Bench to Bedside

May 2016

Home or Away? Comparing Post-Chemo Strategies for Pediatric Leukemia


The Children’s Hospital of Philadelphia can be a second home for families who have a child diagnosed with acute myeloid leukemia (AML) which usually requires several intensive rounds of chemotherapy during three to four-week inpatient hospital stays. Parents set up air mattresses to sleep in the hospital room. School tutors ensure schoolwork doesn’t fall behind. Although it can be a supportive, comforting environment during this distressing time, families often dearly miss their daily routines.

Part of the reason patients with AML stay in the hospital for many weeks is because chemotherapy depletes their neutrophils, which are the blood cell that are the first responders to fight organisms that cause infection. During the periods following treatment when neutrophils are low, called neutropenia, pediatric cancer patients can have a difficult time fighting off bloodstream infections and related complications.

Because of this risk, some physicians prefer that children with AML stay in the hospital for close monitoring following a course of treatment. Other doctors allow patients to go home and return to the hospital if a fever occurs.

However, physician-researchers do not have enough evidence to know with certainty if patients fare better or worse if they are sent home during periods of neutropenia. A collaborative, observational clinical trial being led by a study team at CHOP aims to shed light on how physicians could approach these patient discharge scenarios safely and consistently while also considering family preferences.

“There is a lot of complexity and interplay between medical outcomes and patient experiences,” said Richard Aplenc, MD, PhD, a CHOP pediatric oncologist and AML researcher who is the principal investigator. “We need to know about both sides of the street, in order to have the best and most informed discussions with families about what to do in this situation.”

The study, entitled “Home or Away From Home,” will compare 490 patients’ medical records to determine the risks/benefits of outpatient vs. inpatient management of neutropenia in children with AML. Fifteen U.S. pediatric hospitals from across the U.S. will participate. In addition to collecting data so that the study team can compare each discharge strategy’s medical outcomes including bloodstream infection and delays in subsequent courses of chemotherapy, several sites also will assess patient outcomes by surveying patients and families about their quality of life.

Julia Szymczak, PhD, a medical sociologist, postdoctoral fellow in the division of Infectious Diseases at CHOP, and staff member of the Center for Pediatric Clinical Effectiveness, will add a third dimension to the project by using anthropologic research methods. Over a six-month period, she will conduct semi-structured in-person interviews with focus groups to gather their personal perspectives.

For instance, will some families be willing to take on the risk of complications arising at home that could require a return to the hospital and staying in the intensive care unit? Or if a child is discharged home, could it place additional financial stress on working families who must balance caring for a sick child? Three patient advisory councils from Alex’s Lemonade Stand, the Children’s Oncology Group, and CHOP will help the study team connect with families and eventually disseminate the study’s findings.

“Whether most of their child’s chemotherapy experience is at home or most of it is in the hospital is a big deal for families, so we need to hear from patients and families about what is most important to them,” Dr. Aplenc said.

The study’s innovative combination of three different kinds of research — clinical epidemiology, quality of life, and medical anthropology — helped it gain the attention of the Patient-Centered Outcomes Research Institute (PCORI), which awarded the three-year project $1.8 million. PCORI is an independent, nonprofit organization authorized by Congress in 2010 to fund research to provide patients, caregivers, and clinicians with the evidence-based information they need to make better-informed healthcare decisions.

Read more about Dr. Aplenc’s pediatric AML research and a recent $1 million Hyundai Quantum Grant from Hyundai Hope on Wheels he received to advance new cancer treatments. Dr. Aplenc also is an associate professor of Pediatrics at the Perelman School of Medicine, University of Pennsylvania.

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Studies Support Parent-Teen Communication to Improve Adolescent Health


A teenager’s annual visit with his or her doctor is short. But the list of health-related information a growing adolescent needs can be very long. From acne to alcohol to sexuality and driving safety, there is too much information for any primary care provider to adequately discuss within the space of a brief check-up. Parents, however, can partner with physicians to help teenage patients navigate health-related choices as they grow up. A body of research now underway in the Craig Dalsimer Division of Adolescent Medicine at The Children’s Hospital of Philadelphia is helping to make that vision a reality.

Asking What Teens and Parents Need and Want

The research team began with a patient-centered approach by asking adolescents and their parents what they need instead of simply providing adolescents the health information that physicians chose for them. At a location that is part of CHOP’s Pediatric Research Consortium (PeRC) network, 91 parent-teen pairs met separately with interviewers and discussed their preferences for receiving health information from the pediatrician.

The questions included a wide range of categories, including routine healthcare concerns, physical and mental health concerns, sexual health, injury prevention, and substance use. Interviewers also asked the teens what type of information they hoped their parents would receive from the pediatrician. This foundational study for the larger project is now published online and will appear in a forthcoming issue of the Journal of Adolescent Health.

“The standout results were that both teenagers and their parents expressed high level of interest in getting information from their pediatricians about a wide range of adolescent health topics,” said study leader and Division Chief Carol Ford, MD. “They want a lot of information from us and feel that it would be valuable to them. This did not vary too much by topic. The expressed interest was pretty wide.”

