CCH_RAR_2012

2012

A N N U A L R E P O R T

CINCINNATI CHILDREN’S RESEARCH FOUNDATION ANNUAL REPORT

/////////////// RESEARCH

breakthroughs

2012

A N N U A L R E P O R T

DIVISION ACCOMPLISHMENTS

CINCINNATI CHILDREN’S RESEARCH FOUNDATION ADMINISTRATIVE STAFF

20

Arnold Strauss, MD Director

Christopher Wylie, PhD Associate Chair, Research

Tracy Glauser, MD Associate Director

Kenneth Campbell, PhD Director, Basic Surgical Research

Jeff Whitsett, MD Interim Associate Director

Michael Helmrath, MD Director, Translational Surgical Research

Mitchell Cohen, MD Vice Chair, Clinical Affairs

John Maybury Vice President, Administration & Finance

Adolescent Medicine Allergy/Immunology James M. Anderson Center for Health Systems Excellence Anesthesia Asthma Research Biomedical Informatics Biostatistics and Epidemiology Behavioral Medicine and Clinical Psychology Cancer and Blood Diseases Institute Cellular and Molecular Immunology Center for Technology Commercialization Center for Clinical and Translational Science and Training Clinical Pharmacology Critical Care Medicine Dentistry Developmental and Behavioral Pediatrics Pediatric Dermatology Developmental Biology Drug and Poison Information Center

Sandra Degen, PhD Associate Chair, Academic Affairs

Jana Bazzoli Vice President, Clinical Affairs

46

Thomas DeWitt, MD Associate Chair, Education

Kristine Justus, PhD Vice President, Research Operations & Management

Michael Farrell, MD Associate Chair, Clinical Services James Heubi, MD Associate Chair, Clinical Investigation Jeffrey Robbins, PhD Associate Chair, Research

RESEARCH COMMITTEE MEMBERS OF THE BOARD OF TRUSTEES Nancy Krieger Eddy, PhD Chair Robert Anning Richard Azizkhan, MD Lee Carter Thomas Cody Michael Fisher Arnold Strauss, MD

Nicole Robinson, PhD Assistant Vice President, Center for Technology Commercialization Jeremy Corsmo Senior Director, Office of Research Compliance and Regulatory Affairs

COMMUNITY ADVISORS Steven Goldstein James Schwab Craig Young Thomas Boat, MD

Emergency Medicine Endocrinology Every Child Succeeds Gastroenterology, Hepatology, and Nutrition General and Community Pediatrics General and Thoracic Surgery Global Child Health Hospital Medicine Human Genetics Heart Institute Infectious Disease Mayerson Center for Safe and Healthy Children Neurology Nephrology and Hypertension Neurosurgery Ophthalmology

68

Otolaryngology Orthopaedics Pathology and Laboratory Medicine Pediatric and Adolescent Gynecology Physical Medicine and Rehabilitation Plastic Surgery Psychiatry Pulmonary Medicine Radiology Reproductive Sciences Rheumatology Schmidlapp Center Section of Neonatology, Perinatal and Pulmonary Biology/ Perinatal Institute Sports Medicine Urology

TABLE OF CONTENTS

FROM THE TOP

F E AT U R E S

Message from the Director

2

Message from the Board

4

6

12

BY THE NUMBERS

Program Awards

78

Funding Sources

79

Faculty + Clinical Statistics

80

Training

81

Procter Scholars

83

64

Heart attack drug slows deadly heart damage for kids with Duchenne muscular dystrophy

Sickle cell disease – is a cure in sight?

Promising new gene therapy trial begins this year

30

A giant step for cystic fibrosis

34

Writing the next chapter in organ transplantation

‘Quantum leap’ in CF treatment brings relief, hope for long life

New technology, treatments, follow-up help kids live well, long beyond transplant

54

Surfactant D: growing a big idea

58

Breakthroughs in cancer and blood disease research

RETROSPECTIVE

History of Advances at Cincinnati Children’s Hospital Medical Center

Old drug, new tricks

Start-up company wants to get breakthrough treatment to more babies

Findings hold potential benefits for illness, aging

2012 ANNU A L R E P O RT // 1

DIRECTOR M E S S A G E

breakthroughs C R E AT I N G M E D I C A L

“All of these achievements come from combining the right talent with the right resources in the right environment.”

A R N O L D W. S T RAUSS, MD 2 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

(left)

A R N O L D W. S T R A U S S , M D Director of the Cincinnati Children’s Research Foundation // Rachford Professor and Chair of the Department of Pediatrics, University of Cincinnati College of Medicine

FROM THE DIRECTOR

Our challenge: How do we create breakthroughs in scientific discovery and medical treatment?

We believe it takes the courage to ask difficult questions, the creativity to develop ideas, the intellect and talent of our faculty and staff, and the discipline and dedication to continue our history of scientific discoveries. This is how we have produced the breakthroughs that have benefited children over the 85 years since the founding of our Cincinnati Children’s Research Foundation (CCRF).

This year’s research report summarizes the work of our exceptional research divisions. More detail is available online. In selected stories, we profile the efforts of a few extraordinary scientists and clinicians who have joined forces to tackle some of the most perplexing childhood diseases.

For all of the physicians and scientists here at CCRF, there are countless problems to be solved. Too many of the children cared for at Cincinnati Children’s have diseases, conditions and disorders for which treatments do not exist or are far from ideal. The challenge to find novel therapies and improve current ones sparks, focuses and inspires us. It generates conversations between scientists in our laboratories and physicians on the front lines of the hospital, always asking, “How can we do better?” The challenge encourages collaborations that merge perspectives, experience and ideas to bring about answers.

You will find some of the results described in these pages. For example, advances in organ transplantation that are transforming outcomes; potentially game-changing treatments for children with cystic fibrosis and sickle cell disease; breakthrough findings in restoring stem cell function and reducing the inflammation that causes cancer and other diseases.

All these discoveries are possible because of the collaboration encouraged here. We are privileged to have such an exceptional clinical facility – Cincinnati Children’s Hospital

Medical Center – as our living laboratory. Here, researchers see first-hand the challenges doctors and families face as we care for children from around the world. Within CCRF, we provide the environment and resources to seek answers.

The relationship between the Research Foundation and the Hospital is a major factor in our success. Our collaborative, multidisciplinary approach has helped attract the best and brightest to our research divisions. This year: • We appointed 68 new investigators to the Research Foundation, bringing our total to 631 full- and part-time faculty.

•

We received $107 million in funding from the NIH, placing us once again among the nation’s top-funded pediatric research institutions.

•

Overall, we received more than $173 million in research funding, a nearly 13 percent increase from last year.

•

Our faculty published more than 1,400 articles in peer-reviewed journals.

•

And to keep up with our continuing growth, we began construction of a 425,000-square-foot Clinical Sciences tower that will bring our total research space to 1.4 million square feet.

These achievements come from combining the right talent with the right resources in the right environment. Take a look at what people who are extraordinarily talented and motivated can do. This is how we answer the challenge and create medical breakthroughs.

2012 ANNU A L R E P O RT // 3

B O A R D M E S S A G E

better + longer

HELPING CHILDREN LIVE

(Above, from left) Thomas Cody, Chairman, Board of Trustees; Nancy Eddy, PhD, Research Chair; Michael Fisher, President & CEO of Cincinnati Children’s

Working for and with a medical center that cares for some of the sickest children is a privilege as well as an awesome responsibility. It is heightened by the awareness that our research has helped change the course not only for children in our care, but for countless children around the world.

4 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

What makes these stories even more remarkable is that every breakthrough described here started as an idea, a researcher asking, “why?”

FROM THE BOARD This year’s research annual report showcases some of the breakthrough findings that have placed us among the nation’s leaders in pediatric medicine. In this report, we focus on our research in areas of childhood illness that have troubled doctors for generations.

What happens when a child’s organs stop working? Here, you will read about the latest science in organ transplantation — crucial discoveries that have led to changes in what we do before, during and after transplant. These advanced approaches are helping children live better and longer. But there is much more to be done, and you will also learn where transplantation is heading.

In the battle against sickle cell disease, years of research and preparation have put us on the threshold of testing a potential cure.

We report on a drug for cystic fibrosis that researchers believe will allow some patients to live into later adulthood and beyond — and how our exploration of its use with other drugs might offer the same chance to many more.

Our cancer researchers have discovered a way to reverse the aging of bone marrow stem cells, with exciting potential for slowing the aging process and treating cancers. In another study, researchers discovered a compound that regulates the body’s inflammatory process and appears to stop the growth of cancer.

And there is more, all of it equally compelling. What makes these stories even more remarkable is that every breakthrough described here started as an idea, a researcher asking, “why?”

Moving from that moment of “why” to the “aha” of a breakthrough is the hard work of research. It takes time — years of testing, failing, revising, and continuing forward. It takes long hours of methodical and exacting effort. And it takes support — support for the skilled staff, the right tools, the right

environment, and the time — to make the exploration possible.

Ensuring the support for our research endeavors is paramount. We do it by providing funding through our endowment, our clinical endeavors, philanthropy, business partnerships and other revenue sources. We do it by building state-of-the-art facilities such as our new clinical sciences building, now underway.

And we do it by recognizing the integral role played by our outstanding basic and clinical researchers.

Their science is the fuel for our clinical achievements. Without it, medicine would stagnate. Breakthrough treatments would cease. And children would continue to suffer and die.

The work featured here — just a sampling of our overall research — is evidence of that. We invite you to read on, and see for yourself.

2012 ANNU A L R E P O RT // 5

“The most important part about this kind of trial is to help prove that the medication does work to improve the patient’s life.”

KAN HOR, MD

Dr. Kan Hor, a pediatric cardiologist in the Heart Institute at Cincinnati Children’s, is researching whether eplerenone, a drug commonly used to treat high blood pressure in adults, could stop heart damage in boys with Duchenne muscular dystrophy.

6 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

MUSCULAR DYSTROPHY

buying

time

RESEARCHER EXPLORES WHETHER A HEART MEDICINE COULD HALT A DEVASTATING MUSCLE DISEASE

Kan Hor, MD, is racing the clock to catch a killer. Armed with imaging tools to detect early signs of heart disease, the pediatric cardiologist knows what he is after: Duchenne muscular dystrophy.

But the killer is quick. It destroys muscles in young boys, leaving them wheelchairbound by age 12 and lucky if they reach their third decade of life at all. Most of its victims die of heart problems.

“In the past, these boys were left untreated because of their short lifespan,” Hor says.

“But that’s exactly the reason to treat these patients — so that they can not only live longer but live a better quality of life.”

THE MAGIC BULLET? The magic bullet against Duchenne may be within reach. An anti-fibrosis drug called eplerenone, which has long been used to treat heart attack victims, shows promise against the disease.

Extensive research, including studies in mice affected with Duchenne, suggests that the drug could slow or stop heart damage that makes the disease deadly.

As principal investigator at Cincinnati Children’s, Hor and the Duchenne care team work with doctors from Ohio State University and The Christ Hospital in Cincinnati on a clinical trial that is the first of its kind. It will test the drug regimen to see if earlier diagnosis and treatment with anti-fibrotic medication could help patients with Duchenne survive longer.

“We know that many patients with Duchenne muscular dystrophy die from heart disease, within the second or third decade of life,” Hor says. “By decreasing the scar burden, we hope to see that the function will remain normal longer, which could lead to improved quality of life.”

THE DRUG Eplerenone, which has long been used to treat heart attack victims

A P P L I C AT I O N The drug could slow or stop heart damage that makes Duchenne muscular dystrophy deadly.

T R E AT M E N T U S E It may help to decrease scarring in the heart, which could help patients with Duchenne muscular dystrophy live longer.

2012 ANNU A L R E P O RT // 7

MUSCULAR DYSTROPHY

///////////////////////////////////////////////////////////////

THE SOONER THE BETTER Hor and his colleagues use enhanced cardiac magnetic resonance imaging — more sensitive than a standard echocardiogram — to catch slight declines in heart function even before patients are teenagers.

John “Lynn” Jefferies, MD, Director of Advanced Heart Failure and Cardiomyopathy, says this makes Cincinnati Children’s a bit of a trendsetter.

Advanced non-invasive imaging allows doctors to deliver better care, he says.

“Very few institutions would entertain the possibility of cardiovascular involvement at a young age,” he says. “We feel that because this is such a devastating illness, early diagnosis can lead to early intervention. And early intervention can, in theory at least, lead to better outcomes.”

HOW IT ATTACKS One out of every 3,500 boys is born with Duchenne muscular dystrophy, also known as DMD. It is one of the most common forms of muscular dystrophy. Duchenne is a mutation that leaves boys without the gene that encodes for dystrophin protein. The lack of dystrophin causes muscles to deteriorate.

Patients with Duchenne have trouble moving their hands and arms by their late teens, and it soon becomes difficult to swallow, speak or even breathe without a ventilator.

Until recent improvements in respiratory therapy, patients often died of respiratory failure. Today, most patients die because the disease wears down their heart function.

T H E T R I A L // In the double-blind, randomized trial, 20 patients will receive a placebo, and 20 patients will receive the study medication. Researchers plan to collect preliminary data within about two years.

8 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Doctors at Cincinnati Children’s follow about

500 PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY

DEFINITIVE ANSWERS Doctors at Cincinnati Children’s follow about 500 patients with Duchenne. Over the next year, they will be recruiting 40 boys, age 7 and older, to be part of the clinical trial.

In the double-blind, randomized trial, 20 patients will receive a placebo, and 20 patients will receive the study medication. Researchers plan to collect preliminary data within about two years.

Hor’s goal is to come up with definitive answers that will lead to better treatment and stop the disease from killing more kids.

“The most important part about this kind of trial is to help prove that the medication does work to improve the patient’s life by keeping the function normal for a longer period of time,” he says.

Someday, a stem cell transplant may be able to replace abnormal cells and cure kids with Duchenne, Hor says. “In the meantime, we are hoping to keep our patients alive longer so they may have the potential to receive those treatments in the future.” g

“We are hoping to keep our patients alive longer so they may have the potential to receive those treatments in the future.�

KAN HOR, MD

2012 ANNU A L R E P O RT // 9

SUCCESS S T O R Y

WATCH ONLINE as Andrew Steele and his dad, James, talk with pediatric cardiologist Dr. Kan Hor about what it is like to fight Duchenne muscular dystrophy.

Go to www.cincinnatichildrens.org/story

10 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

’ H I C C U P I N D N A’ L E A D S T O

hope for a cure All James Steele ever needed to know about muscular dystrophy, he learned watching “The Jerry Lewis MDA Labor Day Telethon” as a kid. That was enough — until he had a son diagnosed with the disorder.

Steele and his wife, Ann Marie, sought help for their son Andrew when he was a preschooler. Andrew was a late walker, and could not run and jump like other kids his age. When he was 6, doctors confirmed he had Duchenne muscular dystrophy, a deadly inherited disorder in boys that progressively destroys the body’s muscles.

“It socks you in the gut pretty hard,” Steele says of the diagnosis. “It was devastating for the entire family. But now it’s something we live with. He’s just a 12-year-old kid with one small hiccup in his DNA.”

“My favorite quote is from ‘Back to the Future.’ It goes: ‘If you put your mind to it, you can accomplish anything.’ ” ANDREW STEELE, 12, PAT I E N T W I T H D U C H E N N E M U S C U L A R D Y S T R O P H Y

Andrew is a boy with a big personality and a sense of purpose. He is a computer whiz and an entertainer who wants an iPhone and the freedom to watch YouTube videos whenever he wants. The seventh-grader sees himself — from the Duchenne perspective — as someone with half his life left to figure out how to “get cured.”

He decided to enroll in a research study at Cincinnati Children’s testing a drug that could stall heart damage.

“I believe one day there just might be a cure,” Andrew says. “I’m that hopeful.”

Hospital visits and blood draws have become part of his routine. He has learned how to do wheelies on the wheelchair he uses to go long distances. Sometimes he looks up his condition on the internet and reads about people with Duchenne’s dying young. He wants to beat the odds.

“Even though I have this dreaded disease, I still live happily,” says Andrew, a movie buff who likes to recite his favorite lines. “My favorite quote is from ‘Back to the Future.’ It goes: ‘If you put your mind to it, you can accomplish anything.’ ”

2012 ANNU A L R E P O RT // 11

Dr. Punam Malik, (above), a researcher and hematologist at Cincinnati Children’s, thinks the cure for sickle cell disease lies in a gene we are all born with.

12 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

SICKLE CELL D I S E A S E

applying nature’s

lessons

Scientists go back to basics for treatment that could yield cure for sickle cell disease

In the United States, more than

100,000 P E O P L E H AV E S I C K L E CELL DISEASE.

More than 100,000 people in the United States have sickle cell disease. Some 1,000 children are born in this country each year with the condition, which causes episodes of crippling pain, damage to tissue and organs, and can sometimes be fatal. In Africa, nearly 1,000 children are born with the disease every day.

There are treatments that manage symptoms with varying degrees of success, but the only cure is a bone marrow transplant from a matched sibling. This cure, unfortunately, is only available to 10 to 15 percent of all patients and carries side effects that include rejection of the transplanted bone marrow.

Punam Malik, MD, a researcher and hematologist at Cincinnati Children’s, is about to launch a clinical trial that could change that.

She thinks the cure for sickle cell disease lies in a gene we are all born with.

A P P L I C AT I O N The vector Malik and her team developed prevents the sickle hemoglobin from forming long fibers or polymers, which is what causes them to change shape.

COMING NEXT Phase I/II clinical trial will begin by end of the year in adults, then extend to children.

2012 ANNU A L R E P O RT // 13

SICKLE CELL D I S E A S E BACK TO THE WOMB Malik has identified a way to alter the genetic makeup of sickle cell patients by adding a modified fetal hemoglobin (HbF) gene.

For most people, HbF turns off around six months after birth and we begin producing adult hemoglobin (HbA). But children with the sickle cell mutation begin to produce a defective form of adult hemoglobin, hemoglobin S (HbS), which causes normally round red blood cells to take on the sickle shape that is characteristic of the disease.

In their search to end this cycle, Malik and her team took a lesson from a natural aberration.

“There are human beings in this world who live on fetal hemoglobin even as adults,” she says. “They don’t switch off their fetal hemoglobin gene, ever.”

In Africa, where sickle cell disease is common, adults with the fetal hemoglobin (HbF) gene had only mild cases of sickle cell disease. The researchers also found that when people with HbF had thalassemia — a disorder in which the body produces no red blood cells — they had no symptoms.

Borrowing from nature, Malik and her team developed a treatment that mimics production of HbF. HOW IT WORKS

Malik’s team genetically engineered an HbF producing gene to fool the cell into believing it is actually an adult globin gene, so that it stays “on.” They also manipulated the gene so that it preferentially forms HbF in the presence of HbS.

Malik and her team expect to start the Phase I/II clinical trial by end of year in adults. If all goes well, they will extend the trial to children.

14 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

“We thought, nature has shown us this works — people can live into adulthood with HbF, so let’s figure out a way to put in a HbF gene that doesn’t turn off,” says Malik.

She developed a vector with a HbF producing gene and modified the gene so that its “on” switch remains permanently flipped, counteracting the sickle hemoglobin and preventing sickling. She then worked with scientists in Cincinnati Children’s Vector Production Facility (see next page) to develop the clinical grade of this vector.

“We genetically engineered it to fool the cell into believing that it is actually an adult globin gene, so that it stays on. We also manipulated the gene so that it preferentially forms HbF in the presence of HbS.” The vector Malik and her team developed prevents the sickle hemoglobin from forming long fibers or polymers, which is what causes them to change shape. In the process of testing the vector, the researchers found that it cured thalassemia as well.

“We have mice with sickle cell disease and mice with thalassemia, and we take their bone marrow, remove the stem cells, fix them and give it back to them, and they are cured of the disease,” she says.

EXPANDING THE TRIAL Malik and her team expect to start the Phase I/II clinical trial by end of year in adults.

If all goes well, they will extend the trial to children.

Malik says despite the remarkable success they have had in animal trials, the next steps of applying the treatment to humans will be slow and careful.

“First we have to know: is it safe, is it effective? Is it effective in every sickle patient?,” she says. “Then we have to streamline and simplify the process, and expand it to more people. But we wouldn’t go into a trial if we didn’t think it would work.” g

“There are human beings in this world who live on fetal hemoglobin even as adults. They don’t switch off their fetal hemoglobin gene, ever.”

P U N AM MALIK, MD

MOSQUITOES AND SICKLE CELL When a malaria-carrying mosquito slides her needle-like proboscis into the arm of an unsuspecting victim, she unleashes a parasite and a reproductive free-for-all.

