Oct 31 2014

New Grant to Explore Eradicating HIV from Hiding Places in the Brain

HIVExploring new methods to eradicate HIV that lingers in brain cells despite conventional antiviral treatment is the focus of a new study by investigators at Children’s Hospital and Temple University. They are the joint recipients of a $4.3 million, four-year NeuroAIDS grant from the National Institute of Mental Health.

The grant funds three research projects, each targeting different biological pathways crucial to the persistence of the human immunodeficiency virus that causes AIDS. Investigators from CHOP’s section of immunology and Temple’s department of neuroscience are collaborating on these cell and animal studies to explore methods to enhance the immune system’s ability to attack HIV infection.

“This program represents a fresh look into a longstanding problem in HIV treatment—reservoirs of HIV within immune cells,” said Steven D. Douglas, M.D., chief of the section of immunology at CHOP and a professor of pediatrics at the University of Pennsylvania. “While current antiretroviral treatments can reduce the virus to undetectable levels, HIV persists latently inside cells. If drug treatment is interrupted, the virus comes surging back.”

Dr. Douglas and Jay Rappaport, Ph.D., professor of neuroscience and neurovirology at Temple University School of Medicine, are co-principal investigators of the new grant.

“All three projects seek to bypass vulnerabilities in the body’s immune system that are exploited by HIV,” said Dr. Rappaport. “By using biological tools to reinforce immune function, we aim to enable the immune system to eliminate HIV infection.”

During the first two years of the grant, the project teams will concentrate on basic biology to determine which pre-clinical approaches show the most promise for advancing into studies using animal models in the third and fourth years. The goal of the animal studies is to demonstrate proof-of-concept for strategies that could set the stage for subsequent human trials of innovative HIV treatments.

Project 1, led by Dr. Rappaport, focuses on the metabolism of ATP, the chemical that serves as energy currency in cells. Because HIV infection stimulates enzymes that degrade ATP and weaken immune responses, the research team will explore drug candidates that inhibit those enzymes.

Project 2, led by Tracy Fischer-Smith, Ph.D., assistant professor of neuroscience and neurovirology at Temple, concentrates on signaling proteins that drive immune polarization, in which cells called macrophages shift from protective roles to immune-suppressive activities. The team’s goal is to counteract those proteins’ signals and restore infection-fighting functions to immune cells.

Project 3, led by Dr. Douglas, investigates substance P, a neuropeptide with a key role in promoting inflammation during HIV infection. By manipulating NK-1R, a cell receptor that binds to substance P, the research team aims to disrupt HIV’s entry into cell reservoirs and to block the viral replication that accounts for HIV’s devastating effects.

“HIV infection disrupts immune cells by swinging a biological pendulum off balance into immune-suppressive activities that drive the disease,” said Fischer-Smith. “All three projects aim to modulate the immune system, inhibiting processes that are dangerously up-regulated, and restoring a healthy balance.”

This work is in collaboration with the Penn Mental Health AIDS Research Center at Penn Medicine and CHOP, and Temple’s Comprehensive NeuroAIDS Center—two NIH-supported centers concentrating on mental health and HIV.

Permanent link to this article: http://www.research.chop.edu/blog/new-grant-explore-eradicating-hiv-hiding-places-brain/

Oct 29 2014

Mitochondria Study Offers Insights into Diseases’ Underlying Causes

mitochondriaRecent work by a mitochondrial medicine pioneer from The Children’s Hospital of Philadelphia details how subtle changes in mitochondrial function may cause a broad range of common metabolic and degenerative diseases. Mitochondria are tiny energy-producing structures within our cells that contain their own DNA. The research offers “key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging,” said CHOP Research’s Douglas C. Wallace, PhD.

The new research, published in the Proceedings of the National Academy of Sciences (PNAS), shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. Furthermore, the different proportions of mutant mitochondrial DNA that result in altered nuclear gene expression correspond to the same proportions of mutations in mitochondrial DNA that are associated with diabetes and autism; brain, heart, and muscle disease; or lethal infantile disease.

“By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease,” said Dr. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Existing in hundreds or thousands of copies outside the nucleus of every cell, mitochondria have their own DNA, distinct from the well-known DNA inside the cell nucleus. Although mitochondrial DNA (mtDNA) holds far fewer genes than nuclear DNA, mtDNA exchanges signals with nuclear DNA and participates in complicated networks of biochemical reactions essential to life.

The PNAS study builds on Dr. Wallace’s more than 40 years of investigating the mysteries of mitochondria. And it reinforces the argument he has presented over the course of his career: that mitochondria play a central, largely under-recognized role in all common human diseases. He has long argued that a traditional biomedical approach focusing on anatomy and individual organs does not provide the insights generated from a systems biology, bioenergetics-focused approach.