Parents had slightly higher levels of interest than teens in receiving health information, but teens’ interest was still moderate to high. The topics that parents preferred were more likely to correspond to their adolescent’s age — such as acne for parents of younger teens, and driving safety for parents of older teens. The adolescents’ interest in health topics did not vary with age. Broadly, when the team compared responses within individual parent-child pairs, there was little overall concordance between the information preferences of each teenager and his or her parent.

“One of our take-home messages about that was to be sure that we asked both teenagers and parents what they wanted because they may be very different,” said Dr. Ford, who is also a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Luckily, parents and teens did agree on a shared interest in receiving information about improving parent-teen communication. This interest contributed to how Dr. Ford’s team built the next stages of the project.

Testing Feasible Ways to Meet Teens’ and Parents’ Health Information Needs

“We’re trying to understand how to meet the information needs of parents and teens in a feasible way, to deliver them very high quality information that we know is useful to parents and can impact teens’ health,” Dr. Ford said.

Her team developed written materials including both in-depth booklets and brief pamphlets, focused on guidance to improve parent-teen communication. To do this, they adapted with permission existing health communication materials that had been shown effective by decades of prior research, including information about sexuality and sexual health (developed by Vincent Guilamo-Ramos, PhD, James Jaccard, PhD, and Patricia Dittus, PhD), and information about alcohol use (developed by Dr. Jaccard). Additional materials about teen driving safety were developed by co-investigator Jessica Mirman, PhD, a scientist in the Craig Dalsimer Division of Adolescent Medicine and in the Center for Injury Research and Prevention at CHOP.

The project using these materials is a randomized controlled trial called Patients, Parents, & Professionals Partnering to Improve Adolescent Health (P4). Participating teens and parents in the experimental arms of the P4 trial receive two sets of informational materials, including both the parent-teen communication materials and one of the subject-specific materials, when they come to a primary care appointment in CHOP’s PeRC network. Teens and parents participating in the control arms of the trial receive usual care.

When giving the health information materials to parents and teens in the study, pediatricians endorse the materials and recommend their use. A health coach also briefly reviews the materials with the parent-teen pairs during their visit and then follows up with a phone call a few weeks later to check in on whether they were used and if so how any conversations proceeded.

“These are hard things to talk about, but if the doctor thinks it’s important and gives families tools to make it easier for parents and teens to talk about them, then we hope that those conversations will actually happen and help teens make healthier choices about sexuality or alcohol or teen driving,” Dr. Ford said. Her team’s study will follow up to determine which of those things happen.

The foundational study asking about parents’ and teens’ informational needs may yet spur additional projects and questions. For example, Dr. Ford noted one intriguing finding that both parents and teens highly rated their interest in learning about how to communicate about teens’ strengths. Dr. Ford and the P4 research team hope to pursue further research focused on supporting health by discovering and emphasizing teens’ strengths in the future.

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Mitochondrial Medicine Pioneer Inducted to Italian Academy of Sciences


The exclusive membership rolls of the Italian Academy of Sciences that have listed such luminary names as the Italian scientists Volta, Golgi, and Avogadro, and non-Italians Pasteur, Franklin, and Einstein, have recently added a new name familiar to researchers at The Children’s Hospital of Philadelphia: Douglas Wallace, PhD.

Dr. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP, was inducted into the Academy during its 234th annual meeting May 5 in Rome. Dr. Emilia Chiancone, as president of the Academy, conducted the ceremony inducting Dr. Wallace as a foreign member of the organization.

“We are deeply honored that this very elite international scientific organization has recognized Dr. Wallace’s accomplishments,” said Bryan Wolf, MD, PhD, chief scientific officer and director of the Research Institute.

Founded in 1782 as the Italian Society, the Italian Academy of Sciences has a mission of encouraging scientific research and disseminating the progress of science to schools and the general public. Its membership is limited to 40 Italian scientists and 25 foreign members.

Dr. Wallace’s induction to the Academy recognizes his scientific contributions as the founder of the field of mitochondrial medicine. During the 1970s, Dr. Wallace defined the genetics of the DNA located in the mitochondria, the “power plants” of the cell, including demonstrating that human mitochondrial DNA is exclusively maternally inherited. The mitochondria are located outside the cell’s nucleus in the cytoplasm, and the mitochondrial DNA codes for the wiring diagram of the power plants. Because it is exclusively and directly passed down from mother to child, the mitochondrial DNA can only change by the sequential accumulation of mutations along radiating maternal lineages.

Applying this fact to the study of human evolution, Dr. Wallace reconstructed the origins and ancient migrations of humans out of Africa and around the world based on sequence analysis of mitochondrial DNAs from global indigenous populations. In the realm of human health, analysis of the mitochondrial DNAs of a diverse array of patients led Dr. Wallace to discover mitochondrial DNA diseases and that mitochondrial DNA variation contributes to a wide range of rare and common metabolic and degenerative diseases as well as cancer and aging, thus founding the field of mitochondrial medicine.