The parasite quickly finds its way to the liver, then into the bloodstream, dividing exponentially as it goes. Left unchecked, a single parasite can destroy all of its victim’s red blood cells within two weeks.

In tropical areas of the world where malaria is common, nature has provided some people protection against this assault.

They carry a genetic trait that causes their red blood cells to sickle, or harden into a crescent shape, when infected by the malaria parasite. This appears to stunt the parasite’s ability to reproduce.

The same genetic trait that affords protection from malaria, however, can cause sickle cell disease. People who receive the mutated gene from both parents are at highest risk of developing the lifelong, cripplingly painful and sometimes fatal sickle cell disease.

Sickle cell disease causes red blood cells to have a distinctive crescent-like, or sickle, shape.

The cells are unable to carry oxygen throughout the body; they clump together, blocking blood flow, damaging organs and causing severe pain.

2012 ANNU A L R E P O RT // 15

C O R E L A B O R AT O R Y

16 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

developing a clinical-grade vector O U R C O R E L A B O R AT O R I E S M A K E I T P O S S I B L E Few pediatric hospitals are able to handle every stage of producing the gene therapy for a Phase I/II clinical trial such as the sickle cell study.

Cincinnati Children’s exceptional core laboratories support every stage of cell-based therapy, from developing the vector through its use in patients and follow up testing to evaluate effectiveness.

CHOOSING THE VECTOR

The treatment that will be used in the sickle cell clinical trial began many years ago with the choice of the vector, which serves as the transport medium to deliver the treatment to the cells. Years of research have taught that viruses make good vectors.

Lentivirus was chosen as the vector for this trial because it can handle the large size of the hemoglobin gene being transferred and allows permanent integration of the gene into the target cells. Our scientists modified the virus to remove all potentially harmful genes and any genes that would result in a virus infection.

“The only gene the vector will transfer to the patient’s cells is the gene we have engineered to be part of the trial,” says Han van der Loo, PhD. Van der Loo (at left) directs the Vector Production Facility at Cincinnati Children’s. He and his team have spent two years perfecting the manufacturing process of vector for the sickle cell trial.

“Our challenge was to figure out how to best capture, purify and concentrate the virus, and make enough to serve the clinical trial,” says van der Loo.

“Our challenge was to figure out how to best capture, purify and concentrate the virus, and make enough to serve the clinical trial.”

H A N VA N D E R L O O , PhD

2012 ANNU A L R E P O RT // 17

C O R E L A B O R AT O R Y

///////////////////////////////////////////////////////////////

Once van der Loo and his team were satisfied that the vector process was working as it should, a clinical batch of vector was prepared and samples were sent to outside facilities to be tested for potency, purity and safety. Testing is extensive, and everything hinges on the results.

“FDA approval is based on the lab’s ability to produce this safely and effectively,” van der Loo says. “We have to provide the material at the proper purity and strength for the doctors to do their investigation which is key to the trial.”

WHEN THE TRIAL BEGINS Patients in the study will be followed for

15

YEARS AFTER TREATMENT

Once the trial starts, another of Cincinnati Children’s core laboratories, the Cell Manipulation Laboratory (CML), takes over. Carolyn Lutzko, PhD, and Diana Nordling co-direct the CML. Nordling will oversee what happens in the clinical laboratory from the time the patient’s bone marrow — roughly a quart of it — is removed until the vector is added and the marrow is re-injected into the patient.

“Our job is to make the procedure as safe as possible,” says Lutzko, who came to Cincinnati Children’s two years ago to work on this project. “We have to move

“Our job is to make the procedure as safe as possible. We have to move everything into an environment and a method that can be used in humans.”

C A R O LYN LUTZKO, P hD

18 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

It takes 48 hours of aroundthe-clock, precise testing and teamwork from the time a patient’s bone marrow is removed until it is reinjected with the vector added, says Diana Nordling (at right).

everything into an environment and a method that can be used in humans.” She and her development team have performed dozens of trial runs to make sure the processing method goes smoothly.

It works like this: the patient’s bone marrow will be brought to the clinical lab within 20 to 30 minutes after it is removed. For the next 48 hours, a team working around the clock in a highly controlled environment will isolate the blood stem cells and will twice add the vector that holds the healthy genes produced by van der Loo’s group.

IS IT WORKING?

Nordling’s role is also to ensure FDA requirements for gene therapy are met, which includes extensive testing throughout the procedure to determine if things are working as they should. “We collect the cells and do a lot of testing to make sure the product is safe and it’s what we expect,” she says.

What they expect is that the healthy blood cells with the modified gene will enter the patient’s stem cells and start taking over.

“During the processing we will be looking to see, are the cells alive, are there enough, is the product still free of contamination?” says Nordling.

It could be weeks or months before doctors see evidence of the therapy’s effectiveness.

Patient samples will continue to be analyzed at regularly scheduled visits to determine if the fetal hemoglobin is present, and in what quantity. Patients who participate in the study will be followed for 15 years after treatment.

The hope is that those 15 years will be without an incident of sickle cell disease. g

Ensuring that FDA requirements for gene therapy are met demands extensive testing throughout the procedure to determine if things are working as they should.

2012 ANNU A L R E P O RT // 19

RESEARCH OVERVIEW

division accomplishments

ADOLESCENT MEDICINE Eating Disorders Program // The Eating Disorders Program, directed by Laurie Mitan, MD, provides a safe, supportive, caring environment while using evidence-based approaches to treat adolescents with eating disorders. The program includes clinical, research and training missions, and incorporates faculty and staff from the Divisions of Behavioral Medicine and Clinical Psychology, Child Psychiatry, Nutrition Therapy and others. Working closely with Abbey Tissot, PhD, Associate Director of Research, our program members presented three well-received posters at the 2012 annual meeting of the Academy of Eating Disorders. The posters explore the longitudinal development of eating disorder symptoms as they relate to physical development, meal content and meal timing.

ALLERGY AND IMMUNOLOGY Positive Results from Monoclonal Antibody Clinical Trial // Amal Assa’ad, MD, Clinical Director, was lead author for “Antibody Against IL-5 Reduces Numbers of Esophageal Intraepithelial Eosinophils in Children with Eosinophilic Esophagitis,” published in Gastroenterology. This multicenter, international project showed positive results using an anti-IL-5 antibody to treat eosinophilic esophagitis in children and was the first clinical trial to document the use of a monoclonal antibody in children as young as two years of age. This is promising news for the treatment of eosinophilic disorders, as these conditions are chronic and often present at an early age. This clinical trial was based on basic and translational work

by Marc Rothenberg, MD, PhD, Division Director.

MicroRNA Biomarkers and Regulators of Allergic Disease // Rothenberg has identified a dysregulated microRNA signature that correlates MICRO with disease activity for eosinophilic esophagitis, a severe food allergy. Promisingly, the most elevated microRNA in the signature, miR-21, regulates T cell polarization and activation in preclinical models. are involved in fine-tuning Rothenberg also identified a microRNA, miRinterleukin-13-mediated 375, that regulates interleukin-13, a key immune immune responses. hormone in allergic reactions. These findings are proof of principle that microRNAs are involved in fine-tuning interleukin-13-mediated immune responses and show promise for use of microRNAs, such as miR-21 and miR-375, as noninvasive biomarkers and therapeutic targets for allergic disease.

These findings are proof of principle that

RNAS

New Faculty Member Targets Home Environment in Asthma Outcomes // Recently appointed faculty member Terri Moncrief, MD, researches the impact of single parenthood, family routines and allergic sensitizations on asthma outcomes. Moncrief, under the direction of Robert Kahn, MD, MPH, is executing a multidimensional analysis of the home environment and its effect on asthma morbidity in disadvantaged populations. Several of her studies were presented at national conferences, and her research will help develop tools to identify at-risk children and guide intervention strategies.

20 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Advocacy for Youth in Detention // Paula Braverman, MD, Director of Community Programs, serves as the Medical Director of the Hamilton County Juvenile Court Youth Center, also known as “2020.”

She is recognized nationally for her advocacy and care of detained youth. Braverman was the lead author on a policy statement from the Committee on Adolescence, published in Pediatrics, which outlines standards for health care and evidence-based interventions for youth in the juvenile correctional system. This high-risk population often has unmet physical, developmental, and mental health needs that occur at higher rates than in the general population. The policy statement urges improved identification of health needs when youth enter detention facilities.

Braverman was the lead author on a policy statement that outlines standards for health care and evidence-based interventions for youth in the juvenile correctional system.

JAMES M. ANDERSON C E N T E R F O R H E A LT H S Y S T E M S EXCELLENCE Solutions for Patient Safety // With leadership from Stephen Muething, MD, the Anderson Center is bringing patients and clinicians together to improve care and outcomes. This year the Ohio Children’s Hospitals’ Solutions for Patient Safety (OCHSPS) received $4.3 million from the Center for Medicare & Medicaid Innovation to spread safety programs established at eight Ohio hospitals to 25 more nationwide. OCHSPS was the only pediatric-focused hospital network to receive grant support this year. In January, the network plans to add another 50 hospitals. The network’s goals include reducing hospital acquired conditions by 40 percent, reducing preventable THE TEAM HAS VALIDATED THE MODEL IN readmissions by 20 percent and and is collaborating reducing serious safety events by with researchers 25 percent.

74

worldwide on further refinements.

The MUSIQ of Success // Investigators led by Heather Kaplan, MD, MSCE, have developed a new model that organizations can use to maximize the success of quality improvement projects. The Model for Understanding Success in Quality (MUSIQ) identifies 25 contextual factors that can influence QI success. The team has validated the model in 74 QI projects and is collaborating with researchers worldwide on further refinements.

QI PROJECTS

A PROMIS to Improve Patient Self-Reports // Cincinnati Children’s is one of 12 research centers participating in the Patient Reported Outcomes Measurement Information System (PROMIS), funded by the National Institutes of Health. This project uses measurement science to improve patient selfassessments of their physical, mental and social health. The work includes developing computer algorithms to select the most informative questions for patients based on responses to earlier questions. Esi Morgan Dewitt, MD, MSCE, leads a team of Cincinnati Children’s researchers who are conducting validation studies of PROMIS in children with juvenile idiopathic arthritis, chronic pain, and cerebral palsy. The team also is developing new pediatric measures of pain behaviors and pain quality.

ANESTHESIOLOGY Faculty Research and Honors // Our faculty delivered 78 lectures, presented 27 research abstracts, published 25 peer-reviewed papers and authored 55 review articles and book chapters — a 300 percent increase from the year before. Our faculty also received 15 extramural research grants.

Melissa Neeplo, RN, Anna Varughese, MD, Alex Szabova, MD, Paul Samuels, MD, Joseph Previte, MD, Andreas Loepke, MD, PhD, and Lynn Kling, RN were recognized for exemplary patient-centered care by the Family Advisory Council. Mike Jankowski, PhD, received the Rita Allen American Pain Society Scholarship. The Society for Pediatric Anesthesia awarded first prize to Chris Ward, MD, for his research study on anesthetic neurotoxicity.

And the journal Pediatric Anesthesia declared “Quality in pediatric anesthesia,” — co-authored by Anna Varughese MD, Nancy Hagerman, MD, and Dean Kurth, MD — as the best paper of the year.

Telemedicine Program Launched // Our new telemedicine program in neurophysiological monitoring for orthopedic spine surgery and neurosurgery is the first of its kind for a pediatric anesthesiology department.

Led by John McAuliffe, MD, MBA, Lisa Francis, DO, and Mohamed Mahmoud, MD, the program expanded clinical activity in neuromonitoring by 125 percent.

Major Steps in Training // The Accreditation Council for Graduate Medical Education (ACGME) approved our Pediatric Pain Medicine and Palliative Care fellowships, making us unique among children’s hospitals. We also worked with several medical centers in China to create a two-year pediatric anesthesia research fellowship.

Three fellows from Shanghai and Wenzhou will start in FY13. This effort was led by our program Director, Junzheng Wu, MD, Steve Danzer, PhD, Andreas Loepke, MD, PhD, and Senthil Sadhasivam, MD.

Our faculty delivered 78 lectures, presented 27 research abstracts, published 25 peer-reviewed papers and authored 55 review articles and book chapters — a 300 percent increase from the year before.

2012 ANNU A L R E P O RT // 21

RESEARCH OVERVIEW

division accomplishments

B I O M E D I C A L I N F O R M AT I C S Data Warehousing & Software Development // The data warehousing group, led by Keith Marsolo, PhD, continued adding data from the Epic electronic health record (EHR) into the de-identified i2b2 warehouse and providing investigators with more than 100 research datasets each year. The i2b2 group participates in the seven-center Shared Health Research Information Network (SHRINE), a project to prove the feasibility of creating data-sharing networks and examining co-morbidities in patients with diabetes mellitus II or autism spectrum disorders. The group also supports the institution’s efforts to create a research biorepository.

Pyrosequencing Core // Our Division played a leading role in launching the new Pyrosequencing Core Laboratory for Genomic and Epigenomic Research. This core lab, directed by Hong Ji, PhD, facilitates the study of epigenetic regulation mechanisms underlying normal development and disease pathogenesis. Equipped with a Qiagen PyroMark Q96 system, the core detects and quantifies genetic variation via DNA methylation by pyrosequencing. The core has begun working with several researchers at Cincinnati Children’s and the University of Cincinnati. It also helps faculty write grant proposals, two of which have been funded so far.

Marsolo’s software group developed the data infrastructure used by members of Best Evidence for Advancing Child Health in Ohio Now (BEACON), a network focused on improving outcomes in childhood obesity and mental health and preterm births in Ohio. The group is developing patient registries for eosinophilic esophagitis and bone marrow transplant and is creating a “drug dashboard” for kidney transplant that will pull together adherence data from electronic pill bottles, clinical data and pharmacogenomics information to support pre-clinic planning.

Cooperative Research Grant // Gurjit Khurana Hershey, MD, PhD, to join the Inner City Asthma is principal investigator of an Consortium, the nation’s NIH-funded Asthma and Allergic largest effort to study Diseases Cooperative Research asthma in the inner city.

RESEARCH Center (AADCRC), which focuses CENTERS on characterizing epithelial genes in allergic diseases. Hershey also serves on the AADCRC steering committee. Epithelial cell genes play a central role in allergic disorders. The Center’s work will provide a basis for developing new therapies aimed at epithelial surfaces in the lung (asthma), on skin (atopic dermatitis), or in the gut (food allergy or eosinophilic esophagitis).

Research IT & Security // The Research IT Security group, led by Michal Kouril, PhD, and Nicholas Hunt, focused on the continued migration of applications to the research network environment (RNE). Designed to allow easier access to external users while strengthening security and compliance, the RNE will improve connectivity with outside institutions and provide increased flexibility when handling future demands of research. Technical and legal policies have been established to support federation with the NIH and the University of Cincinnati (UC).

Inner City Asthma Consortium // Cincinnati Children’s is one of 10 research centers to join the Inner City Asthma Consortium, the nation’s largest effort to study asthma in the inner city. Gurjit Khurana Hershey, MD, PhD, is principal investigator for the Cincinnati site. So far, Cincinnati Children’s has been involved in three studies: examining a decrease in fall asthma exacerbations, understanding easy vs. difficult-totreat asthma, and studying immunotherapy against exposure to German cockroach, the most common species infesting apartments and other urban buildings.

EHR-Based Patient Safety Research // The Natural Language Processing (NLP) group, directed

by Imre Solti, MD, PhD — in collaboration with Neonatal Intensive Care Unit (NICU) physicians — received a grant from the National Institute of Child Health and Development (NICHD) to automatically detect medical errors in NICU charts. The group is collaborating with clinical faculty to predict the need to transfer patients to the Pediatric Intensive Care Unit. With ED physicians, the NLP group is automating the appendicitis risk assessment of ED patients with a chief complaint of abdominal pain. Extracting information from the EHR’s narrative text is a crucial step in automating patient safety efforts.

ASTHMA RESEARCH

C I N C I N N AT I C H I L D R E N ’ S I S O N E O F

10

22 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

B E H AV I O R A L M E D I C I N E A N D CLINICAL PSYCHOLOGY CHAMP Study Compares Migraine Medications // The first multicenter NIH trial focused on pediatric migraine prevention will be led by Cincinnati Children’s. Migraine affects more than six million children and teens in the United States, yet no prevention medication is FDA-approved for

B I O S TAT I S T I C S A N D E P I D E M I O L O G Y Research and Education // We contributed to 113 scientific articles, 50 percent more than in FY2011; 15 involved development or application of novel quantitative methods; our faculty were first authors of 11.

We led research projects including the NSF-funded “Extension of Censored Quantile and Empirical Likelihood” (Mi-Ok Kim, PhD); the biostatistical core of the NIH-funded “Hemorrhagic and Ischemic Stroke Among Blacks and Whites” (Jane Khoury, PhD); the HRSA-funded grant, “Impact of Cognition on Language in Pediatric Hearing Loss” (Jareen Meinzen-Derr, PhD); and the NIH-funded grant “Neurobehavioral and Neuroimaging Effects of Traffic Exposure in Children” (Patrick Ryan, PhD, MS).

We contributed to 113 scientific articles,

50

We taught in the UC Colleges of Medicine and Pharmacy and supported the educational goals of the Center for Clinical and Translational Science and Training. Our Graduate Statistics Internship program, led by Bin Huang, PhD, and Siva Sivaganesan, PhD, benefited research projects in eight Cincinnati Children’s divisions. Seven students participated in FY2012, and five more will join next year.

Faculty // New faculty: Lili Ding, PhD, a biostatistician interested in applications of Bayesian THAN IN FY 2011 modeling and inference; Heidi Sucharew, PhD, a biostatistician interested in structural equation modeling, latent variable and profile modeling; Patrick Ryan, PhD, MS, an epidemiologist interested in assessing the impact of environmental exposures on asthma and neurodevelopment; Monir Hossain, PhD, MSc, a biostatistician interested in developing statistical models for detecting spatial and temporal clusters in environmental health and health economics; and Bin Zhang, PhD, a biostatistician interested in survival analysis, longitudinal data analysis and optimal clinical trial design.

PERCENT MORE

childhood migraine. Scott Powers, PhD, Division of Behavioral Medicine and Clinical Psychology and Andrew Hershey, MD, PhD, Division of Neurology, are the principal investigators on this $18 million grant. This 40-site study will compare the efficacy, tolerability, and safety in children of two migraine medications: amitriptyline and topiramate.

Study Explores High-Risk Internet Behavior // A significant portion of US teens view sexually explicit internet content and some engage in online social behaviors that could lead to victimization.

A new study directed by Jennie Noll, PhD, will be the first to compare patterns of internet use with the propensity for high-risk behaviors. Noll is collaborating with Michal Kouril, PhD, Division of Biomedical Informatics, who developed software that assesses adolescents’ “internet footprints.”

New Treatment Adherence and Health Outcomes NIH T32 Fellowship // This T32 training grant, the first of its kind in the United States, will be led

by Dennis Drotar, PhD, and addresses the critical shortage of researchers in treatment adherence and chronic illness management. Fellows will be trained to conduct and lead interdisciplinary research projects and to apply state-of-the-art behavioral, biomedical, and statistical advances to data analysis.

Infrastructure // Our Data Management Center supported 45 studies (up from 22 in FY2011) with grant application review, budgeting data management planning and budgeting, protocol review, database development, and data cleaning. The Biostatistics Consulting Unit was established in 2012 to expedite access to biostatistical consulting and collaboration, and can assist with study design, grant preparation, statistical analysis and manuscript preparation.

2012 ANNU A L R E P O RT // 23

RESEARCH OVERVIEW

division accomplishments Cincinnati Children’s recently became the only pediatric cancer program in the United States participating in all four major national early-phase clinical research consortia.

CANCER AND BLOOD DISEASES INSTITUTE Toward a Universal Cure for SCID // Children with severe combined immune deficiency (SCID) are born lacking an essential gene that allows the immune system to fight infections. Untreated, SCID is fatal. The only effective treatment is a bone marrow transplant that replaces defective immune system cells with new ones. Unfortunately, some children do not have a suitable donor, and those who do can have dangerous complications from the procedure.

An international gene therapy study uses a viral vector manufactured at Cincinnati Children’s to insert a normal copy of the defective gene into the child’s own cells. This stops the disease without any need for bone marrow transplant. Lisa Filipovich, MD, is leading the study at Cincinnati Children’s, and the first child has been enrolled and treated. We anticipate that gene therapy will become an important treatment option for babies with SCID, and offer a cure to all children with fewer complications.

