepsy research and treatment at CHOP, see Children’s Hospital’s Pediatric Regional Epilepsy Program, part of the Division of Neurology.

Permanent link to this article: http://www.research.chop.edu/blog/using-genetics-discover-optimize-epilepsy-treatments/

Oct 10 2014

Making Research Funding Personal

research fundingThe Children’s Hospital of Philadelphia’s Peter M. Grollman, vice president of CHOP’s Office of Government Affairs, Community Relations, and Advocacy recently penned a powerful editorial on Philly.com arguing that tepid government support for medical researchers demands a personal response from voters.

“You, too, may be counting on a cure some day. That’s why it’s personal,” Grollman notes.

Children’s Hospital’s Office of Government Affairs, Community Relations, and Advocacy works “to support the Hospital, the Research Institute, and the entire CHOP health network in its goals of excellent patient care, innovative research and quality professional education.” To further CHOP’s mission of improving the health of children everywhere, the Office partners with community members, advocates on behalf of pediatric medical research, and develops relationships with members of government.

Grollman’s editorial — in which he notes family struggles with Parkinson’s disease, cancer, and Lou Gehrig’s Disease — comes at a time when support for the NIH (which funds most medical research in the United States) has flattened. Though the agency’s funding may seem impressive — in the 2015 budget the agency is allotted $30.2 billion — that number is misleading. Adjusted for inflation, the 2015 budget is about $100 million lower than the 2002 level.

Despite clear evidence showing that robust federal support for biomedical research leads to findings that can improve the health of patients in unexpected ways, government support for medical research continues to be lukewarm. “Research conducted in CHOP’s labs has discovered cures for certain types of congenital blindness and childhood leukemia,” Grollman notes, adding that such “great news should invigorate our government leaders to invest even more in the NIH.”

However, the reaction to success stories like those seen at CHOP “appears to be just the opposite: complacency. To date, the response to the empirical evidence in creating medical breakthroughs has been nothing short of unacceptable,” Grollman writes. “According to a 2013 Congressional Research Service report, after adjusting for inflation, funding for the NIH decreased 22 percent over the past decade.”

Therefore, Grollman calls on voters to make the issue personal.

“When funding for medical research is diminished, we are all impacted. We must respond. We need to move the discussion from our homes to the halls of government, where the personal interests and futures of Americans have been discussed and considered for generations,” he says.

To read more, see Grollman’s editorial on Philly.com. If you’re interested in contacting members of Congress and need to find your representatives and senators, see this tool from OpenCongress.

Permanent link to this article: http://www.research.chop.edu/blog/making-research-funding-personal/

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/

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