Dr. Wallace joined CHOP in 2010 as the founding director of the CMEM. He is also a professor of Pathology and Laboratory Medicine at CHOP and the Perelman School of Medicine at the University of Pennsylvania. His work here has included finding more key insights into the mechanisms by which mitochondria play a role in numerous metabolic and neurological disorders. For example, he demonstrated that the proportion of mutated mitochondrial DNA in a cell can cause changes in the expression of genes in the cell’s nucleus. He proposed and synthesized evidence for a hypothesis that mitochondria are not just a useful tool to trace the history of evolution, but may have played a critical role in shaping how predecessors of modern humans adapted to their environments. He has demonstrated links between psychological stress and mitochondrial dysfunction, which could be a mechanism of how psychological factors lead to physical illness. His ongoing collaborations at CHOP include studies of mitochondrial function in autism, diabetes, brain development defects, and many more areas.

During the event in Rome, Dr. Wallace presented a lecture on the role of mitochondria in metabolic and degenerative diseases. Dr. Wallace is also a member of the U.S. National Academies of Sciences and Medicine and the American Academy of Arts and Sciences.

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Researchers Building Better Behavioral Health Services for Urban Schools


When children from low-income, urban backgrounds gather their backpacks to start each school day, they also bring with them weighty issues that can carry over to their classrooms. Anxiety disorders and aggressive and antisocial behavior are common among inner city students, but counselors in their schools usually are scarce, overextended, and lack adequate training to provide effective behavioral health services.

Enter into the equation researchers at The Children’s Hospital of Philadelphia who teamed up with two schools in North Philadelphia in a pilot study to implement evidence-based prevention practices as part of School-Wide Positive Behavioral Interventions and Supports (SW-PBIS). The program has two tiers: Tier 1 aims to improve schools’ climates overall; Tier 2 provides small group-based services to children who are identified as being at high risk for mental disorders.

Interventions for Tier 2 are based on group cognitive behavioral therapy, which teaches children to pay attention to their bodies and their thoughts and use them as cues to engage in coping strategies and problem-solving. For example, if a child recognizes that he is beginning to feel anxious or fearful on the playground, instead of acting out because he is agitated, he can learn to manage his emotions using relaxation techniques and practicing positive self-talk: “Deep breaths. Take it easy. I can handle this.”

The intervention’s initial success led principal investigator Ricardo Eiraldi, PhD, a psychologist in the department of Child and Adolescent Psychiatry and Behavioral Sciences and program director of the Behavioral Health in Urban Schools program at CHOP, to expand his research to more schools in the Philadelphia School District, including a new grant that he received this year from the National Institute of Mental Health. For two decades, Dr. Eiraldi’s research career has focused on addressing mental health services disparities.

“Low income, ethnic, minority children are much less likely to receive high quality mental health services compared to those in the middle class who are not ethnic minorities, so schools can play a very major role in addressing mental health issues in children,” said Dr. Eiraldi, who also is an associate professor of Clinical Psychology in the division of Developmental and Behavioral Pediatrics at Perelman School of Medicine, University of Pennsylvania.

In an article published in Behavior Modification, Dr. Eiraldi and his study team reported that the pilot study, called Project ACCESS (Advancing Collaboration for Children’s Emotional and School Success) showed children with a diagnosis of depression, anxiety, or behavior problems who received the small group–based services over 14 once-a-week sessions showed a decrease in their diagnostic severity level.

The researchers’ next step was to determine the best ways to train school personnel to execute Tier 1 and Tier 2 interventions on a long-term basis and deliver the program’s components with a high level of fidelity, integrity, and clinical effectiveness. With grant support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, they launched a study in 2013 involving six Philadelphia schools, grades kindergarten through eight. Two school personnel in each school, usually a counselor and a special education teacher, received initial training during a workshop as well as consultation for session preparation or the initial training plus consultation and ongoing coaching for Tier 2 interventions.

“The idea is to create internal capacity within under-resourced schools to be able to provide mental health services to children.” Dr. Eiraldi said.

The study’s results showed that schools in both support strategies successfully delivered and promoted the adoption of SW-PBIS. As in the pilot project, the schools had fewer discipline referrals overall, and school personnel implemented all of the interventions with high levels of fidelity. Jennifer Mautone, PhD, a psychologist in the department of Child and Adolescent Psychiatry and Behavioral Science and an assistant professor of School Psychology in the department of Psychiatry at Penn, was the project director.

But it was not an “easy A” for the study team to get. During the first year of the project, all of the counselors in the school district were laid off due to severe budget problems. Half of the counselors eventually returned to their positions, and in the meantime, the researchers had learned a valuable lesson.

“The project outcomes were very positive, but there are always barriers,” Dr. Eiraldi said. “It is difficult to work with large schools and have everyone involved for a long period of time. There is a lot of turnover, so you have to work with and train new people every year or establish a relationship with a new principal.”

Like all good students, the study team applied this knowledge when constructing their new study. While the two prior studies showed that working with school counselors could be effective, this approach was not very feasible because they often were stretched too thin. In some schools, only one counselor was available for more than 1,000 students.

Instead of focusing on school counselors, the new study will use a “train the trainer” approach to train clinical supervisors and therapists of eight mental health agencies that partner with Philadelphia schools. All children who are eligible for Medicaid and are having some mental health problem can potentially receive school therapeutic services provided by these agencies.

The researchers will compare two updated versions of a cognitive based therapy program (eight sessions vs. 12 sessions), concentrating on children with anxiety. They also will test two ways of implementing the program. The first method is to train the mental health agency supervisors who then will teach and deploy the therapists who work directly with the children in the schools. The second method is the same model, with additional coaching and support provided by the research team to the supervisors.