The Only Pediatric Cancer Program in All Four Consortia // Cincinnati Children’s recently became the only pediatric cancer program in the United States participating in all four major national early-phase clinical research consortia (the NCI Pediatric Phase I/Pilot Consortium, the NCI New Approaches to Neuroblastoma Consortium, the Pediatric Brain Tumor Consortium (PBTC), and the Department of Defensefunded Neurofibromatosis Clinical Consortium).

Cincinnati Children’s is

1

OF ONLY A FEW CENTERS IN THE UNITED STATES

with comprehensive genetic testing for hemoglobinopathies.

PBTC was the most recent addition; Cincinnati Children’s gained membership to this highly competitive cooperative research group this year. In addition, Maryam Fouladi, MD, MSc, Medical Director of Neuro-Oncology, was elected to serve as National Chair of the PBTC. Laboratory Results // In a study published in PNAS, a group led by Jose Cancelas, MD, PhD, reports that Connexin-43, a molecule involved in cell-to-cell communications, can protect hematopoietic stem cells (HSCs) during chemotherapy by regulating reactive oxygen species content in the bone marrow microenvironment.

24 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

A study published in Nature Medicine reports that augmenting the thrombomodulin (Thbd)-activated protein C (aPC) pathway may help reduce tissue injury and mortality caused by radiation exposure.

Hartmut Geiger, PhD, led the study with colleagues at Cincinnati Children’s, Wisconsin and Arkansas.

Yi Zheng, PhD, and colleagues have devised a method for producing chemical compounds that inhibit RhoA GTPase, a critical cell signal transducer involved in cancer cell proliferation. Their findings, published in Chemistry and Biology, suggest a new approach for targeting previously “undruggable” biological molecules.

Unique Hematology Testing // Cincinnati Children’s offers state-of-the-art testing for complex hematological diagnoses. Last year, the Sickle Cell Center and the Division of Human Genetics launched a genetics-based hemoglobinopathy diagnostic service, making us one of only a few centers in the U.S. with comprehensive genetic testing for hemoglobinopathies. Our Special Hemostasis Laboratory has expanded to include bleeding and thrombotic disorders. We recently added several new tests for the detailed diagnosis and characterization of Von Willebrand disease, the most common bleeding disorder in children, making us the only facility in the region offering these assays. We have also added several new tests to evaluate platelet function abnormalities, making our laboratory one of the few laboratories nationally with the capability to diagnose children with platelet disorders.

CELLULAR AND MOLECULAR IMMUNOLOGY Understanding Asthma Pathogenesis // Two mouse model studies involving division researchers suggest novel therapeutic interventions for asthma, the most frequent cause of pediatric emergency room visits in the United States. Ian Lewkowich, PhD, and colleagues detailed the early immunological response triggered by exposure to cockroach frass, a particularly common allergen in the inner city. Findings were published in February 2011 in the Journal of Innate Immunity.

Meanwhile, Fred Finkelman, MD, and colleagues revealed how IL-4 and IL-13 can induce a small set of muscle-associated proteins to stimulate airway hyperresponsiveness. Findings appear in the April 4, 2011, edition of the Journal of Experimental Medicine.

Pathogenesis of Transfusion-Related Acute Lung Injury (TRALI) // Fred Finkelman, MD, and colleagues used a mouse model to advance understanding of TRALI, the leading cause of death from blood transfusion in developed countries.

A study detailing how antibodies to major histocompatibility antigens in transfused blood products can induce pulmonary vascular leak syndrome were published in the Nov. 21, 2011, edition of the Journal of Experimental Medicine. These observations should promote the development of better ways to prevent TRALI.

Treatment of Hemophagocytic Lymphohistiocytosis (HLH) // HLH is a difficult-to-treat and potentially lethal form of anemia. A study (e-published in Pediatric Blood Cancer on April 22, 2012) led by Michael Jordan, MD, shows that treatment with the anti-lymphocyte monoclonal antibody alemtuzumab can help control HLH that has not responded to conventional therapy.

2012 ANNU A L R E P O RT // 25

RESEARCH OVERVIEW

division accomplishments

CENTER FOR TECHNOLOGY COMMERCIALIZATION New Technology Disclosures Reach All-Time High // The Center for Technology Commercialization (CTC) received more than 200 new technology disclosures in FY2012, up from 118 in 2011 and 93 in 2010. The increase reflects a concerted effort to reach out to Cincinnati Children’s investigators to share the benefits of commercialization. We also established collaboration between Cincinnati Children’s and Ben-Gurion University in Israel that focuses on developing new and innovative pediatric medical devices.

MORE THAN

200 NEW TECHNOLOGY

CENTER FOR CLINICAL AND T R A N S L AT I O N A L S C I E N C E AND TRAINING Facilitating Data Access for Researchers // During the past year, we continued to revise Research Central, the portal for investigators to obtain our services.

Meanwhile, more than 200 research projects are using REDCap, our secure web application for building and managing online surveys and databases. Our group also implemented a federated identity management project to make it easier for investigators at Cincinnati Children’s and the University of Cincinnati (UC) to share data. We initiated a new Clinical Research Informatics track in the MS in Clinical and Translational Research program.

DISCLOSURES

were received in 2012.

Innovation Fund Awards $500,000 to Six Projects // Our new Innovation Fund, managed by the CTC, announced the first round of funding totaling $500,000 to support six early-stage projects. The Innovation Fund provides up to two years of funding for projects, and plans to award approximately $1 million per year.

SAC Review Accelerates Commercialization Efforts // This year, the CTC was the first non-faculty division at Cincinnati Children’s to undergo the Scientific Advisory Committee (SAC) Review. This annual review evaluates how well selected Research Foundation entities are performing in key areas of basic and clinical research, education, clinical care and advocacy. The SAC Review confirmed the direction the CTC is heading and identified several areas for growth. Notable goals include creating funding mechanisms to accelerate the development of commercializable technologies; increasing outreach and engagement with industry for licensing and strategic alliances; improving communication and education within Cincinnati Children’s; and expanding CTC resources by adding personnel.

Providing Research Support and Collaboration // Research Central supported 319 consultation requests and has become a model for several other Clinical and Translational Science Award programs.

We offer two RNs with clinical research experience who help define investigators’ needs and connect them with needed services. We also developed a new charge-back mechanism for services provided by Research Central. The Center for Clinical and Translational Science and Training (CCTST) awarded five pilot grants related to clinical research ethics and study design methodology. Finally, our group has worked with Biomedical Engineering and several other divisions and departments at Cincinnati Children’s and UC to form a medical device collaborative to foster cross-campus cooperation in medical device design.

Expanded Funding for Pilot Studies // Our Pilot and Collaborative Translational and Clinical Studies grant program completed its third cycle of grant funding. We received 102 applications and awarded 14 grants totaling $1.2 million. Work has begun on a fourth round of funding. The CCTST also started a Junior Pilot T1 program that made seven awards of $25,000 each to instructors and assistant professors; awarded five “Just-in-Time” grants to support data collection for external grant applications; provided seven retreat/symposium awards to foster transdisciplinary research; and awarded two Clinical Research Feasibility Fund (CReFF) grants.

26 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

CLINICAL PHARMACOLOGY Personalized Therapeutics // Our research seeks to identify pharmacokinetic, pharmacodynamic and pharmacogenetic factors to explain differences in clinical response to drugs and adverse events in pediatric patients. One important focus area is immunomodulating therapies in organ transplantation. With funding from the Anderson Center, we worked with David Hooper, MD, and members of Nephrology, Biomedical Informatics, and the Adherence Center to create a decision support system that provides real-time patient data for more precise management of immune suppressing medication.

We also work with the Genetic Pharmacology Service, the first of its kind in a pediatric institution, on studies of neuropsychiatric drugs.

Pharmacometrics and Quantitative Pharmacology // As part of the medical center’s personalized pain initiative, we identify drug metabolizing genotypes and phenotypes to improve pain management and reduce adverse events. One joint effort with Anesthesia seeks to identify factors that can help customize morphine dosing for postsurgical patients. Another joint effort with the Center for Bariatric Research and Innovation developed a dosing algorithm for the use of propofol in bariatric surgery. We also worked with the Cancer and Blood Diseases Institute to study the use of sirolimus in children with NF1 and plexiform neurofibromas. Results have been submitted for publication.

Training Program in Pediatric Clinical Pharmacology // We are one of three sites awarded a pediatric clinical and developmental pharmacology training grant from the National Institutes of Health. This postdoctoral program seeks to train clinical investigators to become leading innovators in pediatric therapeutics. The program has recruited two talented trainees: Dawn Pinchasik, MD, a second year fellow in Pediatric HematologyOncology and Jason Wiles, MD, a first year Neonatology fellow.

In the past decade, Cincinnati Children’s reduced PICU mortality by 43 percent and hospital mortality rates by 34 percent.

CRITICAL CARE MEDICINE RACE for Results // Cincinnati Children’s won the 2012 RACE for Results Award from the Children’s Hospital Association for reductions in mortality rates.

In the past decade, Cincinnati Children’s reduced PICU mortality by 43 percent and hospital mortality rates by 34 percent. These improvements reflect aggressive efforts to reduce hospital acquired infections, implement electronic health records, improve recognition of clinical deterioration, prevent codes outside of the PICU and mandated hospital wide safety training. This is the fourth time Cincinnati Children’s has won this prestigious award and the second time that the PICU has received the award.

Licensing 3D Animations // Ken Tegtmeyer, MD, and medical animator Jeff Cimprich licensed 3D heart catheterization animations to LungRx this year. This represents the first external marketing of 3D animations from the Critical Care Media Lab, which has been producing 3D animations and clinical research videos for nearly four years.

Faculty Recognition // Ken Tegtmeyer, MD, was elected Chair of the Society of Critical Care Medicine Pediatric Section. Basilia Zinarelli, MD, PhD, was elected President of the North American/United States Shock Society. And Jennifer Kaplan, MD, was appointed to be a permanent study section member for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatrics Subcommittee.

2012 ANNU A L R E P O RT // 27

division accomplishments

RESEARCH OVERVIEW

D E N T I S T RY International Sedation Conference // Stephen Wilson DMD, MA, PhD, Director, was one of four pediatric dentists from the USA invited to participate in an international conference on pediatric dentistry held at the Royal College of Surgeons in Edinburgh, Scotland. He and British colleague Marie Hosey presented summary information on differences of sedation techniques, settings, and procedural events between the two countries.

Wilson is internationally known for his contributions to the field of procedural sedation in dentistry and was a principal writer of the current guidelines on pediatric procedural sedation, “Guideline for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures,” sponsored by the American Academy of Pediatrics and the American Academy of Pediatric Dentistry.

Training // Our advanced pediatric dentistry training program is recognized among pediatric dentistry training programs in the U.S. as a leader in sedation training. Recently, the program began a collaborative effort with the Division of Anesthesiology in providing intravenous sedation of patients to supplement its reputation for performing oral sedations for dental restorative procedures. Our Division is one of a handful of training programs in the U.S. offering these types of experiences for their residents.

D E V E L O P M E N TA L A N D B E H AV I O R A L P E D I AT R I C S Autism Demonstration Classroom // Donna Murray, PhD, received more than $100,000 from the Jack Rubinstein Foundation for Developmental Disabilities to continue developing the autism demonstration classroom, a collaborative project between The Kelly O’Leary Center for Autism Spectrum Disorders, Cincinnati Public Schools and Hamilton County Development Disabilities Services. The classroom pairs educators with a specialized autism team for an intensive two-year experience. In addition to the immersion training, the classroom served as a training site for more than 50 area professionals and students.

43

LEND Training Program // Karen Edwards, MD, MPH, who joined the at Cincinnati Children’s Division as Director of Training in and the University of 2010, was awarded a $4.6 million, L E N D Cincinnati is one of PROGRAMS five-year grant from the HRSA NATIONWIDE Maternal and Child Health Bureau to continue funding for the Leadership Education in Neurodevelopmental and Related Disabilities (LEND) Interdisciplinary Training Program. The LEND Program at Cincinnati Children’s and the University of Cincinnati is one of 43 LEND Programs nationwide.The program trains culturally competent, family-centered leaders to improve the health of children with, or at risk for, developmental disabilities.

THE LEND PROGRAM

A Growing International Presence // The field of developmental-behavioral pediatrics was first recognized in the United States as a subspecialty by the American Board of Pediatrics in 1999. However, only a few other countries have formally recognized this field. In the past year, David Schonfeld, MD, Division Director, delivered keynote addresses for first-ever national conferences held in Ankara, Turkey and Shanghai, China. Our Division continues to host international trainees who seek to establish or expand the field in their countries.

28 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

D E R M AT O L O G Y New Division Director // Kara Shah, MD, PhD, began her position as the Medical Director of the Division in August, 2011. Her special interests and expertise include cutaneous oncology, pigmented lesions, genodermatoses, atopic dermatitis, and nail disorders.

Shah also serves as Co-Director of the newly formed Eczema Center and the Genodermatoses Clinic.

New Fellowship Program // Our Division now offers a one-year fellowship in pediatric dermatology.

Approved by the American Board of Dermatology, the fellowship trains physicians in all aspects of pediatric dermatology, including clinical care, research, scholarly activity, resident and medical student education, and administration and office management. Graduates of this program will be capable of providing specialized outpatient care and inpatient consultative services for children with skin disorders.

Improving Access for Patients // Our priority has been to improve access for patients. We did this by setting a goal of decreasing the number of days for the “third next available” new appointment from 134 to 67 days by July 2012. We far exceeded this goal by better managing demand and adding two nurse practitioners.

As a result, our current average for the “third next available” appointment is between two to three days.

Priority patients with more complicated dermatologic issues who cannot receive appropriate care in the community are now seen within one or two days.

D E V E L O P M E N TA L B I O L O G Y New Collaborations // A new collaboration was established between the Divisions of Neurosurgery and Developmental Biology. Thanks to a generous donation from Robert and Sara McLaurin, and matching contributions from the medical center, the Robert and Sara McLaurin Chair of Pediatric Neurosurgery Research was established and awarded to Kenneth Campbell, PhD. Campbell also was appointed Director of basic science research in the Department of Surgery. Funds from the McLaurin donation are also being used to recruit two new investigators. The first of these, Steven Crone, PhD, from the Department of Neurobiology at the University of Chicago, will arrive this fall.

Craniofacial Group Expands // Rulang Jiang, PhD, arrived this year to take up his position as leader of the craniofacial group, established as a collaboration between the Divisions of Plastic Surgery and Developmental Biology. This rapidly growing group also includes Steve Potter, PhD; David Billmire, MD; Samantha Brugmann, PhD; Christopher Gordon, MD; Donna Jones, PhD; Yu Lan, PhD; Howard Saal, MD; Robert Hopkin, MD; and Rolf Stottman, PhD. The group’s collaborative projects include conducting exome sequencing-based gene identification for specific craniofacial disorders.

Developmental Biology Matrix // The Developmental Biology matrix now includes 22 members with primary appointments in Developmental Biology and 17 members with primary appointments in clinical divisions. This structure was formed to encourage rapid communication and collaboration across divisions. It has matured into a major international center of developmental research that combines fundamental discoveries in developmental mechanisms with applied studies of developmental disorders in children.

D R U G A N D P O I S O N I N F O R M AT I O N C E N T E R Protecting the Public // With 27 certified specialists in poison information and 51 staff certified in national incident management systems, our Drug and Poison Information Center is one of the largest in the country. Our Center serves 20 Ohio counties with a combined population of 3.7 million. Our Center regularly collaborates with county, regional and statewide medical response and disaster preparedness programs, including planning for the World Choir Games held in Cincinnati in July 2012. Meanwhile, we alerted a network of 60 regional hospitals on subjects including blue green algae in local rivers, “bath salts” and synthetic marijuana. We also provided poison control services on The Center serves food poisoning, water quality, concentrated laundry single use detergents, alcohol sanitizers, terrorism preparedness and other issues.

20

Community Outreach // Our Center continued to promote healthy drug- free lifestyles and address other with a combined public health issues. This year, more than 27,000 people population of in Hamilton County benefited from our delinquency 3.7 million. prevention and violence prevention programs. Our Center also was honored to host national “Drug Czar” Gil Kerlikowske, who held a press conference here to announce a new national drug policy. Our staff also was involved with Cincinnati Police Chief James Craig’s Children in Trauma Intervention Camp, a People of Color Wellness Alliance Coalition Grant and other initiatives to respond to health disparities among minorities in Hamilton County.

OHIO COUNTIES

Staff Recognition // Prevention and education specialist Alton “Chris” Nelms, PhD, was honored with the 2012 Dr. Martin Luther King Jr. Humanitarian Award from Cincinnati Children’s. Julienne Closser and Michelle Bilinski earned specialist certification through the American Association of Poison Control Center and Sheila Goertemoeller received the highest grade nationwide on the association’s annual exam.

2012 ANNU A L R E P O RT // 29

C Y S T I C FIBROSIS

just the

BREAKTHROUGH DRUG FOR CYSTIC FIBROSIS

beginning

When Angela Riddell was growing up, few could tell she had been born with the inherited disease cystic fibrosis (CF).

She was active and mostly healthy, swimming and playing softball in rural Preble County, Ohio.

Yet all the while the thick, sticky mucus caused by the disease was taking a toll on her body.

By her early 20s, Riddell’s lung capacity began dropping, eventually falling to 48 percent of normal. Twice a year, sometimes three times, she was hospitalized to battle lung infections, intestinal blockages and pancreatitis. She had lost so much appetite that she often ate only one meal a day.

“It was hard just to get off the couch. I was taking two or three naps a day. I didn’t even want to go outside,” she says.

Now 34, Riddell feels better than she has in years. Her lung capacity has bounced back to 70 percent and she has not needed a hospital stay in more than 18 months.

She owes her remarkable turn-around to participating in a clinical trial of VX-770 — now called Kalydeco. Approved by the FDA just last January, it is the first drug that attacks the underlying causes of CF rather than controlling its downstream symptoms.

Cincinnati Children’s plays an important role in studying combination therapies that could benefit up to 90 percent of CF patients

B R E A K T H R O U G H C F R E S E A R C H C O M E S T O C I N C I N N AT I A significant portion of the early research for VX-770 was led by John P. Clancy, MD, who joined Cincinnati Children’s in January 2011 as Research Director, Division of Pulmonary Medicine, and directs CF-related clinical and translational research.

Clancy studied CF for 17 years at the University of Alabama-Birmingham. He is part of a novel network of academic and industry investigators who have been collaborating for years to develop CF treatments.

“For the right patients, VX-770 is truly a monumental leap. It’s a first-in-class drug, the first therapy that targets the underlying cause of CF,” Clancy says.

Here, Clancy leads efforts to build upon Kalydeco’s success. He is involved with tracking the long-term effects of the drug. He also plays important roles in Phase 2 clinical trials to evaluate whether VX-770 in combination with other compounds — VX-809 and VX-661 — can benefit a wider range of CF patients.

“For the right patients, VX-770 is truly a monumental leap. It’s a first-in-class drug, the first therapy that targets the underlying cause of CF.” J O HN CLANCY, MD

30 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Dr. John Clancy led a significant portion of the early research for

770

VX-

2012 ANNU A L R E P O RT // 31

C Y S T I C FIBROSIS

Chloride ions and water molecules are able to pass through the cell membrane and hydrate the cell surface.

Thin mucus

Cystic fibrosis can interfere with lung function as gas exchange is hampered by the buildup of a sticky mucus, making breathing difficult.

AREA OF DETAIL

Sticky mucus builds up, immobilizing secretions of enzymes in organs and trapping bacteria in cells.

FUNCTIONING CFTR CHANNEL BLOCKED CFTR CHANNEL

Trapped bacteria

ATP

Regulatory domain Phosphate

PROTEIN-ASSIST M E D I C AT I O N S : N E X T WAV E I N C F T R E AT M E N T If upcoming clinical trials confirm the benefits, protein-assist medications could become the next major advance in cystic fibrosis treatment.

Since its FDA approval, about 20 patients in this area have begun using Kalydeco. But that’s just the beginning, Clancy says.

Current Phase 2 trials of the drug in combination with VX 809 and VX 661 for patients with the more common F508del CFTR mutation seek to determine which doses of combination therapy work best with fewest side effects. The most promising combination would then move on to larger-scale Phase 3 clinical trials, which could begin within 12 months.

“We’re advancing to the point where we are offering patients a therapy that treats the root cause of their CF,” Clancy says. “It’s not available to all patients yet, but I see it happening rapidly over the next two to three years.”

Chloride ions diffuse from inside the cell across the membrane to the exterior.