Examining Mitochondrial Mutations’ Effects

For the PNAS paper, Dr. Wallace and his team investigated the impacts of steadily increasing levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person’s mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition that involves brain and muscle impairments. Above the 90 percent level, patients die in infancy.

The investigators analyzed cultured human cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

Dr. Wallace argues that the medical significance of this research extends beyond the province of the relatively rare disorders typically classified as mitochondrial diseases. The gene expression profile—the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders—parallels the profiles found in Alzheimer, Parkinson, and Huntington diseases. “The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart, and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria,” he said.

Significantly, Dr. Wallace added that the research also pertains to aging. Because mitochondrial mutations accumulate as people age, mitochondrial energy production declines, with deleterious effects on the heart, the brain and on interrelated biological systems that sustain health and life.

Future investigations will examine how different diseases are associated with the sorts of abrupt phase changes his group found in the current cellular study, Dr. Wallace noted. Some of the findings noted in the current research might become useful biomarkers in disease studies and drug development.

To read more about this landmark study, see the October issue of Bench to Bedside.

Permanent link to this article: http://www.research.chop.edu/blog/mitochondria-study-offers-insights-diseases-underlying-causes/

Oct 27 2014

Current Imaging Practices for Kidney Stones Deviate From Guidelines

kidney stonesKidney specialists across the country agree that the incidence of kidney stones is rising among children, but clinicians are unsettled on which imaging technology to choose first when diagnosing the condition, despite current guidelines that recommend ultrasound as the initial imaging study.

The Division of Urology at The Children’s Hospital of Philadelphia used to treat just a handful of children with kidney stones a year; now the multidisciplinary team at the Pediatric Kidney Stone Center evaluates and manages children with kidney stones on a daily basis.

A kidney stone develops when some substances that are normally found in the urine become highly concentrated and form solid crystals. Stones usually begin causing symptoms when they block the outflow of the urine to the bladder.

“Kidney stones truly have become a disease of childhood,” said Gregory E. Tasian, MD, MSc, MSCE, a pediatric urologist and epidemiologist at The Children’s Hospital of Philadelphia, who was the lead author of a study appearing in the November 2014 issue of Pediatrics that looked at the prevalence of the first imaging study that children obtain when they are evaluated for kidney stones.

The American Urological Association and The European Society of Paediatric Radiology recommend that a ultrasound be used as the initial imaging study to help clinicians to find a stone and look for any signs of blockage. The guidelines reserve computed tomography (CT), which delivers ionizing radiation and is associated with an increased risk of cancer in children, for cases when the ultrasound is nondiagnostic and the clinicians’ suspicion of kidney stones remains high.

“Stones can recur, so over a lifetime, a patient can be exposed to a lot of radiation both in the evaluation and then the treatment of stones,” Dr. Tasian said. “We want to limit the use of radiation when we can. By using ultrasound as the initial screening tool, we are able to identify the majority of clinically important stones and spare the child radiation.”

The Urologic Diseases in America Project, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, supported the study led by Dr. Tasian to see how closely U.S. hospitals and clinics follow the current guidelines. The cross-sectional study focused on 9,229 children with urinary stones located in the kidney, also known as nephrolithiasis, who underwent imaging from 2003 to 2011. The study team obtained data from MarketScan, a robust database of commercial insurance claims.

The study’s results showed that clinicians deviated frequently from the recommended guidelines. Overall utilization of CT was high: An average of 63 percent of children underwent CT as the first imaging study during a kidney stone episode. Only 24 percent of children with suspected nephrolithiasis underwent ultrasound as the initial study.

“The findings also suggest that there is substantial regional variability in the use of CT,” Dr. Tasian said. “Yet even in states with the lowest initial use of CT, the prevalence was about 40 percent, and it reached almost 80 percent in some of the higher utilizing states.”

The study’s authors suggest that because the availability of CT has increased over the last 20 years and it is recognized as a reliable diagnostic tool to evaluate adults with kidney stones, clinicians are engrained in the practice patterns or resources specific to their local medical communities. They may not be aware that current best practices recently reported in the New England Journal of Medicine demonstrate that ultrasound can be used as effectively as CT to diagnose kidney stones in adults — at a lower cost and without radiation exposure.

Dr. Tasian and colleagues encouraged future studies to determine the barriers to awareness and implementation of recommended imaging practices that aim to decrease the use of ionizing radiation. Researchers also could test the effectiveness of interventions that attempt to change clinical practice and reinforce the use of ultrasound as the initial screening tool, such as clinical pathways and clinical decision support systems.

Addressing these factors promptly is imperative, if the trend that shows the incidence of kidney stones increasing among children by 10 percent annually continues. While the reasons behind this shift in epidemiology are not well known, some clinicians suspect that the rise in obesity rates, less active lifestyles, diets high in salt, and not drinking enough water may be causing more children to have kidney stones.