Eighteen schools in Philadelphia will be chosen for participation, and the researchers expect to enroll 534 students in grades four through eight who present excessive anxiety. By the conclusion of the five year grant, the study team aims to report on the children’s outcomes, implementation outcomes, and cost-effectiveness. Billie Schwartz, PhD, a postdoctoral Fellow in Clinical Psychology at CHOP, is the project director.

“This area of research is called implementation science, which NIH is greatly interested in,” Dr. Eiraldi said. “Lots of money has been spent on research to develop and test effective treatments, but they are either never used in community settings, or they’re used 20 years later. Implementation science is about taking those evidence-based treatments to the community and finding out if they’re effective when implemented by actual clinicians in the real world.”

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Tool to Provide Emerging Disease Updates Wins National Data Sharing Challenge


Frontline physicians must think on the fly, relying on their most current knowledge to provide effective clinical care. Oftentimes, though, it is difficult for them to access, filter, and harness the overwhelming amount of healthcare information that is available in order to stay up to date. Two clinical informatics fellows at The Children’s Hospital of Philadelphia brainstormed about this problem and created an award-winning technology-based solution to help doctors make better decisions based on the very latest public health guidelines and recommendations.

Marc Tobias, MD, and Naveen Muthu, MD, of CHOP’s Department of Biomedical and Health Informatics (DBHi) were inspired by what they had learned during their fellowships about clinical decision support and the challenge of knowledge maintenance. Realizing that public health officials and agencies have poor channels of communicating rapidly and efficiently with clinicians, they began in the fall to conceptualize a way to bridge that gap. Their idea quickly evolved into a prototype: The Population Health Risk Assessment Support Engine (PHRASE Health).

PHRASE is an electronic health record (EHR)-agnostic system designed to identify at-risk populations and provide clinical decision support to healthcare providers at the point of care. The portal allows for a two-way flow of data: public health provides timely updates about evolving disease and patient risk factors through the system, while clinicians consume these recommendations in the EHR and utilize one-click reporting of disease cases back to the public health department.

They submitted PHRASE in December to the “Closing the Data Divide” Virtual Challenge, jointly sponsored by the de Beaumont Foundation, which seeks to transform the practice of governmental public health, and the Practical Playbook, which works to increase collaboration between public health and primary care. Drs. Tobias and Muthu received a prize of $30,000 for their first place finish.

“Dr. Tobias and Dr. Muthu are leading the way in this new medical subspecialty,” stated Anthony Luberti, MD, medical director for Informatics Education in DBHi and director of CHOP’s Clinical Informatics Fellowship Program, in a press release. “PHRASE Health is an example of the kind of innovative technology solutions that can impact health outcomes for patients. We are extremely proud of their efforts.”

Dr. Muthu used the developing story of the Zika virus as a real-world example to demonstrate how PHRASE could be a valuable tool. As recommendations continue to evolve for screening patients in the U.S. who may have been exposed to the virus, PHRASE could help physicians identify which patient populations are most at risk for complications and notify them through a message generated in their EHR.

“We’ve had the opportunity to talk to a variety of public health officials at the city, state, and national level,” Dr. Tobias said. “It’s been an amazing experience to get all of the positive feedback from bringing the newest technologies to a historically frustrating problem.”

Here’s how the platform could work: When a physician opens a patient’s chart or places a specific order for that patient, the EHR would call out to the PHRASE web server. Based on certain data, such as demographic, geographic, or social factors, PHRASE will determine what specific diseases or conditions a patient is currently at risk for, based on determinants defined by public health officials. It also will issue patient-specific recommendations that the clinician needs to be aware of and alert them via the EHR. The platform is based on interoperability standards, which means it will be compatible with multiple types of EHRs.

“The big picture is that public health officials, guideline makers, and other domain experts will be fully integrated with frontline providers so that providers can receive the best decision support at the point of care,” Dr. Muthu said. “We can also use current data from the EHR through the same platform for reporting purposes to send data back to public health entities.”

The prototype is functional but needs to be refined and tested at CHOP with the support of CHOP’s Office of Entrepreneurship and Innovation before a sustainable model will be ready to be implemented. The development process has engaged a wide range of partners from both healthcare and public health, including collaborations with the Philadelphia Department of Public Health and the Pennsylvania Department of Public Health.

“We’re thrilled for the opportunity to show our work and get feedback from the larger public health community and excited to move forward,” Dr. Muthu said.

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What It Takes to Become a Vaccine Champion: A Q&A With Paul Offit


Paul Offit, MD, director of the Vaccine Education Center at The Children’s Hospital of Philadelphia, isn’t your stereotypical scientific personality who prefers to stay behind the microscope instead of the limelight. Along with a talented team at CHOP, Dr. Offit invented a rotavirus vaccine that dramatically reduced the incidence of the disease in the U.S., following its approval and inclusion in the recommended vaccine schedule for babies in 2006. Back then, CHOP had about 400 admissions for rotavirus-induced dehydration in the hospital every year, Dr. Offit said, but now it is a rare event.