The closed CFTR channel blocks the normal flow of water molecules and chloride ions.

Cell membrane

VX-770 Trapped water molecule

HOW VX-770 CAN HELP VX-770 can help by binding to the protein to open the channel and restore chloride transport. This will help restore cells’ ability to clear mucus and remove trapped bacteria and pollutants.

Bacteria

Trapped chloride ions

COMBINED THERAPY TO HELP MORE PATIENTS Cystic fibrosis affects about 30,000 people in the United States. The disease obstructs the pancreas and prevents the digestive system from absorbing food.

It also causes thick, sticky mucus to build up in the lungs, which can lead to lifethreatening infections.

All these symptoms occur because people with CF produce defective versions of CFTR, a critical protein needed to form chloride channels that allow salt and fluids to flow correctly through cells.

Kalydeco helps restore this process, but only for patients with the G551D mutation in CFTR, a group that comprises about 4 percent of all CF patients. People in this group produce a CFTR protein that fails to open correctly, limiting chloride transport after they reach the cell membrane.

“We believe VX-770 binds to these CFTR proteins and helps open them so that chloride transport is restored,” Clancy says.

32 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

“I didn’t think I’d make it to my daughter’s graduation. Now I might be able to see her get married and have children.”

ANGELA RIDDELL

ADOPTING ‘ORPHAN’ DISEASES The development of VX-770 is one result of an unusual “venture philanthropy” arrangement between the drug maker, Vertex Pharmaceuticals, and the Cystic Fibrosis Foundation.

The foundation provided key funding to explore a massive library of small-molecule compounds to find the few compounds most likely to affect disrupted CF protein functions. The work involved large amounts of expensive, high-throughput screening analysis.

However, nearly 90 percent of CF patients have a different mutation — Delta F508. These people produce a misfolded CFTR protein that gets destroyed before it ever reaches the cell membrane.

Previous studies have shown that the VX-809 and VX-661 compounds can help the Delta F508 mutation work better in patients. Yet by themselves, these compounds may not be enough to impact CF symptoms.

Researchers believe that a combined approach can boost the effect. The idea: use VX-809 or VX-661 to help more delta F508 CFTR protein reach the cell membrane, then use VX-770 to help increase its activity and chloride transport.

If successful, this combination therapy would benefit nearly all people with CF, Clancy says.

A CHANCE TO REACH RETIREMENT AGE Clancy says VX-770 represents a potential quantum leap in CF treatment.

“This drug may add decades to life expectancy,” Clancy says. “Living to reach retirement age becomes a real possibility. That hasn’t been the case for most CF patients.”

Angela Riddell says she feels incredibly fortunate that she was part of the VX-770 clinical trial.

“I didn’t think I’d make it to my daughter’s graduation. Now I might be able to see her get married and have children,” she says. g

Without such funding, pharmaceutical companies are often reluctant to invest in the basic research needed to attack “orphan” diseases, a large group of diseases that each affect fewer than 200,000 people.

Many pediatric diseases fall into the orphan disease category.

“The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development,” FDA Commissioner Margaret Hamburg, MD, said in a press release issued after the drug was approved.

(Above) Angela Riddell says Kalydeco treatment restored lung capacity so that she can now enjoy time with her daughter, Macy.

2012 ANNU A L R E P O RT // 33

O R G A N TRANSPLANTS

ORGAN

next

TRANSPLANTATION:

the

Julie Bonn battled bouts of rejection of her transplanted liver over several years. Now a medical student, she plans to become a gastroenterologist. Watch her story at www.cincinnatichildrens.org/story.

34 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

chapter

Replacing a patient’s ailing organ with a healthy one has been a major step forward for medicine. Doctors have mastered the technicalities of the procedure and patients are living longer with better ways to guard against rejection. But it is no cakewalk. Here are some of the advances that Cincinnati Children’s doctors are exploring that they hope could make transplants a thing of the past.

transforming liver care “We wanted to advance the field.

We wanted to figure out ways to better treat liver disease, which meant better understanding its causes.”

WILLIAM BALISTRERI, MD

Julie Bonn is a vibrant 24-year-old with a bright and promising future. Twelve years ago, that future hung in the balance.

“I went from being perfectly healthy to status 1A on the liver transplant list,” she says.

Status 1A is as serious as it gets. It started with what Bonn describes as mild flu-like symptoms.

Within a month and without explanation, she went from active pre-teen to severely lethargic, edematous, jaundiced liver transplant candidate.

When Bonn entered Cincinnati Children’s Liver Care Center and the care of William Balistreri, MD, doctors knew she would last little more than a week without a new liver. She went to the top of the transplant list and fortune smiled on her: a liver became available.

Over the next few years, Bonn battled bouts of rejection, a 50-pound weight gain from steroids, and all the attendant issues that go with receiving a transplanted organ. Even though she has not had a rejection episode in nearly 10 years, Bonn still takes daily immunosuppressive medication.

She will be the first to tell you it is all worth it. But now, as a medical student with plans to become a gastroenterologist, her dream is to find a better way.

Balistreri shares that dream. By the early 1980s, he had already spent nearly two decades as a pediatric gastroenterologist and had watched too many children die from liver disease. He teamed up with surgeon Frederick Ryckman, MD, to create a place that would solve the problems of childhood liver disease, the Pediatric Liver Care Center at Cincinnati Children’s.

2012 ANNU A L R E P O RT // 35

O R G A N TRANSPLANTS

“Getting at the origins of untreatable liver disease is essential, because growing up with a transplant comes with so many long-term complications.”

G REG TIAO, MD

36 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

CINCINNATI CHILDREN’S SURGEONS HAVE PERFORMED

500

liver transplants

including some in neonates weighing under three pounds.

“It was the first in the United States and maybe the world,” says Balistreri, who remains Julie Bonn’s doctor. “We wanted to advance the field. We wanted to figure out ways to better treat liver disease, which meant better understanding its causes.”

And they have achieved much of what they set out to do. The Center is now recognized around the world for its treatment of childhood liver disease. Surgeons have performed well over 500 liver transplants, including some in neonates weighing under three pounds. NIHfunded research explores the causes of liver disease and how to improve transplant outcomes.

For Balistreri, however, the real breakthrough will come when liver transplants are no longer necessary. He recalls one of the Liver Center’s early cases, a set of identical twin boys who arrived with liver disease so advanced it seemed transplant was their only hope.

Their family had already lost a child to the same disease.

Balistreri and his team drew on what they had learned in their research and avoided having to make the awful choice of which twin would get the transplant.

“We had been looking at aspects of liver metabolism,” he says, “ and we hit a home run.”

They discovered the boys were unable to produce bile acid compounds critical to liver structure and function. Once the doctors gave the children the compounds, they began to thrive and continue to do well to this day. A third brother, born later with the same disease, also was given the compounds and flourished.

THE NEXT CHALLENGE Not all liver disease has been understood or treated so successfully, however. Liver Center researchers have now set their sights on preventing biliary atresia, the leading cause of pediatric liver transplants.

When Greg Tiao, MD, Surgical Director of liver and intestinal surgery, is not performing liver and kidney transplants, he can be found in the lab, working on an NIH-funded study of the causes of biliary atresia. Tiao’s is one of three NIH grants held by researchers at Cincinnati Children’s who are looking into the theory that biliary atresia has a viral cause.

“We suspect that a perinatal viral infection —

specifically, rotavirus — targets the biliary epithelium for injury,” Tiao says. The immature fetal immune system is unable to fight the virus, leading to an inflammatory response that destroys the bile duct.

Other Cincinnati Children’s researchers looking at the link between viruses and biliary atresia are Jorge Bezerra, MD, the studies’ senior investigator, who examines how immune changes take place after viral infection. Alex Miethke, MD, focuses on whether natural killer (NK) cells might be triggers of the fetal response.

Getting at the origins of untreatable liver disease is essential, says Tiao, because growing up with a transplant comes with so many long-term complications.

“We want these kids to live to 80, or longer,” Tiao says. “But there are consequences with 80 years of immunosuppression.”

Other research at Cincinnati Children’s has begun to explore whether some transplant patients might be able to live without immunosuppression. But the ultimate goal is to make transplants a thing of the past.

“As excited as I was about establishing the liver transplant program,” says Balistreri, “I would be even more excited if we could abandon it because we’d found definitive cures.” g 2012 ANNU A L R E P O RT // 37

O R G A N TRANSPLANTS

when hearts are beyond repair The Berlin EXCOR device is the only one currently approved by the FDA for use in children. (top) In June 2012, Zion Coleman, 10, became the first child with sickle cell disease to receive a heart transplant at Cincinnati Children’s. His sister Zhania, 7, received her heart transplant six weeks later. Both had advanced cases of cardiomyopathy.

38 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

For several decades, heart transplant has been the sole option for children whose hearts are damaged beyond repair. Success rates, particularly in the critical early months after heart transplant, have improved, largely due to advances in medical knowledge and therapies.

But long-term survival has proven more challenging, leaving transplant surgeons far from content with their progress so far, and continuing to search for better ways.

Clifford Chin, MD, is Medical Drector of pediatric heart transplant services at Cincinnati Children’s. He attributes better survival rates in the crucial first year after transplant to advances in identifying kids at higher risk for rejection, even before the surgery takes place.

“We are using new technologies to detect potentially harmful antibodies in these children, and treating them aggressively while they are waiting for transplant,” Chin says. The treatment continues during the operation and throughout the post-transplant course, enabling children to overcome the initial rejection hurdles.

Longer-term survival remains a challenge, particularly because many children develop coronary artery disease in the transplanted heart. That, too, is leading to more careful monitoring and interventions to stave off problems. “We are now using a very sensitive technology, intravascular ultrasound, to detect and intervene on early disease,” Chin says. “And we are embarking on a number of research studies to enhance our knowledge of the rejection process with the aim of preventing disease.”

While doctors work to improve the odds, the facts remain that the number of children who need transplants is growing and transplantable hearts are in short supply.

FINDING ALTERNATIVES “We need something better,” says cardiovascular surgeon David Morales, MD. “Technology is going to be our answer.”

Morales, who joined Cincinnati Children’s in June 2012, is world-renowned for his work using mechanical assist devices in children. He implanted the first total artificial heart in a teenage boy in Texas two years ago. The young man, who subsequently had a heart transplant, is now a freshman in college.

Though the technology is still in its infancy, it is growing up fast, and it will be a game changer, Morales believes. As more companies race to

Dr. David Morales believes mechanical assist devices are useful for far more than bridging the wait for a heart transplant.

“By placing a device in someone who needs a transplant, can we recover the heart, then take out the device and the child will never need transplant?”

D AV ID MORALES, MD

2012 ANNU A L R E P O RT // 39

O R G A N TRANSPLANTS

develop smaller, better heart assist devices, doctors are finding innovative ways to use them to help children.

BRIDGING THE WAIT Cincinnati Children’s transplant surgeon Alistair Phillips, MD, uses technology to buy children more time. As of June, Phillips had performed 12 heart transplants in less than a year, yet still had eight more children on the waiting list.

“The waiting time for hearts has increased in this region. Even status 1A patients wait on average two to four months,” he says.

Phillips uses the Berlin EXCOR device — the only one currently approved by the FDA for use in children — to keep weakened hearts beating until an organ becomes available for transplant.

Mechanical devices can potentially do much more than bridge the wait time for a donor heart.

Morales has already used them to get kids through temporary bouts of illness that impair heart function.

“For kids who have temporary causes of heart failure, such as myocarditis, we can put a device in temporarily, recover the heart, then take the device out,” he says.

Devices also offer options for children who have heart failure but are not candidates for transplant.

Morales, Lynn Jefferies, MD, and an interdisciplinary team are assessing the potential for using assist

devices in patients with Duchenne muscular dystrophy whose heart problems dominate their illness or who may improve overall with the use of the device.

“We will not cure their disease, but we will hopefully improve their quality of life,” Morales says.

AVOIDING TRANSPLANT ALTOGETHER He also wants to explore using assist devices to give a child’s weakened heart a chance to grow stronger — to such an extent that transplant might be unnecessary.

“By placing a device in someone who needs a transplant, can we recover the heart, then take out the device and the child will never need transplant?”

Morales’ question is more than rhetorical. He has already done this for one teenage boy, who is doing well a year and a half later. “He still takes medications, but he runs around, plays athletics, and has avoided transplant,” Morales says.

Although current devices are far from perfect, both surgeons envision a day when artificial devices put an end to heart transplant waiting lists.

“Ultimately there will be devices that will stay in place with internal battery systems and rechargeable battery systems,” says Phillips.

“Technology is in its infancy now, but the miniaturization of these systems is coming. I always say, ‘Don’t bet against the engineers.’” g

Drs. Clifford Chin (left) and Alistair Phillips see better outcomes in heart transplant patients due to improved treatment before, during and after surgery.

40 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

NEW DEVICES With more children needing transplants and fewer hearts available, companies are racing to develop better, smaller assist devices.

“Technology is in its infancy now, but the miniaturization of these systems is coming.”

A L I S TA I R P H I L L I P S , M D

THE HEART O F T H E M AT T E R Much of the research at the Heart Institute at Cincinnati Children’s focuses on better understanding rejection after transplant, says transplant surgeon Alistair Phillips, MD. Studies led by Lynn Jefferies, MD, Jeffrey Towbin, MD, and Clifford Chin, MD, are looking at how viral infections can affect transplant success.

“Some viruses actually cause the immune system to attack aspects of the vascular system,” says Phillips.

“This can lead to chronic rejection and can accelerate coronary vasculopathies, which is the reason these hearts fail long-term.”

As a result of this research, the transplant team takes steps to build resistance to viral infection.

Several hours before transplant, patients receive intravenous immunoglobulin (IVIG). “The concept is that using this pooled blood product drawn from the community will help build antibodies to any viruses present at the time,” Phillips says.

Another measure used during surgery is plasmapheresis, which “washes” the patient’s blood of accumulated antibodies and lessens the likelihood of the immune system attacking the newly-placed heart.

Chin and his colleagues recently presented results with IVIG at the American Transplant Congress Scientific Sessions. “Using IVIG, we were able lower the preformed antibody burden in 13 patients,” he says, adding that all 13 patients survived their critical first year after transplant.

2012 ANNU A L R E P O RT // 41

A F T E R C A R E

“Having younger recipients has taught us what we have to do to make the kidneys work successfully.”

MAR I A A L O N S O , M D

MONITORING KIDNEY PATIENTS New steps to ensure cholesterol and blood pressure checks at post-transplant visits are helping kids keep these levels under control.

MAY ’12

80% 60% 40% 20%

JULY ’10

0

CHOLESTEROL LEVELS

100% (Percent of Patients)

100% (Percent of Patients)

BLOOD PRESSURE LEVELS

80% APR ’12

60% 40%

NOV ’08

20% 0

Kidney patients with adequately controlled blood pressure over time.

42 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Kidney patients with adequately controlled cholesterol over time.

KIDS ARE LIVING LONGER AND BETTER— B U T I T TA K E S C O N S TA N T V I G I L A N C E .

after kidney transplant Transplant surgeon Maria Alonso, MD, has been transplanting kidneys for nearly two decades. A lot has improved in that time.

“We know more about organ matching. The nephrology doctors are preparing kids better, getting them to grow with good nutrition. And we’ve learned a lot technically,” she says.

Much of that technical expertise has come from transplanting increasingly tiny infants, Alonso says.

Many of the babies Alonso now transplants would not have made it to birth just a few years ago, or would have died shortly after birth. But advances in fetal medicine have changed that.

“Our fetal medicine colleagues can bring babies with congenital urological abnormalities to term with healthier lungs, and we’re being asked to transplant them,” she says. “Having younger recipients has taught us what we have to do to make the kidneys work successfully.”

Working successfully means that, with careful tending, the kidneys continue to function into the child’s adulthood.

“In 30 years, half the kids who receive a living donor kidney today will continue to have a healthy, functioning kidney,” she explains.

Getting young people to follow the medical regimens REQUIRED AFTER KIDNEY TRANSPLANT is an enormous challenge.

2012 ANNU A L R E P O RT // 43

Goebel (above) and his team have published extensively about the difficulties of getting young transplant patients to comply with treatment.

LIFE AFTER TRANSPLANT

Helping patients determine what happens during the years after transplant is no easy task, especially for teenage patients, says Jens Goebel, MD, Medical Director of kidney transplantation at Cincinnati Children’s.

“Getting young people to follow the medical regimens required after kidney transplant is an enormous challenge,” he says. In the first year after transplant, kids may take up to a dozen medications a day. Many of those medications can cause weight gain and other changes in physical appearance that are particularly difficult for teenagers.

Goebel and his team have published extensively about the difficulties of getting young transplant patients to comply with treatment. In one recent article in Pediatric Transplantation, he and Cincinnati Children’s adherence researcher Ahna Pai, PhD, discuss 33 patients coming to Cincinnati Children’s for dialysis; nearly 43 percent had a transplant that failed because they did not take their immunosuppressive medication.

THE RISK OF HEART DISEASE

And there are other obstacles.

“The biggest long term health challenge for these patients is cardiovascular disease,” says David Hooper, MD, a nephrologist at Cincinnati Children’s. “The risk is about 50 times that of the general population.”

Even though the risk of heart disease for kidney transplant patients is well documented, Hooper says, it has not been a priority in their post-transplant care.

The answer seems simple enough — monitor the patients for elevated blood pressure and cholesterol. But it has not happened.

“Only half of all kidney transplant patients have blood pressure that’s controlled,” 44 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Blood pressure is being measured and documented according to guidelines more than

90

PERCENT OF THE TIME

Hooper says. “There are 20 to 25 medications known to be effective at controlling blood pressure, so why are we not controlling it?”

He says the reasons are complicated. Patients are seen at various locations by different providers and caregivers often focus on immediate concerns such as avoiding organ rejection.

“It’s easy for longer term health issues to get lost in the mix,” Hooper says, “but ultimately it’s the cardiovascular care that’s allowing these kids to live longer or not.”

BUILDING A SAFETY NET

So Hooper and his colleagues have built fail-safe measures into Cincinnati Children’s system.

New standards for outpatient care help assure that providers check for elevated blood pressure and cholesterol when transplant patients come back for checkups.

“Now, more than 90 percent of the time, blood pressure is being measured and documented according to guidelines at all locations,” he says.

Hooper and his team also developed “planned medical visits,” in which they review a patient’s records to plan for health-related issues that need extra attention.

“We look at things like, are they struggling to get to visits? Do they need help remembering to take their medications? Or are they ready to work on diet and exercise?” Hooper says.

“Before the clinic visit, we’ve assessed a behavior that might need changing and have identified who will work with the patient.”

The measures have been well received by providers, which has led to an upswing in capturing blood pressures and cholesterol — and in the number of patients experiencing better control of those factors.

Patients are also warming to the approach, but slowly, says Hooper.

“I’ve seen some kids respond well. Others just aren’t ready. In that case, we just work with them and wait for a time when they are ready.

We explain that it’s not a sprint, it’s a marathon.

Taking care of his health needs to be something a kid adopts for life.” g

“The biggest long term health challenge for these patients is cardiovascular disease. The risk is about 50 times that of the general population.”

D AVID HOOPER, MD

2012 ANNU A L R E P O RT // 45

RESEARCH OVERVIEW

division accomplishments

EMERGENCY MEDICINE PECARN Research Grows // Cincinnati Children’s is one of 18 institutions in the Pediatric Emergency Care Applied Research Network (PECARN). Richard Ruddy, MD, is a principal investigator and is the Vice Chair, Steering Committee. We enroll in four network studies including defining the biosignatures in febrile infants and a knowledge implementation project to reduce CT scan use in mild head injury. Our node is sponsoring a proposed study to examine the use of probiotics in gastroenteritis.

ENDOCRINOLOGY Diabetes and Arterial Stiffness // Adult studies demonstrate that African Americans with type 2 diabetes have an increased risk of stroke and myocardial infarction compared to Caucasians. A team led by Amy Shah, MD, confirms similar racial disparities exist in adolescents. Additionally, the investigators demonstrated racial variance in the risk factors associated with arterial stiffness. In Caucasians, blood pressure appeared to be the largest risk factor, while age was the largest factor for African Americans. These findings suggest that race-specific approaches should be considered to limit complications associated with type 2 diabetes.

Findings were published in March 2012 in Pediatric Diabetes.