A recent study by Dr. Tasian also proposes that climate change may play a role, as warmer days may contribute to dehydration, which leads to a higher concentration of calcium and other minerals in the urine that promote the growth of kidney stones.

Jose E. Pulido, MD, of the Division of Urological Surgery at the University of Pennsylvania’s Perelman School of Medicine; Ron Keren, MD, MPH, of CHOP’s Center for Pediatric Clinical Effectiveness; and Urologic Diseases in America Project collaborators from the RAND Corporation and the University of California, Los Angeles also contributed to the CT imaging for kidney stones study.

Permanent link to this article: http://www.research.chop.edu/blog/current-imaging-practices-kidney-stones-deviate-guidelines/

Oct 24 2014

Penn Medicine Awards of Excellence Honor Faculty

excellenceThe 2014 Penn Medicine Awards of Excellence recognize faculty from The Perelman School of Medicine who exemplify the highest values of innovation, commitment to service, leadership, dedication to patient care, and scholarship and teaching. Four recipients’ distinguished work encompasses their scientific endeavors at The Children’s Hospital of Philadelphia:

“I am extremely proud of this year’s distinguished recipients of the Penn Medicine Awards of Excellence,” said J. Larry Jameson, MD, PhD, executive vice president of the University of Pennsylvania Health System and dean of The Perelman School of Medicine at the University of Pennsylvania. “The contributions of these clinicians and scientists exemplify the outstanding quality of patient care, mentoring, research, and teaching of our world-class faculty. They epitomize the preeminence and impact we all strive to achieve in our shared mission to improve human health, eradicate disease, and provide compassionate care.”

The awardees shared their reactions to this outstanding accomplishment and described some of the projects that demonstrate their drive, dedication, and professionalism. Congratulations to all of the winners!

Dr. Blobel is a hematology researcher in the Department of Pediatrics at The Children’s Hospital of Philadelphia and a professor of pediatrics at The Perelman School of Medicine: “The award recognizes the highly productive people in our group who have carried out all the work and made the lab into what it is today.

“In recent years what we consider to be our breakthroughs are related to two major areas of investigation. One involves the study of higher order chromatin architecture and the development of reagents to alter it with an eye on therapeutic uses. In particular, we have developed an approach that might be suitable as a strategy to treat sickle cell anemia.

“The other involves studies into epigenetic ‘memory’ as it pertains to cell division. During mitosis our chromatin undergoes massive changes in the way it is organized, and virtually all genes are silenced, and it is believed that specific mechanisms are in place that ensure that the correct gene expression patterns are restored upon exit from mitosis. We think that such mechanisms help cells to maintain their identity and differentiation state. Our lab has gained insights into this question and in the process developed tools that are useful to investigators pursuing similar questions.”

Read our latest blog about Dr. Blobel’s work.

Dr. Miller is a psychologist and director of research for the Division of Adolescent Medicine at The Children’s Hospital of Philadelphia, as well as an assistant professor of pediatrics: “I am so gratified to work at CHOP and Penn, with such a rich array of collaborators doing interesting and innovative work. My research on child and adolescent decision making has depended on the support of multiple clinical programs and principal investigators at CHOP, as well as an effective and talented research staff.  The overall goal of my work is to identify the ways in which children and adolescents can be involved in decision making about their own health, to enhance their sense of control and facilitate effective decision making as they mature.”

Read our latest blog about Dr. Miller’s work:

Dr. Liu is a pediatric neuro-ophthalmologist and faculty member of the Ophthalmology Division at The Children’s Hospital of Philadelphia, and a professor of neurology and ophthalmology at Penn: “I have to admit that I was humbled by the Lindback Award. Looking at some of the comments about my teaching, I didn’t realize that I had had such a positive influence as a teacher. To follow in the footsteps of other highly acclaimed, great teachers is really quite an honor — one that I never really expected.”

Dr. Marsh is an assistant professor of neurology and pediatrics at The Children’s Hospital of Philadelphia:  “I am thrilled to have been awarded the Leonard Berwick teaching award. I work hard to infuse my clinical teaching with the basic science fundamentals that are important for all students and residents to remember during their clinical training.  In my role as a physician scientist, I study the basic physiological mechanisms underlying a disease, infantile spasms, that I diagnosis and treat in children. Hence, in my day-to-day work, I attempt to merge the science and clinical realms and instill this approach to the students I teach.  I find my work, going from basic mechanisms to the patient, very fulfilling and one of the most rewarding parts of my job.”

Permanent link to this article: http://www.research.chop.edu/blog/world-class-faculty-honored-achievements/

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/

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