Dr. Offit’s career has evolved into being an author and vocal advocate for vaccine safety, childhood immunization, and stricter vaccine waiver requirements. He is the Maurice R. Hilleman Professor of Vaccinology and Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania.

Last year, Dr. Offit was inducted into the American Academy for Arts and Sciences along with the likes of journalist and novelist Tom Wolfe and singer-songwriter Judy Collins. He also joined the class of 2015 Fellows elected by the American Association for the Advancement of Science, which recognizes individuals for their contributions to science and technology. And the honors kept coming earlier this year when the University of Pittsburgh awarded him the Porter Prize, which honors an individual’s exceptional performance in health promotion and disease prevention.

His latest accolade was becoming a Vax Pack Hero, one of about 50 central figures who played roles in the history of vaccines and are featured in a new program created by the Vaccine Education Center. It consists of a web-based video game, trading cards, and an educational website designed to teach kids about how vaccines fight germs.

It’s easy to understand why Dr. Offit has a growing fan club, with his warm laugh, sharp intellect, and ability to speak with conviction. Yet, his outspokenness also has earned him a pile of hate mail that he admits is sometimes hard not to take personally. Read on to get more insights into why this vaccine champion is so passionate about protecting children and willing to take on the controversy.

How difficult is it to make a vaccine?

It’s really hard. Pretty much everything has to go right. It took 10 years to do the research to figure out which parts of the virus made you sick and which parts of the virus conferred a protective immune response. Then we constructed viruses that had the best of both worlds, which is to say that the vaccine wouldn’t have the proteins that were associated with virulence, but it did have the proteins that induced an immune response.

Our success involved a unique combination of talents among the three of us. The rotavirus vaccine wouldn’t have happened unless that team was in place at CHOP. We each brought something different to the effort that allowed it to become a vaccine. Stanley Plotkin, MD, was a veteran vaccine researcher. H. Fred Clark, DVM, PhD, was a brilliant scientist. Between the two of them, I was in the right place at the right time.

What do you see as your important contribution to the team?

Doing all the research and making the right strains was the easier part. The bigger hurdle was the research and development, working with a pharmaceutical company to do all those things you need to do to make a product. We constantly were meeting with the company to keep on track because vaccines are never big money makers. Vaccines are given once or a few times in one’s lifetime. They’re never going to be blockbusters. I was an NIH-funded researcher, but I also brought a personality that was persuasive.

Fortunately, there was somebody at Merck named Penny Heaton, senior director for vaccine clinical research, who ran that program and got it to completion. She was the star who ultimately helped us build the Phase 3 trial that was submitted to the Food and Drug Administration. You have to prove safety and efficacy before a vaccine is licensed. That was a prospective, placebo-controlled, 70,000-plus participant, 11 country, four year, $350 million trial.

From start to finish, how long did it take to create the vaccine?

It took 26 years. Once it was approved, the even harder part was implementation. Getting the vaccine into the developing world would never have happened without Bill and Melinda Gates. When they found out that rotavirus, which is a common cause of severe vomiting and diarrhea in infants, was the single biggest killer of young children in the world, they were willing to buy the vaccines at slightly above costs. Merck, to their credit, saw all their ethical and moral responsibilities to distribute the rotavirus vaccine. Two-thousand children a day die of rotavirus in the developing world, but it is lessening because of the vaccine; it probably saves hundreds of lives a day.

Why did you choose to pursue infectious diseases as a specialty, and what would you say to young physician researchers who are considering practicing in this area?

As a child, I was operated on for congenital club feet. I didn’t have polio, but I ended up recovering in a polio ward for almost two months back in the days when you would have one visiting hour a week. I saw those children in the polio ward as vulnerable, helpless, and alone. It’s still a vivid image. I think that wanting to protect children from harm is what drove me to pediatrics and why I wanted to help make vaccines.

There are always emerging viruses and bacteria, like Zika. There is much that we don’t know still and much for us to learn. It’s not just a matter of treating infections; we can actually prevent infections, and in addition, we can eliminate infections. Three infectious diseases have been eliminated from the face of the earth by vaccination: small pox, type 2 poliovirus, and a cattle disease called rinderpest. Infectious disease experts have the power to actually eliminate diseases. What other subspecialty can claim that?

Why did you establish the Vaccine Education Center?

The 26-year effort to make rotavirus vaccine taught me how difficult it was to make them and prove that they are what you claim them to be. When you claim that a vaccine is safe and effective, it must stand on a mountain of evidence. But at the same time, I realized that as very hard as they were to make, vaccines are very easy to damn. And so in the late 1990’s there was a concern that the combination measles, mumps, rubella vaccine caused autism, a concern that clearly was ill-founded and ultimately disproven. But it got an enormous amount of traction and still has traction. Then there was the notion that preservatives in vaccines could cause neurodevelopmental problems, including autism. That was also proven to be wrong but still hangs out there.

A lot of scientists weren’t weighing in on these issues. We were keeping our heads down and doing the science, but we didn’t feel the need to comment publicly. It’s not generally what scientists are trained to do or feel we’re good at. I think we all assumed other people were doing it, but they weren’t. So we created the Vaccine Education Center to try and explain the science of these issues to the public in a compelling manner.