16

Classifying Diabetes // In 1997, the American Diabetes Association presented a framework for classifying the types of diabetes based on etiology. Years later, the SEARCH for Diabetes in centers in the SEARCH Youth Study becomes the first to offer a practical for Diabetes in Youth application of the diagnostic criteria. The study Study network. establishes four main categories: autoimmune plus insulin sensitive; autoimmune plus insulin resistant; non-autoimmune insulin sensitive; non-autoimmune insulin resistant. Cincinnati Children’s is one of six centers in the SEARCH network. Lawrence Dolan, MD, is principal investigator for the Cincinnati center.

Cincinnati Children’s is

OF

Insights in Placental Development // Little is known about the transcription factors and signaling molecules critical to the differentiation of placenta stem cells into syncytiotrophoblast cells — the cells responsible for most functions of the mature placenta. Recent studies by Stuart Handwerger, MD, and colleagues provide important new insights into this process. Findings show that the transcription factors TFAP2A, NR2F2 and FOXF1 are critical to placental development. In pathologic pregnancies, AP-2 expression is suppressed in mild preeclampsia, diabetes, hypertension and fetal growth retardation. However, expression is increased in severe preeclampsia. Further studies of NR2F2 and FOXF1 are in progress.

46 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Clinical and Prevention Research // Findings from a study led by Lynn Babcock, MD, MS, on predictors of post-concussion syndrome were published online June 22 in Brain Injury. Benjamin Kerrey, MD, Matthew Mittiga, MD, Gary Geis, MD, and Andrea Rinderknecht, MD, conducted a video review of rapid sequence intubation that revealed failed attempts and adverse effects were more common than previously reported. Their findings, published online March 15 in the Annals of Emergency Medicine, prompted our Division to trial a bundle of improvements to decrease complications. Gregory Faris, MD, received a Young Investigator Award for his project on predictors of post-concussion syndrome.

In prevention research, division members continued important work in smoking prevention, led by Melinda Mahabee-Gittens, MD, MS; cultural issues across ethnic groups, led by Lisa Vaughn, PhD; injury control, led by Mike Gittelman, MD, and Wendy Pomerantz, MD; mental health screening by Jacqueline Grupp-Phelan, MD, MPH, and teen STIs, led by Jennifer Reed, MD. Quality Improvement Research // Srikant Iyer, MD, MPH, was awarded the best scientific paper at the Institute for Healthcare Improvement meeting for his work on “Flow in the ED Fast Track.” Evaline Alessandrini , MD, MSCE, presented her work on “Time to Critical Intervention in High Risk Cancer Patients” at the Pediatric Academic Societies annual meeting in Boston.

E V E RY C H I L D S U C C E E D S Growth of Program // Every Child Succeeds (ECS) is the largest of three agencies in Greater Cincinnati providing home visits for families. The agency is recognized by the Pew Center on the States as a premier home visitation program for its efficient operation, commitment to quality and documented outcomes for mothers and infants. Those results include an infant mortality rate of 4.7 per 1,000 live births for enrolled families compared to 13.3 per 1,000 for the city of Cincinnati; 99 percent of enrolled mothers receiving at least four prenatal visits; and 97 to 98 percent of children achieving normal development as measured by motor skills, language development and other factors. These results have attracted interest from beyond Greater Cincinnati. Ohio’s Help Me Grow program is now modeled after Every Child Succeeds. Programs in Connecticut, Massachusetts and Kentucky use our Maternal Depression Treatment Program.

Quality Improvement // ECS is using a $200,000 grant from the Ohio Department of Health to work with the Anderson Center to teach quality improvement strategies to other home visiting programs. We offer tested products and services created by ECS to other agencies through our social enterprise program. We also are preparing training modules to provide distance learning opportunities for home visitors.

Research // ECS maintains an expanding database that includes information about 18,750 families and more than 390,000 home visits. Our agency has received federal grants to study the effect of maternal depression treatment on infants and young children, and to evaluate the usefulness of various home safety products in preventing injuries and accidents. We are using a two-year, $200,000 Social Innovation Fund grant to learn how best to link children with early learning programs. We also are testing ways to improve linkages among families, home visitors and physicians’ offices through our Medical Home Initiative.

The results from Every Child Succeeds have attracted interest from beyond Greater Cincinnati.

Ohio’s Help Me Grow program is now modeled after the program.

G A S T R O E N T E R O L O G Y, H E PAT O L O G Y, A N D N U T R I T I O N Digestive Health Center // The Digestive Health Center (DHC), directed by Jorge Bezerra, MD, recently received a $5.5 million NIH renewal grant to continue its work. Our Center is one of only 17 core centers supported by the National Institutes of Diabetes & Digestive & Kidney Diseases and the only one focused on pediatric digestive diseases. Since 2007, the DHC has grown from 58 to 88 investigators who have published more than 440 peer-reviewed articles.

Intestinal Rehabilitation Program // Led by Noah Shroyer, PhD, the basic science and translational research program in intestinal rehabilitation has characterized a network of transcription factors that control intestinal development. Shroyer collaborates with Jeffrey Whitsett, MD, and James Wells, PhD, on a project to broaden this genetic network to evaluate embryonic intestinal organogenesis. Shroyer, Wells and Michael Helmrath, MD, MS, have developed 3-dimensional gastrointestinal organoid cultures from mouse and human tissues. These organoids serve as a platform to discover novel therapeutics for intestinal diseases, and eventually may provide patient-specific source material for transplantation.

Cincinnati Center for Eosinophilic Disorders (CCED) // Research at the Cincinnati Center for Eosinophilic Disorders (CCED) involves basic, clinical and translational studies. Phil Putnam, MD, and James Franciosi, MD, MS, have led projects including epidemiology, quality of life research, building specimen databanks, and forging a multicenter registry collaboration with eight pediatric and adult hospitals. The CCED team participated in a major clinical trial of anti-Il5 in children with eosinophilic esophagitis. Findings were published in 2011. Overall, the CCED team participated in 10 manuscripts, including a major revision of the Consensus Recommendations for Diagnosis of Eosinophilic Esophagitis in children and adults.

Marc Rothenberg, MD, PhD, continues basic research to understand the genetic and immunologic bases for eosinophilic gastrointestinal disorders.

2012 ANNU A L R E P O RT // 47

RESEARCH OVERVIEW

division accomplishments Using the ADHD project as a prototype, Brinkman and colleagues are working to expand the concept to HPV vaccination and treatment for juvenile idiopathic arthritis.

G E N E R A L A N D C O M M U N I T Y P E D I AT R I C S Innovation and Research in Physician Education // Melissa Klein, MD, is principal investigator for two new training grants, totaling $2.8 million, that are expanding our focus on physician education.

The General Pediatric Master Educator Fellowship, funded by a Health Resources and Services Administration (HRSA) Faculty Development in Primary Care award, will train academic medical educators to understand and apply adult learning theory. Fellows will complete a master’s degree in Education. A second HRSA grant expands the Primary Care Track of the Cincinnati Children’s residency program by 30 percent. This program helps pediatric residents prepare for careers in primary care emphasizing care of children from underserved communities.

G E N E R A L A N D T H O R A C I C S U R G E RY Intestinal Rehabilitation Center // Michael Helmrath, MD, focuses on adaptive response of stem cells following surgical loss of the bowel. His NIH-funded studies on intestinal stem cells explore how to culture and expand both murine and human intestinal epithelium. As Surgical Director of the intestinal rehabilitation center, Helmrath is also establishing an intestinal failure registry and outcome trials.

Fetal Care Center // With support from an NIH award, Sundeep Keswani, MD, studies the molecular mechanisms underlying the fetal regenerative wound healing phenotype.

This work may yield a wide range of therapeutics for diseases characterized by excessive fibroplasia. Keswani is also Surgical Director for the Pediatric Advanced Wound Care Service, which opened in January, 2012.

Helen Jones, PhD, investigates placental insufficiency and intrauterine growth restriction with a focus on developing a nanoparticle delivery method for placental treatment. Jones was awarded a URC interdisciplinary award from the University of Cincinnati in July 2011 and a Pathway to Independence Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development in April 2012. She was appointed program Co-Director for the Placental Association of the Americas (PAA) symposium 2013 and program Director from 2014 forward.

Bariatric Surgery // Thomas Inge, MD, PhD, and Todd Jenkins, MPH, PhD, codirect the Center for Bariatric Research and Innovation. The Center partners with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to lead the national effort to gather data and publish evidence-based recommendations for weight loss surgery in adolescents. The NIDDK-funded Teen LABS study, the largest multicenter study of outcomes following weight loss surgery, received five additional years of funding in 2011; five-year funding renewal was also granted to the study’s data coordinating center, overseen by Jenkins and C. Ralph Buncher, ScD.

48 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Innovative Services for At-Risk Children // Resident education and curriculum evaluation have been integral to two new programs. The Child Health Law Partnership (Child HeLP) is a collaboration with the Legal Aid Society. Keeping Infants Nourished and Developing (KIND) is an alliance with the FreeStore FoodBank.

Klein, Robert Kahn, MD, MPH, and colleagues have published eight manuscripts in the past year highlighting the positive effects of these programs.

Shared Decision-Making to Improve Care in Pediatrics // With funding from a Cincinnati Children’s Place Outcomes Research Award and the National Institute of Mental Health, William Brinkman MD, MEd, is working to translate research into clinical practice using shared decision-making between patients, parents and clinicians. Brinkman recently led a team of parents, pediatricians, psychologists, and graphic designers to develop a shared decisionmaking process for treating children newly diagnosed with attention deficit hyperactivity disorder (ADHD).

This project led to presentations at four national and international meetings, one publication, and one manuscript currently under review. Using the ADHD project as a prototype, Brinkman and colleagues are working to expand the concept to HPV vaccination and treatment for juvenile idiopathic arthritis.

G L O B A L C H I L D H E A LT H

H O S P I TA L M E D I C I N E

Influenza in Suzhou, China // Steven Black, MD, and Mark Steinhoff, MD, evaluated the epidemiology of laboratory-proven influenza hospitalizations of children in China, collaborating with colleagues at the Suzhou Children’s Hospital and Fudan University, Shanghai. The study showed that influenza occurred throughout the year, with peaks in the winter and in August and September, and was a significant cause of childhood hospitalization. This is one of the first population-based studies of influenza disease in children in China, and has prompted further studies.

Clinical Innovation // The Division of Hospital Medicine, and its precursor the General Inpatient Service, have a long tradition of innovation and early adoption of innovations, including family-centered rounds and evidence-based guidelines. Over the past year, our physicians have led four new projects: earlier transition to oral antibiotics for osteomyelitis, use of probiotics for gastroenteritis, elimination of overuse of voiding cystourethrograms for first-time urinary tract infection, and use of narrower-spectrum antibiotics for communityacquired pneumonia. Key leaders of this body of work include Michael Vossmeyer, MD, Joshua Schaffzin, MD, PhD, Michelle Parker, MD, Patrick Conway, MD, MSc, Karen Jerardi, MD, Dena Elkeeb, MD, Jeffrey Simmons, MD, MSc, Christine White, MD, MAT, Samir S. Shah, MD, MSCE, Amy Guiot, MD, Patrick Brady, MD, MSc, and Eric Kirkendall, MD, The Division also implemented a novel bedside physician hand-off process at our Liberty campus, a project led by Craig Gosdin, MD, MSHA.

Data suggests that providing influenza vaccines to pregnant women can influence a developing infant’s growth.

Influenza Vaccine Trial in Bangladesh // Steinhoff and colleagues in Bangladesh evaluated the effects of antenatal influenza vaccine on fetal growth. A secondary analysis of data from a randomized prospective trial showed that there was a substantial increase of 200g in mean birth weights among infants born to mothers who received influenza vaccine, a new finding regarding the effects of influenza in pregnancy. They also showed that immunizing the mothers decreased the proportion of infants who were small for gestational age, from 44.8 percent to 25.9 percent, a significant reduction of 42 percent. These data suggest that influenza infection in pregnancy influences the growth of the developing infant.

Vitamin D in the Middle East // Adekunle Dawodu, MBBS, MRCP, carried out an assessment of sunlight exposure on vitamin D status in Middle Eastern women, who are known to have relatively low serum vitamin D levels, despite abundant sunlight. Dawodu arranged for volunteers to expose their faces, arms and hands in a culturally acceptable manner to direct sunlight for 15 minutes a day, twice a week, for four weeks. Compared to women who did not have this sun exposure, women exposed to more sunlight saw mean serum vitamin D levels significantly increase by 31 percent.

Improving Pneumonia Care // Community-acquired pneumonia is the most common serious bacterial infection in children. Division Director Samir S. Shah co-authored national pneumonia management guidelines that were sponsored by the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society. The new guidelines recommend ampicillin or amoxicillin as first-line treatment for pneumonia. Previously, children typically received “broad spectrum” antibiotics such as ceftriaxone, an unnecessary practice that contributes to antibiotic resistance.

Notable Accomplishments // Jeffrey Simmons received the Cincinnati Children’s Clinical Care Achievement Award for his exceptional commitment to patient- and family-centered care, mentoring junior faculty, and developing innovative models of clinical care. // Michelle Parker was recognized at the 17th International Scientific Symposium on Improving Quality and Value in Health Care for her work focusing on increasing use of a probiotic, Lactobacillus, to treat acute gastroenteritis. // Samir S. Shah was named inaugural associate editor of the Journal of the Pediatric Infectious Diseases Society and was promoted to deputy editor of the Journal of Hospital Medicine.

2012 ANNU A L R E P O RT // 49

RESEARCH OVERVIEW

division accomplishments HUMAN GENETICS National Research Resource for Pulmonary Hypertension // William Nichols, PhD, leads the new National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH). This project is using a five-year, $10 million National Heart, Lung and Blood Institute grant to build a biorepository of blood samples obtained from participants in the national REVEAL registry. Twenty four centers nationwide are contributing to the biorepository, which is based here at Cincinnati Children’s. Genomic DNA, plasma, lymphocyte cDNA, and transformed lymphoblasts from 3,000 PAH patients will be available to the research community. Whole genome SNP genotypes and DNA sequence data also will be generated and shared.

Exome Sequencing Initiative // Cynthia Prows, MSN, CNS, is launching a series of projects to measure the performance of exome sequencing in clinical settings. The work, funded by the Oxley Foundation, will generate sustainable collaborations between Human Genetics faculty and colleagues from other Cincinnati Children’s divisions and the University of Cincinnati College of Medicine.

Rare Disease Meets Common Neurodegenerative Diseases // Ying Sun, PhD, You-Hai Xu, PhD, and Division Director Gregory Grabowski, MD, are leading a project to elucidate the events that lead to CNS involvement in Gaucher disease. This work serves as a model for more common brain diseases, including Parkinson’s and Alzheimer’s diseases. During the past year, pathogenic links have been established between the autophagy and lysosomal systems and the glycosphinoglipid disruption in Gaucher disease mice. Results from this work could lead to new therapies for Gaucher disease and other conditions.

HEART INSTITUTE Advanced Cardiomyopathy and Heart Failure Diagnosis and Treatments // The Heart Institute has become an international leader in heart muscle disease (cardiomyopathies) and its associated treatments. We have developed the largest Advanced Pediatric and Young Adult Cardiomyopathy and Heart Failure Program in the United States, directed by John Lynn Jefferies, MD, MPH, and Jeffrey Towbin, MD. Our Heart Transplant Program, under the medical direction of Clifford Chin, MD, and surgical leadership of Alistair Phillips, MD, is one of the largest and most successful in the United States. We performed 14 transplants in the past year and 10 the previous year, with 100 percent survival. Recently, the Heart Institute has become a leader in mechanical circulatory support with the addition of cardiothoracic surgeon David Morales, MD, our new Chief of Cardiothoracic Surgery. Eight children with end-stage heart failure received mechanical circulatory support this year, six of whom were successfully transplanted and are doing well.

Members of the Heart Institute also published more than 170 manuscripts this year.

Heart Institute Joins International Research Consortium // Under the leadership of Jeffrey Robbins, PhD, the Heart Institute received one of four grants given worldwide by the Fondation Leducq to study how proteotoxicity — cell malfunctions caused by misfolded proteins — can lead to heart disease and failure. The consortium for this study is led by Cincinnati Children’s, and includes laboratories at the University of Texas-Southwestern, University of North Carolina at Chapel Hill and premier academic medical

The Institute has performed

Pediatric Heart Network Consortium // The Heart Institute successfully competed for a renewal grant to continue serving as one of nine “core” sites in the Pediatric Heart Network (PHN) through 2016. This competition was open to all academic centers in North America. The National Heart, Lung and Blood Institute created the network to conduct clinical studies in children with heart disease, especially for rare conditions that cannot be adequately studied by a single institution.

The network has completed at least 10 important multicenter studies. The most recent study, which began in 2007, is evaluating therapies used to treat Marfan syndrome. Cincinnati Children’s has been a core site in the PHN since 2006. James Cnota, MD and Catherine Krawczeski, MD, serve as principal investigators.

24

transplants in the past two years with

100

SURVIVAL

50 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

centers in Germany, Great Britain and Italy. The goal is to find novel treatments for a variety of heart diseases.

INFECTIOUS DISEASES New Faculty // Three new faculty members will join the Division in the FY13 academic year: Joe Qualls, PhD, from St. Jude Children’s Hospital, as assistant professor; Sing Sing Way, MD, PhD, from the University of Minnesota as associate professor; and Lara Danziger-Isakov, MD, MPH, as associate professor. Each brings a new area of expertise to the division’s research efforts; Qualls in macrophage biology, Way in the immunology of pregnancy and Danziger-Isakov in transplant infectious diseases.

Expanded Clinical Activities // Clinical revenues topped $700,000 in billings for the first time. This amount doubles the billing total in 2008. We also opened a new general infectious diseases clinic at our Liberty campus in the northern Cincinnati suburbs and a travel medicine clinic at the Burnet campus.

Research // Research grants and industry sponsored projects also hit a new high — $11.8 million in the past fiscal year. Grant funding and industry sponsored projects are expected to increase even more in the coming year, with several faculty having obtained new funding that will begin in FY13. The Division ranks second in overall funding among all divisions in the Cincinnati Children’s Research Foundation.

Research grants and industry sponsored projects also hit a new high — $11.8 million in fiscal year 2012.

M AY E R S O N C E N T E R F O R S A F E A N D H E A LT H Y C H I L D R E N CHECK Foster Care Clinic // Mary Greiner, MD, joined the Mayerson Center faculty this year. Greiner completed pediatrics training at Wake Forest University and child abuse training at Cincinnati Children’s. In addition to protecting children from abuse, her interests include improving outcomes for children in foster care. Through a joint appointment with the Division of General and Community Pediatrics, Greiner has opened the CHECK Foster Care Clinic, an evaluation clinic for Hamilton County children who are placed into foster care.

Awards, Appointments and Publications // This past year our Division published 16 peer-reviewed articles and was awarded $516,238 in grants and contracts.

Kathi Makoroff, MD, Director of our child abuse pediatrics fellowship, was elected Vice President of THE CENTER the Ray Helfer Society and was appointed Medical PUBLISHED Director of Cincinnati Children’s Continuing Medical PEER-REVIEWED Education (CME) Department. Brooks Keeshin, MD, A R T I C L E S was awarded a prestigious Doris Duke Fellowship

16

for the Prevention of Child Abuse and Neglect. This fellowship supports creating new knowledge on the dynamics of abuse and neglect and effective strategies for preventing child maltreatment.

New Clinical Service // Our Division began a new clinical service with the Shriner’s Hospital for Children in Cincinnati, providing consultations to burn surgeons when child abuse or neglect is suspected.

2012 ANNU A L R E P O RT // 51

RESEARCH OVERVIEW

division accomplishments

NEUROLOGY Headache Center // Our Headache Center, in its 15th year, offers a UCNS-certified Headache Medicine fellowship. Research includes clinical trials, outcome studies and understanding the molecular and neurophysiological basis of migraine. We identified gene expression patterns for medication overuse and menstrual-related migraine. An NIH study demonstrated cortical dysfunction during migraine in children and was extended to the effects of chronic migraine. With the Division of Behavioral Medicine and Clinical Psychology, we completed an NIH study of coping skills training in managing chronic migraine.

We collaborate with the Center for Clinical and Translational Research and the Department of Biostatistics and Clinical Trials Statistical and Data Management Center at the University of Iowa on a 40-site study comparing amitriptyline and topiramate in preventing children’s migraine.

NEPHROLOGY AND HYPERTENSION New Tests for Atypical HUS // Hemolytic uremic syndrome, or HUS, can lead to kidney failure and death. Atypical HUS is particularly lethal if not quickly identified and treated. Bradley Dixon, MD, developed blood tests to more rapidly evaluate atypical forms of HUS. The tests, in use by our clinical laboratory, look for the most common causes of atypical HUS, identify conditions that resemble atypical HUS and help clinicians rapidly treat the disease. The clinical laboratory has become a regional resource for HUS testing and continues as a national resource for tests that diagnose other disorders including acute kidney injury and chronic kidney disease.