Do you think the recent measles outbreaks in the U.S. also have helped to change how the public views vaccines?

As much as we’ve been talking for the last 15 plus years in our Vaccine Education Center to try and warn people that if they chose not to vaccinate, then they’re taking a much riskier choice, nothing educates like the virus. The outbreak that started in southern California at the beginning of 2015 and spread to 25 other states and into two provinces in Canada was a great educator.

You didn’t have to convince me to vaccinate my children. I had measles. I had mumps. I had German measles. I had chickenpox. I had those diseases. I know what they felt like. But my children didn’t grow up with these diseases; they don’t see these diseases today. For them it’s a matter of faith. The measles epidemic is a perfect example. In southern California, there were elementary schools where fewer than 50 percent of children in those schools were vaccinated. And then the measles outbreak hit, and those parents ran to get their children vaccinated. So fear sells. It’s too bad it came to that.

What do you think is on the horizon for vaccine research?

I think the next great wave of vaccines will be the pregnancy platform. Both the whooping cough (pertussis) and influenza vaccines are now required during pregnancy to protect both the child and the mother. I think that you will eventually see a Group B strep vaccine to protect the baby. You’ll see a respiratory syncytial virus vaccine, again to protect the baby. These are diseases that occur in the young child, including those less than four months old when it’s too young to get an active vaccine. A passive vaccine program essentially will be of value.

What gives you a sense of accomplishment in your current roles?

I love my role here in the Vaccine Education Center. My career will continue to focus on educating either by speaking or writing op-ed pieces or books. My most recent book, for example, Bad Faith, was about the 1991 measles epidemic in Philadelphia that centered on two fundamentalist churches. We had 1,400 cases of measles and nine deaths. That was unprecedented in the vaccine era. We watched those parents who chose not to vaccinate their children also chose not to seek medical care out of “respect for religion.” And that really upset me. There had been a law on the books allowing for religious exemption of vaccination for 10 years when that happened. What those parents were doing was perfectly legal. But when that outbreak hit, we got a court order to vaccinate them.

This book helped exorcise the demons, if you will, having lived through that experience. All of the money that was made from the royalties of the book went to a group called Children’s Healthcare is a Legal Duty, which has a mission to overturn the religious exemption from child abuse and neglect laws that exists in most states, which they recently did in Tennessee. That’s when you feel like you’ve done something. It’s all about child advocacy. I think each one of my books is about trying to protect children from harm. Again, it’s for the same reason that I wanted to make vaccines. Maybe I still see a little of myself as a child in that polio ward.

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Seeking Serotonin-Connected Solutions to Heart Valve Disease


The mitral valve is the most mechanically active part of our bodies, going through a range of motion unlike any other in the four-chambered heart. Each time its two leaflets snap closed, the resulting blood flow stoppage contributes to the “lub” sound of our “lub-dub” heartbeat. This continuous, persistent motion is our essential bass beat powering us through our lives, without our regular noticing.

Malfunctions of the mitral valve are fairly common without our noticing, too. At least 2.5 percent of the U.S. population has heart valve disease, affecting either the mitral or aortic valve, with most cases either discovered incidentally in the context of some other health issue or else going undetected until they cause severe illness. By the time people need surgical replacement of a faulty heart valve, there is often collateral damage to the rest of the heart from years of the valve’s persistent malfunction with each and every beat. No drug treatments are available for heart valve disease itself, only for the symptoms caused by the disease.

A research team at The Children’s Hospital of Philadelphia and University of Pennsylvania is working on a complex study of mitral valve disease that shows early potential to prevent long-term heart damage in young men and boys who are prone to a possible genetic subtype of mitral valve disease. The team recently received a grant from the National Heart, Lung and Blood Institute (NHLBI) to pursue research that could confirm the existence of this genetic subtype and explain its mechanism of disease, for which serotonin-related drugs could be an effective treatment approach.

“There’s a lot to be learned in terms of why serotonin systems are normally present in heart valve cells, and why they seem to go haywire in the disease state,” said study leader Robert Levy, MD, a cardiologist at CHOP and professor of Pediatrics at Penn’s Perelman School of Medicine, who specializes in heart valve disease.

Emerging Knowledge of How Serotonin Affects the Heart

Most people who are familiar with serotonin know it as a “happy” neurotransmitter because it has been most extensively studied in the brain in connection with depression. Common antidepressant drugs, such as fluoxetine (Prozac), work by blocking transport of serotonin back into cells and out of the synapse between neurons. As a result, more serotonin remains active in the synapse, engaged in more signaling, which helps to reduce depressive symptoms.

But serotonin influences the body in many more places than the brain. Spurred by clues that serotonin affects valve disease risk, including a popular weight-loss drug (fenfluramine/phentermine, or fen-phen) that acts on serotonin and was pulled from the market by the Food and Drug Administration in the 1990s for causing rapid-onset severe valve disease, Dr. Levy and other cardiac researchers have been working to determine what this hormone does in heart valves.

The picture is complex, and more unanswered questions remain than answered ones. They do know that in heart valves, as in the brain, serotonin can signal to receptor proteins on the heart valve cell’s surface, and it can enter the heart valve cells via serotonin transport proteins. When serotonin signals the receptors, it appears to set off reactions within heart valve cells that collectively lead to either maintenance of valve structure, or in valve disease, thickening of the leaflets. When it passes through the transport protein to a heart valve cell, it is broken down and not re-released.