NIH Pediatric Nephrology Center of Excellence // Prasad Devarajan, MD, Division Director, was awarded a five-year, $3.8 million Center of Excellence (P50) grant by the National Institute of Diabetes and Digestive and Kidney Diseases.

One of only three such centers nationally, we will fund translational research in

3.8

$

M I L L I O N Center of Excellence

acute kidney injury, nephrotic syndrome and lupus kidney disease. The Center will bring together investigators from Cardiology, Critical Care, Rheumatology, Developmental Biology, and Bone Marrow Transplant. We will fund research cores in genomics, proteomics, and biomarker development; administrative and enrichment cores will train future pediatric nephrology researchers.

grant was awarded by

Drug wins FDA approval // People with tuberous sclerosis complex (TSC) sometimes develop renal tumors and Kidney Diseases called angiomyolipomata. Until recently, only surgery or endovascular procedures helped control these tumors; many patients had bilateral, multifocal kidney involvement that was previously untreatable. Research by John Bissler, MD, demonstrated that the drug Everolimus shrunk the renal tumors in patients with TSC renal disease. As a result, the FDA approved Everolimus as the first drug that alters the progressive nature of these tumors. It is now recommended as the first line of therapy for TSC renal tumors. the National Institute of Diabetes and Digestive

52 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Epilepsy Center // Our research investigates drug-gene interactions on individual variation in response to anti-epileptic drugs; examines gene expression patterns in blood and brain; studies sleep medications’ effect on EEG patterns; looks at spikes and language development; images generalized spike discharges with functional MRI/ magnetoencephalography; and uses technology to develop clinical decision support algorithms.

The Center has six NIH-funded epilepsy researchers.

Our NIH-funded, 29-center U01 trial, the largest pediatric epilepsy trial ever funded in the U.S., will better identify the pharmacologic factors that affect response to therapy. Our research on epilepsy adherence was recently published in JAMA. Tuberous Sclerosis Complex (TSC) Program // Research in our Tuberous Sclerosis Clinic, the largest in the world, has resulted in a new FDA indication for renal tumors associated with TSC, and has identified new therapies for epilepsy, cognitive impairments, lung disease, and skin tumors. The focus of our research is mTOR inhibition, also applicable to non-TSC patients with a variety of disorders. Darcy Krueger, MD, PhD, received two multi-million dollar NIH RO1 grants, one of which will use TSC to study autism.

N E U R O S U R G E RY During the past year, the surgical epilepsy program, led by Francesco Mangano, DO, has published peer reviewed articles on improved pre-surgical evaluations and outcomes. Mangano and Weihong Yuan, PhD, are co-investigators on a National Institute of Neurological Disorders and Stroke study of advanced MR imaging in the field of hydrocephalus.

continues research on the tethered spinal cord, and has recently published a paper on the outcomes, benefits and risks of the surgery most often performed for this condition.

Charles Stevenson, MD, leads our brain tumor program, which continues to grow and was selected this year as a member institution of the Pediatric Brain Tumor Consortium. Stevenson and colleagues in the Fetal Care Program continue to perform successful in utero repair of myelomeningocele defects. We are one of the few children’s hospitals in the country capable of offering this advanced surgical treatment to families.

— waves of low frequency electrical activity that occur after brain injury —in childhood trauma.

Understanding this phenomenon is key to targeting therapies to improve outcome following traumatic brain injury in children.

Karin Bierbrauer, MD, is principal investigator for a national registry to study children with Chiari malformations and syringomyelia, an accumulation of fluid in the spinal cord at the base of the skull. She

Ellen Air, MD, PhD, teamed with palliative care on options for chronic cancer pain. She is also working to understand cortical spreading depressions

Developmental biologist Kenneth Campbell, PhD, recently joined our Division as the Robert and Sarah McLaurin Chair of Pediatric Neurosurgery Research.

His work in the molecular genetic mechanisms that control normal brain development is relevant to congenital birth defects in the central nervous system.

Campbell will help foster basic and translational research and provide research opportunities for neurosurgical residents and fellows.

OPHTHALMOLOGY Pediatric Low Vision Rehabilitation Program // We recruited Terry Schwartz, MD, Professor of Pediatric Ophthalmology, and Rebecca Coakley, MA, CLVT, to build a comprehensive low vision program in Ohio and surrounding states. The two have worked for the past 16 years to build a low vision rehabilitation program around the world. We recruited Kelly Lusk, PhD, to lead the research for this program.

The program provides access to the visual environment for children from age 3 through high school who have permanent vision impairment. It provides comprehensive eye evaluation, low vision devices, evaluates children for assistive technology, screens for orientation and mobility and recommends classroom adaptations. A low vision device library dispenses magnification aides as well as non-optical devices. Follow up services are included in the evaluation.

The goal is to collaborate with the regional education system and those who teach children who are visually impaired. The program helps schools and teachers provide children with the tools to become independent and employable. It optimizes the child’s visual function both at home and school. Our team has successfully collaborated with other departments to gain outside funding to increase the scope and delivery of this specialized service.

2012 ANNU A L R E P O RT // 53

“Many of the babies we treat, especially the very small babies, have good initial responses to surfactant replacement, which saves their lives.”

J E F F WHITSETT, MD

Cincinnati Children’s disclosed a record

188 DISCOVERIES AND RESEARCH TOOLS IN THE PAST YEAR.

THE DRUG Recombinant human surfactant protein D (SP-D)

A P P L I C AT I O N The drug will enable premature babies to breathe more easily until their lungs are fully developed.

E X PA N D E D U S E It may treat other conditions, including cystic fibrosis and smoking-related chronic obstructive pulmonary disease (COPD).

54 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

S U R FA C TA N T T H E R A P Y

big idea

grows FROM HELPING TINY BABIES

NEW DRUG DEVELOPMENT

Start-up company pursuing a dramatic improvement to artificial surfactant reflects the future of pediatric drug development Fueled by more than $150 million a year in research funding, innovation happens every day at Cincinnati Children’s. But even the best ideas cannot improve child health until they manage to cross a funding desert that stands between intriguing concepts and real-world therapeutics.

“What you have is a no-man’s land between what academic medical centers will typically do and what the big drug companies are looking for,” says Steven Linberg, President and CEO of a Cincinnati Children’s spin-off company formed in 2011, Airway Therapeutics. “Universities generally are not in the drug development business and drug companies don’t want to sink a lot of money into development when they aren’t sure of the returns.”

Start-ups like Airway Therapeutics fill that gap, Linberg says. The company’s key initiative will be recombinant human surfactant protein D (SP-D), a product based on years of research led by Jeff Whitsett, MD. Whitsett, Co-Director of the Perinatal Institute at Cincinnati Children’s, helped develop the first generation of artificial surfactants, which enable premature babies to breathe more easily until their lungs are fully developed.

More recently, Whitsett’s work has focused on making surfactant therapy more effective. He and his colleagues found that naturally occurring surfactant protein D— which is not currently included in the available surfactants used for preemies — may play a crucial role in preventing later respiratory problems.

“Many of the babies we treat, especially the very small babies, have good initial responses to surfactant replacement, which saves their lives,” Whitsett says. “But many develop bronchopulmonary dysplasia. These babies require long hospitalizations with oxygen support and they have recurrent viral and bacterial infections that go on for many months.”

Airway Therapeutics believes that adding surfactant protein D back into a marketed surfactant where nature originally put it could dramatically reduce intensive care stays and deaths among these infants.

SURFACTANT PROTEIN D This naturally-occurring substance is not currently used in treatments for premature infants. But it could prevent bronchopulmonary dysplasia and other respiratory problems later in life.

2012 ANNU A L R E P O RT // 55

BIG IDEAS BEGIN AT C I N C I N N AT I CHILDREN’S Research at Cincinnati Children’s has led to the creation of seven start-up companies in recent years: •

Airway Therapeutics LLC

•

AssureRx Health Inc.

•

Ausio Pharmaceuticals LLC

•

Bexion Pharmaceuticals LLC

•

Enable Injections LLC

•

QI Healthcare

•

SpineForm LLC

HELPING TREAT LUNG DISEASES Bronchopulmonary dysplasia (BPD) compromises respiratory function when the lungs are inflamed or scarred or the alveoli are damaged.

BRONCHIOLES

ALVEOLI LUNG

Conditions such as chronic bronchitis and chronic obstructive pulmonary disease (COPD) cause inflammation and mucus, resulting in restricted air passages.

56 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

ALVEOLI (CROSS-SECTION)

With conditions like emphysema, the alveolar membranes break down.

“What drug companies are looking for is a little bit more development, a little more proof of concept, to give them a better idea of what they’re gambling on.”

STEVEN LI N B E R G , P R E S I D E N T A N D C E O O F A I R WAY T H E R A P E U T I C S

USE BEYOND INFANTS Surfactant protein D also may prove useful in treating other conditions, including cystic fibrosis and smoking-related chronic obstructive pulmonary disease (COPD), Whitsett says.

“We know from animal studies that SP-D is dramatically protective against septic shock in newborns. We also know that smoking destroys SP-D, making emphysema more likely to develop. So it turns out that SP-D has implications throughout life,” he says.

Cincinnati Children’s has been making a human recombinant form of SP-D for several years to use in lab tests. Airway Therapeutics is leading the effort to scale up production for use in human clinical trials.

Currently, the protein is going through validation tests to confirm that the production process meets the strict quality standards required for human studies, Linberg says. If successful, a Phase III human clinical trial could begin in 2014.

ABOUT THE CTC The Center for Technology Commercialization (CTC) protects our innovations through patents; assists in further developing technologies through research partnerships; and delivers products to the market through licensing and forming start-up companies.

A MODEL FOR THE FUTURE The surfactant D project reflects the kind of translational research to be expanded at the new Clinical Sciences Building, a 15-story research tower under construction at Cincinnati Children’s main campus.

The building, along with other expanded capabilities at Cincinnati Children’s, helps address a challenging reality for pediatric medicine. With large pharmaceutical companies often unwilling to take risks to develop drugs with small market potential, pediatric medical centers must take on more of the early-stage work themselves.

“I see this as the future for drug development,” Linberg says. “The days of big pharmaceutical companies developing all their products inhouse are over.”

Cincinnati Children’s is becoming a leader in this trend. Not only has the medical center supported the formation of Airway Therapeutics, it invested funds to launch the company.

“What drug companies are looking for is a little bit more development, a little more proof of concept, to give them a better idea of what

they’re gambling on,” Linberg says. “Cincinnati Children’s has been very helpful. They did much more than sign a licensing agreement. They put up money and they’ve remained involved scientifically.”

When and if the improved version surfactant reaches market, Cincinnati Children’s stands to benefit from milestone payments and royalties that will help support more research.

The medical center already has launched seven start-up companies and there will likely be more. Scientists at Cincinnati Children’s filed a record 188 invention disclosures in the past year, according to the medical center’s Center for Technology Commercialization (CTC). That reflects a five-year average of 97 disclosures a year. g

2012 ANNU A L R E P O RT // 57

HEMATOLOGY + CANCER

molecular

Scientists break through limitations, discover new possibilities to overcome disease

mavericks

One study counters accepted scientific dogma — unlocking new clues to the health problems people face in old age.

Another describes a new drug candidate that could control disease-fueling cell inflammation, with enormous potential for battling disease.

And a third suggests a therapeutic approach that could improve survival for children with acute myeloid leukemia (AML) with less toxicity to healthy cells.

These are a few research highlights from the past year for the Division of Experimental Hematology and Cancer Biology, as its scientists continue to make bold inroads into uncharted scientific territory.

“We continue to publish novel findings that take on some current controversies and unmet challenges in life sciences,” explains Yi Zheng, PhD, Division Director and a collaborator on the studies. “Our goal is clear — to work with physicians and clinical researchers to translate what we learn from these bench-side studies to improve the clinical care of patients with deadly diseases, like cancer.”

“Our goal is clear — to work with physicians and clinical researchers to translate what we learn from these bench-side studies to improve the clinical care of patients with deadly diseases, like cancer.”

Y I Z H E N G , PhD

58 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

2012 ANNU A L R E P O RT // 59

HEMATOLOGY + CANCER

Geiger noted the study bridges several areas of research previously considered unrelated — Cdc42 signaling, epigenetic cell polarity, aging and stem cell rejuvenation.

Dr. Hartmut Geiger’s laboratories at Cincinnati Children’s and the University of Ulm School of Medicine in Germany have unlocked scientists’ understanding of cellular aging.

60 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

R E J U V E N AT I N G

HSCs will help produce blood cells that are critical components of the immune system.

PICKING NATURE’S LOCK Prevailing scientific literature said it could not be done. The aging of hematopoietic stem cells (HSCs) in the bone marrow — the body’s blood making factory — was locked in by nature and irreversible.

Then a team of scientists at Cincinnati Children’s and Ulm University School of Medicine in Germany — led by hematology researcher Hartmut Geiger, PhD — published a study this spring in Cell Stem Cell showing they had done “it.”

The researchers used a substance called CASIN to pharmacologically inhibit the activity of a protein that regulates cell signaling (Cdc42) and rejuvenated aged HSCs to become functionally younger.

W H AT I S I T ?

Rejuvenating hematopoietic stem cells in the bone marrow.

A P P L I C AT I O N It could boost the immune system in elderly people, reducing the likelihood of infections and certain malignancies.

E X PA N D E D U S E It may be beneficial in treating certain types of childhood cancers.

“The findings are novel and significantly advance this field of study,” says Geiger, a scientist and faculty member at Cincinnati Children’s and the University of Ulm. “They also span a wide arc — from the initial identification of a molecular pathway’s relevance to successful pharmacological targeting and rejuvenation of HSCs.” Geiger noted the study also bridges several areas of research previously considered unrelated — Cdc42 signaling, epigenetic cell polarity, aging and stem cell rejuvenation.

If the findings can be translated to humans, the implications would be considerable. HSCs produce blood cells that are critical components of the immune system. Rejuvenating aging stem cells could lead to reinvigorating the faltering immune systems of older people, making them less susceptible to infections, anemia and certain kinds of malignancies.

The findings also may extend to childhood cancers, according to Zheng and Geiger.

Disruptions in cell polarity — the relative placement and spacing of vital cellular components — are suspected of playing a role in certain cancers.

Understanding the molecular reasons for disruptions in cell polarity and how to resolve them — an area of study Zheng says is just emerging — could benefit children with certain cancers.

Similarly, Cdc42 protein activity is abnormally

high in numerous cancers — a focal point of Zheng’s research for years. New knowledge on the protein’s activity, and how to manipulate it, will help future cancer research.

ALL FIRED UP Inflammation’s role in the disease process is an important part of the cancer research team’s work.

“Inflammation has recently been implicated as a key helper or modifier of many diseases, including cancer,” explains Zheng. “Effective anti-inflammation agents that do not cause unwanted toxicity could certainly help control and suppress inflammation, and would therefore be therapeutic in inflammationassisted diseases, like cancer and obesity.

This remains an unmet clinical need.”

The body requires inflammation to fight pathogens, but only to a certain extent.

A virtual mountain of research shows that excess and chronic inflammation can generate biological havoc on the human body.

Past efforts to find new drugs that tamp down so-called reactive oxygen species (ROS) molecules in cells —which help fuel inflammation — have been complicated by toxicity issues and a lack of specificity in how molecular 2012 ANNU A L R E P O RT // 61

HEMATOLOGY + CANCER

///////////////////////////////////////////////////////////////

The body requires inflammation to fight pathogens, but only to a certain extent. A virtual mountain of research shows that excess and chronic inflammation can generate biological havoc on the human body. processes are targeted. But Zheng and his colleagues — including division collaborator Marie-Dominique Filippi, PhD — published a study in Chemistry & Biology that reported the scientists had overcome this problem.

Using computer-assisted drug design — verified by laboratory tests on human and mouse inflammatory cells — the researchers designed two versions of a small molecule inhibitor they named Phox-11 and Phox-12.

The inhibitors precisely target and block the molecular binding of a signal sensor for ROS with an inflammation protein called p67-phox — hence the name of the new compounds.

LESS INFLAMMATION, NO TOXICITY The new compounds convincingly demonstrated the ability to tamp down disease-fueling inflammation in the cells of mouse models of pulmonary disease without being toxic. As a result, Phox11 and 12 have been transferred into a technology commercialization research and development phase through the Center for Technology Commercialization at Cincinnati Children’s.

Zheng says the drugs may benefit people suffering from a variety of diseases, including chronic obstructive pulmonary disease, ischemia-induced lung and brain damage and hypertension, among others.

62 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

DOUBLE TEAMING LEUKEMIA Nearly half of children with acute myeloid leukemia (AML) die from relapsed or refractory disease, despite current treatments using the maximum doses tolerated safely by patients. Those stark odds highlight the need for new and improved targeted treatments, according to division scientist James Mulloy, PhD. One problematic form of AML — responsible for a significant number of cases — is mixed-lineage leukemia (MLL) associated with a chromosome abnormality involving a gene called AF9.

A study by Mulloy and colleagues — published November 2011 in the journal Blood — describes how the scientists double teamed and stopped this type of AML in mice by using gene targeting to block a protein pathway that drives the onset and growth of AML. The experimental combination therapy included a small-molecule inhibitor developed at Cincinnati Children’s called NSC23766.

The targeted pathway involves the Rac protein family — part of a class of proteins known as Rho GTPases. Rho GTPases coordinate a variety of functions in hematopoietic cells — migration, cytoskeleton rearrangements, proliferation and survival. Rac signaling also regulates cell functions in initiating and spreading hematopoietic cancers. The second component of the targeted pathway involves the protein family Bcl-2, which regulates cell apoptosis — or programmed cell death.

Building on extensive previous research, the scientists disrupted the anti-apoptotic function of Bcl-2 proteins in the mice.

The researchers then added NSC23766 to the treatment regimen to further block Rac activation in the leukemic cells. This combination treatment was highly effective in targeting the survival of leukemic cells in AML. The researchers also found this therapeutic approach does not harm healthy blood cells in mice, suggesting it might be less toxic to patients if further developed for humans. g

Researchers at Cincinnati Children’s designed

2

VERSIONS OF A MOLECULE INHIBITOR

T H AT P R E C I S ELY TARGET A N D B L O C K BINDING OF A S I G N A L S E N S OR WITH AN I N F L A M M AT I O N PROTEIN

“Inflammation has recently been implicated as a key helper or modifier of many diseases, including cancer.”

Y I Z H E N G, PhD

2012 ANNU A L R E P O RT // 63

HISTORICAL OVERVIEW

CINCINNATI CHILDREN’S RESEARCH FOUNDATION

a legacy of

innovation WILLIAM COOPER P R O C T E R // A businessman and philanthropist, Procter helped lay the groundwork for the institution Cincinnati Children’s is today.

64 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Using this bubble defoam oxygenator heart-lung machine developed by chemist Leland Clark, doctors at Cincinnati Children’s performed one of the earliest open heart surgeries.

Researchers are pioneers, journeying into unknown territories, and occasionally discovering a whole new world. Cincinnati Children’s has a rich history of encouraging the intellectual curiosity, innovative spirit and persistent drive that fuels breakthrough discoveries. Here, just a sampling of what has brought us to where we are today.

In 1924, one small research laboratory was available for the Department of Pediatrics, and no one was using it. It did not stay that way for long.

1924 was the year Albert Graeme Mitchell, MD, arrived as the B.K. Rachford Professor and Chair of Pediatrics of the University of Cincinnati College of Medicine.

A man with big ideas, he quickly found an equally visionary partner — businessman and philanthropist William Cooper Procter, President of the Board of Trustees of The Children’s Hospital (now Cincinnati Children’s).

ALBERT GRAEME MITCHELL, MD

// The B.K. Rachford Professor and Chair of Pediatrics of the University of Cincinnati College of Medicine, Mitchell was a visionary who understood the importance of research.

Together they laid the groundwork for the institution Cincinnati Children’s is today.

By the end of 1926, they affiliated Cincinnati Children’s with the College of Medicine as the Department of Pediatrics, opened a new hospital building that increased capacity from 90 to 200 beds, and recruited students into a newly accredited pediatric residency program.

Mitchell was ready for the next step: research.

He argued that “unless effort is made to study and investigate problems in a manner which will add in a constructive way to existing knowledge, we have all of us failed to function to the fullest extent.”

Convinced, Procter made a breathtaking gift of $2.5 million to build and endow The Children’s Hospital Clinic and Research Foundation. When it opened in 1931, Cincinnati Children’s became the nation’s first pediatric hospital with a building dedicated to research.

EARLY INNOVATORS Mitchell’s first hire was George Guest, MD, who became a Co-Founder of the Society for Pediatric Research and its President in 1942.

Josef Warkany, MD, arrived from Vienna on January 1, 1932, for a one-year research fellowship. He spent his entire and highly productive career at Cincinnati Children’s.

Warkany gained fame when he showed that mercury in teething powders and ointments caused acrodynia, a painful childhood disease. His work led to mercury being removed from these products. He went on to do pioneering research on nutritional and environmental factors that cause birth defects. In 1971 he completed the influential textbook, Congenital Malformations.

In 1939, the Research Foundation recruited another promising young scientist: Albert Sabin, MD. 2012 ANNU A L R E P O RT // 65

HISTORICAL OVERVIEW

///////////////////////////////////////////////////////////////

Graeme Mitchell and William Procter would marvel at what their vision has become.

Today Cincinnati Children’s ranks second in NIH funding for pediatric research.

A L B E R T S A B I N , M D //

The Sabin vaccine’s effectiveness and ease of administration made it the vaccine of choice in WHO’s campaign to eradicate polio.

66 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

LELAND CLARK, PhD In the early ’50s, pediatric cardiologist Samuel Kaplan, MD, and surgeon James Helmsworth, MD, worked with Clark to perfect the bubble defoam oxygenator heart-lung machine.

Sabin spent 30 years at Cincinnati Children’s. His research on polio proved that the virus enters the body through the digestive tract. He found polio resistant antibodies in some children, suggesting they had been infected by a weakened strain that produced immunity. Based on these observations, he developed the world’s first attenuated live-virus vaccine.

In 1957, the World Health Organization (WHO) chose Sabin’s vaccine for worldwide testing. The first U.S. test was in Cincinnati on April 24, 1960. The Sabin vaccine’s effectiveness and ease of administration made it the vaccine of choice in WHO’s campaign to eradicate polio.

R I C H A R D W A R D , PhD Ward worked with David Bernstein, MD, to develop an attenuated live-virus vaccine for rotavirus, now marketed as Rotarix.

THE WAR YEARS During WWII, Sabin worked on vaccines against Japanese B encephalitis, sandfly fever and dengue fever. Merlin Cooper, MD, helped develop a vaccine for dysentery. Samuel Rapoport, MD, and Paul Hoxworth, MD, developed new methods for preserving blood, which saved lives on the battlefield.

After the war, A. Ashley Weech, MD, who succeeded Mitchell as Pediatric Chair, said, “The science of war has left a legacy to the science of peace.”

SENSORS AND SURGERY Leland Clark, PhD, a chemist and inventor, joined the Research Foundation in 1968, but his collaboration with Cincinnati Children’s started years earlier.

He began developing his bubble defoam oxygenator heart-lung machine in the 1940s while at Antioch College. In 1951, he contacted the heart care team at Cincinnati Children’s.

Pediatric cardiologist Samuel Kaplan, MD, and surgeon James Helmsworth, MD, worked with Clark to perfect the machine and perform one of the earliest open heart surgeries reported in the Journal of the American Medical Association (October 4, 1952).

Clark also developed the first sensor to measure

glucose in blood and the Clark oxygen electrode, which is used worldwide in medical and industrial applications.

DISCOVERY CONTINUES In 1988, neonatologist Jeffrey Whitsett, MD, announced breakthrough research on surfactant. His team identified and cloned two proteins essential to human surfactant.

The discovery made it possible to produce synthetic human surfactant for treating premature infants with respiratory distress syndrome. Today surfactant replacement saves thousands of lives every year.

It was during the 1980s that Richard Ward, PhD, and David Bernstein, MD, began work on an attenuated live-virus vaccine for rotavirus, now marketed as Rotarix. First licensed in Mexico in 2004, the vaccine is used in over 100 countries. In 2009, WHO recommended that rotavirus vaccine be included in all national immunization programs.

Graeme Mitchell and William Procter would marvel at what their vision has become.

Today Cincinnati Children’s ranks second in NIH funding for pediatric research. Earlier this year, we broke ground for a new research tower that will make us the nation’s largest pediatric research facility.

The researchers who make their discoveries there will stand on the shoulders of giants.

Their innovations and achievements will be both proud legacy and inspiration for future generations. g

2012 ANNU A L R E P O RT // 67

RESEARCH OVERVIEW

division accomplishments

O T O L A RY N G O L O G Y Simulation in Otolaryngology // Kaalan Johnson, MD, joined our Division this year and established a simulation and training program. His work culminated this May in the first Annual Midwest Airway Course. The course, designed to prepare residents for the challenges of performing rigid endoscopy, was well attended and received positive feedback. Plans are to make this course an annual event.

Festschrift for Robin Cotton, MD // A two-day Festschrift honoring the career and accomplishments of Dr. Robin Cotton was held last year in Boston. The twoday event brought experts from every field of pediatric otolaryngology together to lecture on current topics. The proceedings were published in a special supplement in the fall 2012 Laryngoscope.

Christian Pueschel Memorial Research Award // The National Down Syndrome Congress awarded Sally Shott, MD, the Christian Pueschel Memorial Research Award. This award is given to an outstanding physician who improves the lives of children with Down syndrome through research and treatment of ear, nose and throat conditions.

O R T H O PA E D I C S Recognition and Expansion // U.S. News and World Report magazine ranked our Division of Pediatric Orthopaedic Surgery among the top four in the country. Faculty presented at annual meetings of the Pediatric Orthopedic Society of North America (POSNA) and the American Academy of Orthopaedic Surgeons (AAOS). They also participated in collaborations and conferences in Greece, Brazil, India, and Saudi Arabia.

We welcomed Sheila Chandran, MD, and Jaime Rice-Denning, MD, this year. Chandran has a special interest in pediatric gait and the Ponseti technique for managing clubfoot. Rice-Denning specializes in orthopaedic trauma cases.

Motion Analysis Gait Lab Opens // Our Motion Analysis Gait Lab uses the latest technology to evaluate and treat orthopaedic and mobility issues. The lab’s research will use outcomes data to characterize the effectiveness of current treatments and to develop and implement innovative techniques. This year, the Gait Lab had 113 patient visits, more than projected for the first year of operations.

This year, the Gait Lab had 113 patient visits, more than projected for the first year of operations.

68 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

HemiBridge Spine Clip Clinical Trial Progresses // This year, we enrolled five patients in the HemiBridge™ System US FDA Investigational Device Exemption clinical safety trial. The first patient has completed the six-month follow-up visit, with early indications of positive results. Methods to assess implant performance are currently under study.

Preliminary results of the device’s effects on spine biomechanics in an in vivo model have been published.

Biomechanical effects of the device on spine motion were determined in an in vitro and a computational model. Growth inhibition predictions of the computational model correlated with previously reported histomorphometric growth plate structural patterns.

Audits were completed for regulatory clearance in Europe and patents in Mexico were approved. In the United States, we continued plans for Humanitarian Use Device (HUD) designation, a step toward simplifying the next phase of clinical study and streamlining the regulatory path to US market clearance.

PAT H O L O G Y A N D L A B O R AT O R Y M E D I C I N E Cancer Biology Program // Faculty members of our Division, including Gang Huang, PhD, and Mohammad Azam, PhD, participate in funded studies that support Cincinnati Children’s work with cancers of the hematopoietic system. This was in evidence at the Ninth International Workshop on the Molecular Aspects of Myeloid Stem Cell Development in Leukemia jointly sponsored by the Cancer and Blood Diseases Institute of Cincinnati and the Division of Pathology and organized

by Lee Grimes, PhD, Division of Immunobiology. Investigators and leaders in the field of cancer biology from the United States, Europe, Canada, Australia, and Japan attended.

Molecular Basis for Lung Disease // Clinical pathologist Kathryn Wikenheiser-Brokamp, MD, PhD, studies the genetic and developmental basis of lung disease and lung cancer. She has identified critical functions for the RB/P16 and P53 tumor suppressant pathway in pulmonary epithelial cell growth in the context of lung development, injury repair and carcinogenesis. Her studies are supported by the NIH and the American Cancer Society.

Wikenheiser-Brokamp is part of a multi-institutional team of physicians and researchers who discovered DICER1 mutations in a familial tumor predisposition syndrome that develops pleural pulmonary blastoma.

She leads a consortium exploring how DICER1 and the micro RNAs it generates control organogenesis and oncogenesis. Her work is funded by the NIH and the Saint Baldrick’s Research Consortium.

Neuro-Oncology Program // Under the direction of Maryam Fouladi, MD, Cincinnati Children’s has been selected to become a full member in the NCI Pediatric Brain Tumor Consortium. This consortium is the National Cancer Institute’s primary mechanism for developing new drugs for children with brain tumors and will allow CCHMC to become a national center for the treatment and management of pediatric brain tumors. Lili Miles, MD, of our Division will head the pathology diagnostic service and review of children referred for brain tumors, and will establish and provide laboratory support to develop pathologybased markers to support this effort.

2012 ANNU A L R E P O RT // 69

RESEARCH OVERVIEW

division accomplishments In the past year, our Division has transitioned to a new clinical home, joining a larger clinical multidisciplinary genitourinary practice at our main hospital location.

P E D I AT R I C A N D A D O L E S C E N T G Y N E C O L O G Y In the past year, our Division has transitioned to a new clinical home, joining a larger clinical multidisciplinary genitourinary practice at our main hospital location. We expanded services to new satellite locations and evening sessions, increasing clinical volume to record levels. Staff roles have also expanded; we developed a new gynecology nursing role. In addition, faculty presented at international venues in India, Ghana, Bosnia, and more.

Visits to the Head Injury Clinic have tripled over the past three years with MORE THAN

1,200 O U T PAT I E N T V I S I T S T H I S PA S T Y E A R

P H Y S I C A L M E D I C I N E A N D R E H A B I L I TAT I O N Shari Wade, PhD, and Brad Kurowski, MD, MS, with Lynne Babcock-Cimpello, MD, Division of Emergency Medicine, obtained Place Outcomes and Ohio Emergency Medical Services grants to develop and test a web-based intervention to facilitate recovery after mild traumatic brain injury (TBI).

Kurowski, with Michael Gittelman, MD, Division of Emergency Medicine, obtained an Ohio Emergency Medical Services grant to evaluate the impact of educating athletes on concussion prevention. Additionally, Kurowski received a University of Cincinnati Research Council grant to evaluate balance testing in evaluating concussion.

Wade worked with the Cincinnati Veterans Administration (VA) Medical Center to obtain a VA-sponsored grant to adapt web-based treatments for TBI to veterans. She is working with psychologists in the United Kingdom and New Zealand for funding to adapt and test interventions for pediatric TBI in those countries.

Through the Comprehensive Children’s Injury Center (CCIC), our Division is improving the care of children after traumatic brain injury. The CCIC nominated Kurowski to direct the development of an outpatient Head Injury Clinic. We have tripled our outpatient visits over the last three years, with more than 1200 visits this past year. The CCIC has also helped us increase our community outreach and has allowed us to develop innovative interdisciplinary research projects.

70 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Research // Our Division continued its focus on improving the diagnosis and treatment of sexually transmitted infections in adolescent women and preserving future fertility in children, adolescents, and young women treated for malignancies.

Jill Huppert, MD, secured more than $250,000 in industry-sponsored funding for STD diagnostic tests. With colleagues from Johns Hopkins, she co-authored and won funding for a U-54 grant.

Huppert’s expertise resulted in being the lead author for the trichomoniasis chapter in Netter’s Infectious Diseases (2011). In addition, her quality improvement work on improving STD care has recently been accepted for publication in Pediatrics.

Oncofertility // Our Division joined with the Division of Hematology /Oncology to build the Oncofertility Program, which focuses on the impact of medical treatment on future fertility for patients being treated with chemotherapy or radiation. Leslie AyensuCoker, MD, began enrolling patients in an innovative project, Ovarian Tissue Cryopreservation, which allows the cryopreservation of ovarian tissue before treatment with gonadotoxic drugs. Ayensu-Coker was awarded the ACOG/Merck Research Award in Adolescent Preventive Services for GonadotropinReleasing Hormone Agonist (GnRHa) and ovarian preservation. She also jointly submitted an NIH R21 grant for the evaluation of ovarian toxicity in pediatric oncology with Frank Biro, MD, Division of Adolescent Medicine, and Karen Burns, MD, Division of Oncology.

P L A S T I C S U R G E RY Craniofacial Anomalies Team // The craniofacial anomalies team is an interdisciplinary clinical team comprised of Genetics, Plastic Surgery, Physical Therapy, Speech Pathology, Audiology, Dentistry, Psychiatry, Neurosurgery, Otolaryngology and Nursing. Our primary goal is to improve the health outcomes for patients with craniofacial abnormalities, such as cleft lip and palate. We held our first Cincinnati Children’s Craniofacial Research Symposium on January 26, 2012. This symposium brought together researchers in the Divisions of Biomedical Informatics, Developmental Biology, Human Genetics, Plastic Surgery, and clinicians in the CCHMC Craniofacial Anomalies Team.

Neonatal Skin Development // Marty Visscher, PhD, is currently studying premature infants who lack vernix caseosa, have an incompetent skin barrier and who are predisposed to infection. She studies ontogeny of stratum corneum barrier development in premature infants as a function of gestational age, over time, and compared to full term infants. To do this, Visscher uses quantitative measures of barrier integrity, hydration, pH, and collection of skin surface samples to determine lipid composition, stratum corneum structural proteins and specific cytokines. Visscher collaborates with researchers from Johns Hopkins University on a parallel study on the effect of topical massage oils on neonatal skin integrity.

Quantitative Skin Imaging and Analysis // Visscher studies multiple imaging modalities to characterize the disease/healing processes and treatment for skin conditions including hemangiomas, pressure ulcers and burn scars. Affected sites are evaluated with high resolution color imaging, thermal imaging (static, dynamic), three dimensional surface scans (3dMD Medical Imaging System), and biomechanical properties and compared with clinical assessments. We continue to investigate causes and evaluate interventions to reduce skin compromise.

Research Projects and Collaborations // Samantha Brugmann, PhD, studies the function of primary cilia in craniofacial development. Using both avian and murine model systems, her laboratory is examining how loss of ciliary proteins affects neural crest cell development.

This work is supported by an R00 from the National Institute of Dental and Craniofacial Research (NIDCR) and a Trustees grant from Cincinnati Children’s.

The lab interest in cilia has also extended into a more translational direction. Working with the laboratory of Rolf Stottmann, PhD, in the Division of Human Genetics, the Brugmann lab uses next generation sequencing technology to identify genetic variants in three families with ciliopathic features here at Cincinnati Children’s.

The goal of this project is to identify novel, ciliary genes responsible for human disease. This work is funded by a Pilot grant from Cincinnati Children’s.

Brugmann collaborates with Jim Wells, PhD, Division of Developmental Biology, on a project designed to engineer human intestinal organoids innervated with a neural crest-derived enteric nervous system. This work is funded by a U18 grant from the National Center for Advancing Translational Sciences.

Marty Visscher, PhD, studies premature infants who lack vernix caseosa, have an incompetent skin barrier and who are predisposed to infection.

Brugmann welcomed post-doctoral fellow Ching-Fang Chang to the lab in March 2012.

Christopher Gordon, MD, and visiting research scientist Armando Uribe-Rivera, in collaboration with Bruce Aronow, PhD, are investigating the role of microRNAs as master controllers of craniofacial development.

2012 ANNU A L R E P O RT // 71

division accomplishments

RESEARCH OVERVIEW

P S Y C H I AT R Y Improving Mental Health Care for Rural Populations // In a pilot program, we have partnered with employers to provide mental health care to children via teleconferencing. We currently serve a three-state region outside of Ohio; diagnoses include ADHD; disruptive behavioral problems; mood disorders, and eating disorders.

P U L M O N A RY M E D I C I N E New Developments in Treating Cystic Fibrosis // Although improvements have been made in treating cystic fibrosis (CF) for several decades, all previous therapies have targeted downstream symptoms rather than early steps in the disease cascade.

2012 brought FDA approval of the first drug targeting the root cause of CF. Kalydeco, or ivacaftor, restores activity to one of the mutant proteins that causes CF, G551D, found in about 5 percent of all patients. Adult and pediatric patients with this mutation who were treated with kalydeco had greater than 10 percent improvement in lung function, gained more weight and reduced their risk of pulmonary exacerbations by more than 50 percent.

John Clancy, MD, has now completed phase II trials of a second drug, lumicaftor, in patients who have the most common CF-causing mutation (F508del, found in nearly 90 percent of CF patients).

The drug restored lung function in these patients. Phase III studies are targeted for late 2012.

greater than

10 PERCENT

improvement in lung function in patients who were treated with kalydeco

NIH Training Grant // Our division was one of only two pediatric pulmonary centers in the United States to receive the National Institutes of Health Ruth L. Kirschstein National Research Service Award (NRSA) program. This program funds research training opportunities for medical students in basic or clinical research in pediatric pulmonary and sleep medicine. Eight applicants were selected and matched with mentors covering a variety of pediatric respiratory research areas including asthma, cystic fibrosis, lung cancer and sleep apnea.

Carolyn Kercsmar, MD, was awarded a $150,000 grant from the John A. Schroth Family Charitable Trust to develop multimedia discharge instructions for patients with asthma to improve asthma control and decrease re-admissions.

This innovative study will feature the child and parent as “stars” in their own educational video to enhance their asthma management skills. The overall goals are to reduce the use of emergency department and inpatient services due to asthma, and to improve the percentage of patients with well controlled asthma in the Greater Cincinnati community. Knowledge gained from this model can spread to other programs nationwide.

72 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Patients have access to both psychotherapy and medical care; we also provide an infrastructure and access point for children who need more intensive services, such as inpatient care. The groups participating in the program are highly satisfied with excellent patient outcomes; plans are to expand throughout the Midwest.

Improving Medical Care and Safety // Children with intellectual disabilities and severe mental health challenges often struggle in medical care facilities, resulting in aggressive episodes or refusal of care.

We are leading a collaborative effort at Cincinnati Children’s to improve care for these young people.

We can now predict who will struggle to comply with medical care and develop mitigation strategies and improved psychosocial outreach for better care. This program has been extremely effective in preventing aggressive episodes, evidenced by decrease of injury rates among care providers. Patients and staff are now involved in interactions that are safer, more comprehensive, and able to produce outcomes of enhanced medical care and decrease staff and patient injury.

School Based Mental Health // Access to mental health care remains a challenge in our region. In response, we have established a number of schoolbased mental health clinics. In these settings, our doctors or advanced practice nurses lead on-site mental health teams to address students’ mental health problems. They provide psychiatric and preventive services. This on-site, school-based mental health care has contributed to improved school retention rates and student outcomes.

RADIOLOGY Safer Imaging // Led by one of our faculty, The Alliance for Radiation Safety in Pediatric Imaging formed in 2007 to minimize children’s medical radiation exposure. The Alliance has grown to include more than 72 organizations and 800,000 radiologists, radiological technologists, medical physicists, and others.

Our continued research and development has led to a program that optimizes the dose and image quality for each child prior to a CT scan. This program is being commercialized and promises to further improve pediatric radiation dose reduction across the country.

Our “Right Patient, Right Exam” initiative sought to decrease inappropriate imaging from requisition errors. Through the efforts of our technologists and radiologists, more than 800 potential errors were caught and corrected.

Liver Imaging – Improving Diagnoses // CCHMC is the first pediatric institution to perform MR Elastography, a method developed at the Mayo Clinic to assess liver fibrosis and inflammation without the need for biopsy.

We also lead the advanced imaging of focal liver lesions in children using a new liverspecific MR contrast agent, Eovist. This contrast agent has increased accuracy and confidence in identifying liver lesions in children, resulting in improved cancer treatment and monitoring. Our faculty have published the two authoritative papers in the medical literature on the use of Eovist in pediatric liver tumor imaging.

Improving Outcomes in Interventional Radiology // Interventional radiology techniques offer treatment options where no effective therapies have been available. One such area is refractory retinoblastoma, an aggressive tumor of the eye. If traditional treatment options fail, the only recourse has been removal of the eye. Working with the Cancer and Blood Diseases Institute, our Interventional Radiology team performs selective ophthalmic artery infusion to deliver high doses of chemotherapy directly to the tumor, at levels that would be toxic if given by traditional routes. Initial results show the therapy is well-tolerated and shows promise in curing these children while preserving their vision.