In 2009, Dr. Levy led a team that identified how one of those diet drugs, fenfluramine (Fen), acts on serotonin in heart valves when it triggers risk of valve disease: It is analogous to Prozac in the brain, in that it shuts down the transporter protein and keeps more serotonin in an active signaling state.

Investigating a Gene Variant Affecting the Serotonin Transport Protein

Now Dr. Levy and colleagues are weaving together their growing knowledge about serotonin activity in heart valves with questions about a common gene variant that has largely been a focus of study in neuroscience.

The variant in question occurs in the gene for the serotonin transport protein, specifically in the promoter region that helps control the gene’s expression. About half the population is heterozygous, having one copy of the gene with its full-length promoter region, and one shorter variant copy of the gene with a 44-base-pair section deleted from the promoter region. Roughly a quarter of the population is homozygous with two full-length copies, and another quarter is homozygous with two copies of the shorter variant.

Dr. Levy and colleagues hypothesized that having two copies of the shorter gene variant could increase risk of earlier onset of severe valve disease; their idea was that having less transporter protein in heart valves in the first place would be a bit like taking the transporter-blocking drug Fen, which caused rapid-onset valve disease. So Dr. Levy and his co-investigator, Giovanni Ferrari, PhD, an assistant professor in the department of Surgery at Penn, decided to look at the damaged heart valves from cardiac surgery patients at Penn who were participants in a registry that Dr. Ferrari leads. They predicted that the younger surgery patients would be homozygous for the short form of the serotonin transport gene at above-average rates.

“What we found was actually the opposite of that,” Dr. Levy said. “That was really a pretty big surprise.”

Among the surgery patients whose heart valves they have examined so far, Dr. Levy and colleagues found that a group of younger patients (under age 55) was nearly twice as likely to be homozygous for the full-length form of the serotonin transport gene as they would have predicted from the variant’s distribution in the general population. Fewer of these patients than predicted were heterozygous for the gene variant, while about the typically expected proportion (one in four) was homozygous for the shortened form of the gene.

One other surprising thing stood out based on their early analysis of surgical samples: The effect they found was sex-specific, affecting only younger men in the study population. Both women of all ages and older men who needed mitral valve surgery had the gene variant at the usual expected distribution in the general population. Additionally, women were underrepresented in the surgical population, outnumbered two to one by men — even though women are generally twice as likely as men to experience mitral valve disease. These sex-related differences are so far unexplained.

Dr. Levy and his team are moving forward, working to confirm their early findings by establishing whether the individuals who are homozygous for the long form of the serotonin transport gene do indeed have more of the transport protein in their heart valves, as they expect. They also have more work to do using in vitro and animal models to explore the mechanism by which the long form of the transporter gene may cause damage. Their revised hypothesis is that, among individuals with two copies of the long form, serotonin is transported and dismantled within heart valve cells to a greater extent, releasing reactive oxygen species in the process and causing damage via oxidative stress.

“I think this genotype in the future will be used as a biomarker for looking at risk in patients with mitral valve prolapse,” Dr. Levy said. “Especially for males, it will be important to learn if they have the full-length form as their transporter polymorphism genotype.”

Looking Ahead

If Dr. Levy’s team confirms that this genotype puts boys and young men at elevated risk of serious valve disease, the good news is that researchers already have a head start on finding potential drug therapies — and this could mark the first general drug opportunity for heart valve disease. That is because serotonin-related therapies have been widely studied for decades in the context of neuroscience. Drug companies have large libraries of compounds that have been considered for potential use against depression and other mental and neurological health conditions. Many compounds that were rejected from consideration because they cannot cross the blood-brain barrier might still be candidates for keeping heart valves healthy.

“Mitral valve prolapse is detected in childhood,” Dr. Levy said. “Knowing about these diseases in childhood and starting treatment before there is chronic damage to the heart is really a great possibility, and it’s a very important reason to do these studies.”

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Collaborations on Language-Focused Autism Research Gain Momentum


Quiet. Sing-song-y. Robotic. Too fast. Too slow. Despite the contradictions among some of these terms, researchers and clinicians have noticed that these various atypical qualities of spoken language are more common than average among individuals on the autism spectrum. Explanations and practical uses for that observation are harder to come by. But it is clear that there is enormous potential to learn in the area of overlap between autism spectrum disorder (ASD) and speech-language variation.

For example, measurements of voice characteristics and speech patterns could be a valuable tool for research because they are a naturally occurring indicator of what is happening in the brain, noted Julia Parish-Morris, PhD, a postdoctoral fellow in the Center for Autism Research at The Children’s Hospital of Philadelphia, during her research presentation at the inaugural Workshop on Linguistic Approaches to Autism and Neurodevelopmental Disorders (LAAND) May 9.

Dr. Parish-Morris spearheaded organizing the workshop to bring together a small, diverse group of researchers and clinicians who share an interest in this emerging area of research. The workshop was held at the Linguistic Data Consortium (LDC) at the University of Pennsylvania in the week preceding the International Meeting for Autism Research (IMFAR) in Baltimore.

“I hope that bringing together researchers from multiple disciplines looking at autism through the lens of language will lead to new and stronger collaborations,” Dr. Parish-Morris said. “Different people bring different backgrounds and perspectives to the same questions.”

Using Voice as a Measurable Indicator of ASD

Efforts to use voice or speech as a systematic and measurable indicator of ASD or its clinical symptoms are still in their early days. Published empirical research to date on voice in ASD has been “scarce, unsystematic, and contradictory,” according to Riccardo Fusaroli, PhD, an assistant professor at Aarhus University in Denmark who led a meta-analysis of this work. He presented findings from the analysis at the LAAND workshop and has a manuscript under review.

Sustained and systematic research into using voice as an indicator of ASD could yield dividends, however. Dr. Parish-Morris noted that language metrics may be especially useful for measuring ASD because speech is fundamentally social — while many ASD-associated deficits are also social — and most children on the autism spectrum acquire spoken language, or at least vocalize in some way that could be measured even if spoken language is not their primary form of communication.

One way she and colleagues are beginning to explore the use of voice as an indicator of ASD is through analysis of existing recordings of ASD behavioral assessment interviews. Worldwide, thousands of video and audio recordings of Autism Diagnostic Observation Schedule (ADOS) assessments fill the closets and hard drives of autism research centers and behavioral health clinics. This widely used behavioral assessment method for ASD involves play-based interactive interviews between a clinician and patient or research participant. These interview sessions are commonly recorded for reliability and clinical supervision purposes, then stored away.

Seeking to Describe and Explain Patterns of Speech Disfluency in ASD

At the LAAND workshop, Joseph Donaher, PhD, of the Center for Childhood Communication at CHOP, shared one project focused on ASD and lapses in speech fluency that uses recorded speech from ADOS interviews as a data source.

He pointed out that in his specialty of speech-language pathology, differentiating specific types of speech disfluency gives clues to the underlying cognitive or neurological process that a speaker is experiencing. For example, repeating a word commonly reflects that the speaker is struggling to think of the next word or phrase, whereas repeating syllables is a stuttering-like disfluency, which in many cases has a neurological cause.

Working together for the past year or so, Dr. Donaher, Dr. Parish-Morris, and colleagues, have used ADOS recordings to better understand the relationship between ASD and speech disfluency patterns. In their preliminary results discussed at the workshop and presented at IMFAR, children with ASD had an overall similar level of disfluency compared to other children, but the pattern of disfluency type was unexpected. Children with ASD were more likely than the comparison groups to have stuttering-like disfluencies and less-studied atypical disfluencies, such as prolongation of syllables.

Linking Linguistic Characteristics With Clinical Characteristics in ASD

In another project shared at the LAAND workshop, Dr. Parish-Morris and CAR’s director, Robert Schultz, PhD, have teamed up with the LDC at Penn, with collaborators including LDC Director Mark Liberman, PhD and Executive Director Christopher Cieri, PhD.

This CAR/LDC collaboration is processing and analyzing ADOS recording samples in an effort to correlate linguistic factors with children’s clinical characteristics. The project is currently in a pilot phase to assess feasibility and to identify which linguistic factors can be most useful, and it has included ADOS evaluations of 100 children so far. The team has evaluated differences between children with and without ASD in subject matter (such as frequency of using words about friends vs. words about family), rate of speech, and overall word choice.

This type of analysis is potentially extremely powerful because these ADOS recordings come with metadata from the original CAR research studies for which families enrolled — ranging from behavioral data, to genetics and brain scans. (CHOP’s Institutional Review Board approved the reuse of the selected ADOS recordings for linguistic study.)

If the team is successful in its goal of applying machine learning tools to classify and learn from these language samples, then such research could potentially grow into a large-scale enterprise, including larger volumes of speech samples from sources other than ADOS recordings. The LDC’s experience with scalable speech-sampling methods via phone banks could provide the groundwork for such future collections.

Future Aspirations: Continued Collaboration and Shared Data Collection on Language and ASD

Dr. Liberman, who is also a professor of Linguistics and Computer and Information Science at Penn, closed the workshop with a discussion of how a large-scale, multi-site collaboration and data source for speech-language studies of ASD could proceed in the future.

The LDC has a repository of more than 250,000 speech samples collected via phone calls from 25,000 individual speakers over decades of linguistic studies. Open sharing of data about these samples has transformed speech/language research, and similar shared-data repository efforts could be the future of biomedical research, including the linguistic analysis of ASD, Dr. Liberman said.

Dr. Parish-Morris is hopeful that the inaugural workshop on language and ASD will become the first in a series of annual meetings to bring together more researchers as interest in this subject continues to grow.

The McMorris Autism Early Intervention Initiative Fund at CHOP and Penn funded the workshop. Additional speakers were Lisa Blaskey, PhD, a pediatric neuropsychologist in the department of Radiology at CHOP who brought a clinical perspective on language disorders and ASD; Ani Nenkova, PhD, an associate professor of Computer and Information Science at Penn, who shared ongoing research on associations between ASD-like characteristics and perceptions of written text; and Ethan Weed, PhD, of Aarhus University, who shared research on how interactive alignment between speakers differs among speakers on the autism spectrum.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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