REPRODUCTIVE SCIENCES Fetal Programming and Environmental Exposures // S.K. Dey, PhD, Jeff Whitsett, PhD, and Susan Fisher, PhD, University of California San Francisco, organized “Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Pre-Term Birth, ” a meeting jointly sponsored by the New York Academy of Science and Cincinnati Children’s. Held in New York City, the meeting drew 140 researchers and clinicians to discuss factors affecting prenatal development and how to better deal with those factors.

Funding and Research // All five of full-time faculty members are funded by at least one external grant, and three of the five have more than one external grant.

Overall, our Division is supported by five NIH, five private and two internal grants.

Although the underlying mechanisms of preterm birth and prematurity are still unknown, uterine decidual senescence via the mammalian target of rapamycin complex 1 (mTORC1) signaling is a novel approach to its understanding. We were able to reverse decidual senescence with a low dose of rapamycin (an inhibitor of mTORC1 signaling) or Celebrex, an anti-inflammatory and COX-2 inhibitor. This work was highlighted by the American Association for the Advancement of Science in Cell Signaling, Biology of Reproduction and Cell Cycle.

Adjunct Professors Abroad Doing Well // The Division of Reproductive Sciences has two adjunct professors stationed at universities abroad. Yasushi Hirota, MD, PhD, at the National Institute of Genetics of Japan in Shizuoka, Japan, published two papers with members of Dey’s lab. He also received a research award from the Japan Society of Reproductive Medicine and an outstanding presentation award from the Japan Society of Obstetrics & Gynecology. Hirota received three new grants in 2012 and was named to the editorial board of the journal Molecular Human Reproduction.

Hyunjung (Jade) Lim, PhD, at Konkuk University in Seoul, South Korea, published three papers and was awarded a five-year grant to explore the development of molecular cell biological markers for oocyte and ovarian tissue cryopreservation.

2012 ANNU A L R E P O RT // 73

RESEARCH OVERVIEW

division accomplishments

RHEUMATOLOGY International Accomplishments // Collaborating with Seattle Children’s Hospital, Edward Giannini, MSc, DrPH, showed that aggressive treatment early in the disease course leads to better therapeutic responses and outcomes in juvenile idiopathic arthritis. Michael Henrickson, MD, MPH, published a comprehensive evaluation of the pediatric rheumatology workforce. An institution-wide initiative led by Michael Barnes, PhD, created a biobank for tissues and DNA expected to have 750,000 samples before the end of the year; the bank will be used for research. The continuing efforts of Susan Thompson, PhD, and colleagues led to discovery of a gene important for juvenile idiopathic arthritis.

Since the start of the Schmidlapp Women Scholars Program, 12 of the scholars have been promoted, two to professor and three awarded tenure.

SCHMIDLAPP CENTER Schmidlapp Program // Since the start of the Schmidlapp Women Scholars Program, 12 of the scholars have been promoted, two to professor and three awarded tenure. The scholars have published 435 papers since their naming as scholars, and have received nine NIH R01 grants, four NIH K Awards and 10 foundation grants for a total of $17 million in direct costs. This is an eleven-fold return on investment, indicating the success of this program.

Undergraduate Support // Faculty and parents of undergraduates supported by the Schmidlapp Program have donated more than $72,000 to support our future women researchers and clinicians, with over $16,000 raised this fiscal year.

Office for Faculty Development // The Office for Faculty Development (OFD) has provided a variety of seminars, networking opportunities, and career development resources for faculty members. A total of 1,163 faculty attended an OFD event in FY12. In addition, mentorship programs, a strategic plan for recruitment and retention of women and minority faculty members, and two leadership programs have been launched in the past year.

74 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Work with Micro-RNA’s Leads to Important Findings // Nan Shen, MD, has revealed many of the details of how small RNA, or micro-RNAs, control the production of particular inflammatory mediators known as cytokines. His research has important clinical implications for treating immune and autoimmune diseases such as systemic lupus erythematosus, allergy and asthma.

Cincinnati Children’s was named an

NIH FUNDED MEMBER

Center for Autoimmune Genomic Etiology Joins eMERGE Consortium // The efforts of John Harley, MD, resulted in Cincinnati Children’s being named an NIH-funded

member of the eMERGE (electronic MEdical Records eMERGE Network and GEnomics) Network. The project is a consortium of biorepositories linked to electronic medical records data for conducting genomic studies. We are helping lead the national initiative to use genetic data with electronic medical records to deepen our understanding of childhood diseases and to usher in an era of personalized medicine.

OF THE

S E C T I O N O F N E O N AT O L O G Y, P E R I N ATA L A N D P U L M O N A R Y B I O L O G Y / P E R I N ATA L I N S T I T U T E The Center for Prevention of Preterm Birth // This endeavor is unique among children’s hospitals in developing a platform to circumvent the leading causing of infant mortality, preterm birth. To accomplish this goal, Cincinnati Children’s has committed substantial institutional resources to maintaining the current areas of accomplishment in lung development and complications of prematurity. In addition, this year we recruited Louis Muglia, MD, to head the Center and to continue our breakthrough work.

Number One Neonatology Program // Our work in helping prevent prematurity and improving outcomes for infants born prematurely has made us a leader in the field. Our efforts were recognized this year by U.S. News and World Report, who named us the number one neonatology program in the nation in their 2012 issue of “Best Children’s Hospitals.”

First MRI in a Neonatal Intensive Care Unit // We established the first MRI scanner in a newborn intensive care unit in the world. Previously, infants most in need of this imaging modality were prevented from study because of the risks of transporting them out of the NICU. The novel, safe implementation of this imaging system within the Cincinnati Children’s NICU will be transformative in newborn care.

Expanding Newborn Care Services // In October 2012, the Perinatal Institute will offer clinical services for newborns in the Kettering Health Network hospitals in Dayton, Ohio. This will add 5,000 deliveries per year to our service area and enhance opportunities for patientfocused research and quality improvement.

Leading Pulmonary Research // Jeff Whitsett, MD, and colleagues received a National Institute of Health award to study “Airway Progenitor Cell Proliferation and Differentiation During Lung Repair” as part of a consortium for the study of lung repair and regeneration.

This effort focuses on transcriptional mechanisms controlling proliferation and differentiation of airway epithelial cell progenitors. The investigative team plans to generate new antibodies, gene expression data and transgenic models with broad application to the field of pulmonary biology and medicine.

Jeff Whitsett, MD, and colleagues received a National Institute of Health award to study “Airway Progenitor Cell Proliferation and Differentiation During Lung Repair” as part of a consortium for the study of lung repair and regeneration.

2012 ANNU A L R E P O RT // 75

RESEARCH OVERVIEW

division accomplishments

SPORTS MEDICINE Research Team Wins Nicolas Andry Award // The research team of Tim Hewett, PhD, Greg Myer, PhD, Mark Paterno, PhD, Carmen Quatman, PhD, and Kevin Ford, PhD, received the 2012 Nicolas Andry career achievement award by the Association of Bone and Joint Surgeons (ABJS). The award recognized the group’s work on the paper titled, “A Systematic Approach to Prevent Anterior Cruciate Ligament Injury.” The ABJS recognizes individuals through this award who have conducted and published work pertaining to the musculoskeletal system that has significantly contributed to orthopaedic knowledge and practice.

The Division of Urology was ranked fourth in the nation in pediatric urology by U.S. News and World Report.

UROLOGY Clinical Accomplishments // Our Division was ranked fourth in the nation in pediatric urology by U.S. News and World Report. We saw an exponential increase in referrals to our Urogenital Center evaluating and managing complex genitourinary conditions.

The Center for Disorders of Sex Development (DSD) was established for patients with congenital chromosomal, gonadal or anatomical variations of sex development.

Shumyle Alam, MD, and Eugene Minevich, MD, traveled to Ecuador and Pramod Reddy, MD, Paul Noh, MD, and Minevich traveled to Israel to perform complex urological surgeries.

Other Accomplishments // We developed care processes and outcomes for three urologic conditions: posterior urethral valves, anorectal malformation and neurogenic bladder.

Research and Fellowship Program // Division Director Reddy’s basic science laboratory focuses on the relationship between CNS and lower urinary tract, and stress-induced changes in bladder function and morphology. Reddy leads the darifenacin clinical trial of treating neurogenic detrusor overactivity.

William Robert DeFoor, Jr., MD, is principal investigator on an NIH trial, “Randomized intervention for children with vesicoureteral reflux (RIVUR).”

Noh investigates oxybutynin chloride topical gel for detrusor overactivity associated with neurological conditions in children. DeFoor and Minevich are comparing low-friction hydrophilic catheters versus standard urethral catheters in children with neuropathic bladder on clean intermittent catheterization. Elizabeth Jackson, MD, began a study, “Nocturnal Enuresis: Comparison of Buzzer and Voice Alarms on the Rate of Resolution of Bedwetting.”

Joo-Seop Park’s, PhD research focuses on pluripotency and differentiation of nephron progenitor cells during organogenesis of the kidney and bladder. His lab studies transcriptional and epigenetic controls of cis-regulatory modules that act downstream of signaling pathways.

Nicholas Cost, MD, from Emory University School of Medicine, began his ACGME fellowship training in July 2011. Our fellowship program is recognized internationally and we had two international fellows: Eddie Riachy, MD, from Lebanon and Anis Ansari, MD, from India.

76 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

Other Recognition // Michael Shaffer, DO, was named one of the top sports medicine doctors in the Tri-state area in the December 2011 issue of Cincy Magazine.

Shaffer’s special interests are in injury prevention, altered foot mechanics and manipulative treatment of spine and pelvis-related dysfunction. He specializes in evaluating and treating female athletes and serves as our Fellowship Director.

NFL Charities Award // For the fifth time in six years, the Division of Sports Medicine received a grant from the National Football League (NFL) charities organization.

The project, titled “Neuromuscular Predictors of Outcome following Anterior Cruciate Ligament Reconstruction: a Prospective and Longitudinal Study of the Effect of Meniscus Injury,” will be led by Paterno. Other division staff participating with the project include Hewett and Laura Schmitt, PhD, co-investigators; Myer and Ford, associate investigators; and Staci Thomas, coordinator.

Anterior cruciate ligament injuries combined with meniscal pathology are among the most disabling injuries sustained by athletes. The goal of the project is to understand the mechanisms underlying outcomes following anterior cruciate ligament reconstruction (ACLR) in a young, athletic population with meniscus injury.

by the numbers AWA R D S , F U N D I N G + S TAT I S T I C S

2012 2012 ANNU A L R E P O RT // 77

2012

AWARDS + FUNDING

180,000,000 160,000,000 140,000,000 120,000,000 100,000,000 80,000,000

$153,736,426

Approximately $13.7 million of ARRA awards received in FY11 were awarded for a three-year period. One third is reflected in each of FY11 and FY12; the remainder will show in FY13.

$173,105,905

Total Costs (Prime and Sub-awards)

$153,186,208

Approximately $6.8 million of ARRA awards received in FY10 were awarded for a two-year period.

Half is reflected in FY10, and half is reflected in FY11.

ARRA AWARDS

$137,214,868

OVERALL SPONSORED PROGRAM AWARDS

REGULAR AWARDS

2009

2010

2011

60,000,000 40,000,000 20,000,000 0

2000

2001

2002

2003

2004

2005 2006

2007

2008

2012

FISCAL YEAR

N AT I O N A L INSTITUTES O F H E A LT H AWARDS

REGULAR AWARDS

ARRA AWARDS

Total Costs (Prime and Sub-awards) 160,000,000 140,000,000

$106,605,269

120,000,000

DISTRIBUTION OF FUNDING

60,000,000

$112,975,374

80,000,000

$117,331,809

Approximately $1.8 million of NIH ARRA awards received in FY11 were awarded for a three-year period. One third is reflected in each of FY11 and FY12; the remainder will show in FY13.

100,000,000 $99,981,467

Approximately $6.8 million of ARRA awards received in FY10 were awarded for a two-year period.

Half is reflected in FY10, and half is reflected in FY11.

2009

2010

2011

40,000,000 20,000,000 0

2000

2001

2002

2003

2004

2005 2006

2007

2008

2012

FISCAL YEAR

STATE 1%

OTHER 8%

STATE 1%

OTHER 6% INDUSTRY 7%

INDUSTRY 10%

FY 2012 FEDERAL 81%

78 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

FY 2011 FEDERAL 86%

CINCINNATI CHILDREN’S RECEIVED

81

Federal Funding in FY2012

Foundation and other awards in 2012 nearly doubled.

SOURCES OF FEDERAL FUNDING FY2012 National Institutes of Health (NIH)

106,605,269

Agency for Healthcare Research and Quality (AHRQ)

5,230,896

Department of Health and Human Services (DHHS)

4,199,378

Health Resources & Services Administration (HRSA)

3,047,672

Centers for Disease Control (CDC)

2,189,339

Department of Defense Army (DOD)

2,001,528

Department of Education (DOED)

1,048,942

Food & Drug Administration (FDA)

647,022

US Department of Agriculture

587,900

USAF/AFMC

500,009

National Science Foundation (NSF)

388,465

Department of Veteran Affairs

101,214

Department of Labor (DOL)

78,489

Department of Justice

48,131

United States Department of Health & Human Services

14,500

US Army Medical Research & Material Command

11,653

Total

F O U N D AT I O N A N D OTHER AGENCY AWARDS FY2012 Bill & Melinda Gates Foundation

2,931,682

March of Dimes

1,236,837

Cystic Fibrosis Foundation

1,124,687

Ohio Department of Health

1,003,105

American Heart Association

817,591

Substance Abuse & Mental Svc Admin

760,534

Ohio Department of Jobs & Family Services

634,915

Ohio State University

495,580

Admin on Development Disabilities

476,391

Burroughs Welcome Foundation

468,657

Miscellaneous Other (108) Total

8,232,140 $18,182,119

$126,700,407

2012 ANNU A L R E P O RT // 79

2012

F A C U LT Y + C L I N I C A L S T A T I S T I C S

D E PA R T M E N T O F P E D I AT R I C S AND RESEARCH F O U N D AT I O N FA C U LT Y

T O T A L F A C U LT Y M E M B E R S appointments in Pediatrics

570

Part-time/primary

TOTAL:

appointments in

631

Pediatrics

P E D I AT R I C FA C U LT Y B Y RANK AND TRACK

68 26

61

Full-time/primary

Clinical

Instructor

Adjunct

Research

Field Service

NEW FACULTY MEMBERS WERE APPOINTED

During FY2012 FACULTY DEPARTED (including retirements)

Tenure track

Tenured

9

5

16

5

0

0

142

24

67

7

39

0

Assoc. Professor

75

16

23

8

9

22

Professor

45

16

5

3

0

95

Asst. Professor

35

INSTRUCTORS

GENDER DISTRIBUTION

279

153

ASSISTANT PROFESSORS

361

ASSOCIATE PROFESSORS

TOTAL RATIO

270

Full-time: 239

FEMALE

FEMALE 43%

Black

Hispanic

Asian

Total

Full-Time Males

4

6

64

74

Full-Time Females

9

3

36

48

Part-Time Males

0

0

5

5

Part-Time Females

0

0

3

3

80 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

MALE 57%

31

Part-time faculty

164

PROFESSORS

Full-time: 331 30

MALE

MINORITY DISTRIBUTION

During FY2012

TOTAL RATIO

FEMALE 39%

MALE 61%

RESIDENTS Pediatrics

117

Medicine/Pediatrics Pediatric Physical Medicine and Rehabilitation

STUDENTS

Dental

Junior Medical Students in the Pediatric Clerkship Senior Medical Students entered Pediatric Training

165

11

177

Psychology

6

A

I

N

I

N

G

7

Anesthesia

14

Surgery * 째

136

Radiology *

33

394 Total in 2012

* Rotating

째 Includes General Surgery, Pediatric Adolescent Gynecology, Cardiothoracic, Neurosurgery, Otolaryngology, Ophthalmology, Plastic, Orthopaedic & Urology

21 PSYCHI AT RY / CHI L D PSYCHI AT RY / PEDIAT R I C S

P E D I AT R I C H O U S E S TA F F RECRUITMENT Candidates by area interviewed in 2012.

7

PM&R

20

Dermatology *

P E DIATRIC

60

5

Neuro/Pediatrics

278

MEDICINE/ P E D I AT R I C

13

Human Genetics/Pediatrics

Total in 2012

R

5 10

Psychiatry/Child Psychiatry/Pediatrics

Senior Medical Students entered Medicine/Pediatric Training 1

T

28

28

NEURO/ PEDIATRIC

7 HG PEDIAT R I C S

2012 ANNU A L R E P O RT // 81

2012

F A C U LT Y + C L I N I C A L S T A T I S T I C S

353 TOTAL FELLOWS IN FY2012

Total number of fellows increased by 10 since 2011.

FELLOWS Adolescent Medicine

3

1

• Transition Medicine

Allergy/Immunology

11

Cardiology

10

• Cardiac Electrophysiology

1

• Cardiac Imaging

1

• Fetal Cardiology

1

• Interventional Cardiac Cath

1

Critical Care Developmental Disabilities Emergency Medicine Endocrinology

1 14 6 12 9

Gastroenterology • Pediatric Transplant Hepatology

11 1

General Pediatrics • Pediatric Primary Care Research

3 2

Hematology/Oncology

• Neuro-Oncology

Hospital Medicine

4

Psychology

15

Medical Genetics

1

Pulmonary

8

• Clinical Biochemical Genetics

1

• Clinical Cytogenetics

1

• Clinical Molecular Genetics

2

5

Anesthesia

Child Abuse

Infectious Disease

Neonatology

12

Nephrology

6

Neurology

Quality Scholars in Transforming Health Care 2 Radiology

8

• Body MRI

0

• Pediatric Neuroradiology

1

Rehabilitation Medicine

2

Rheumatology

5

• Clinical Neurophysiology

1

• Clinical Neurosciences

1

Sleep Disorder Medicine

1

• Pediatric Epilepsy

1

• Headache

1

Sports Medicine

2

Surgery

2

Ped Adolescent Gynecology

2

Neurosurgery

1

Ophthalmology

1

• Colorectal Surgery

2

Orthopaedics

2

• ECMO

1

• Fetal Surgery

1

• Pediatric International Surgical Fellow 1

• Hand & Upper Extremity Surgery

0

• Surgery of the Spine

1

• Trauma Surgery

1

Otolaryngology

6

• Vascular Anomalies

1

Pathology

2

Urology

1

Plastic Surgery

0

Total, Clinical Fellows

217

2

Psychiatry

5

Total, Research Postdoctoral Fellows

136

14

82 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

3

PROCTER SCHOLARS THIRD YEAR Eric Mullins, MD Cancer & Blood Diseases PROJECT: Mechanisms Linking Hemostatic Factors to Neuroinflammatory Disease

Ajay Perumbeti, MD, FAAP Hematology/Oncology PROJECT: Genetic Approaches to Correct Human Sickle Cell Anemia

Sundeep Keswani, MD Pediatric General & Thoracic Surgery PROJECT: Molecular Mechanisms of Regenerative Wound Repair

Stephanie Merhar, MD Neonatology PROJECT: Safety, Tolerability and Efficacy of Levetiracetam as Initial Monotherapy for the Treatment of Neonatal Seizures

Elizabeth Schlaudecker, MD Infectious Diseases PROJECT: Influenza Infection and Immunization in Pregnancy

SECOND YEAR Tanya Kowalczyk Mullins, MD Adolescent Medicine PROJECT: Adolescent Sexual Behavior and Incident Sexually Transmitted Infections Kasiani Myers, MD BMT & Immune Deficiency PROJECT: Leukemogenesis and Genomic Instability in Fanconi Anemia

FIRST YEAR Jonathan Howell, MD, PhD Endocrinology Investigating the Regulatory Pathways that Control Endocrine Cell Function within the Pancreas and Intestine Benjamin Mizukawa, MD Oncology Targeting Cdc42 in Leukemia Stem Cells

2012 ANNU A L R E P O RT // 83

2012

F A C U LT Y + C L I N I C A L S T A T I S T I C S

2012 OUTPATIENT VISITS BREAKDOWN

CLINICAL ACTIVITY

Type

Number

Surgical procedures

OUTPATIENT VISITS

962,911

2012 ADMISSIONS BREAKDOWN

Emergency Room Visits

27,094 124,274

Primary Care (PPC) Burnet, Hopple & Batesville

65,347

Total Outpatient Visits

Sub-specialty Care Burnet

456,883

DURING FY2012

Outpatient Liberty

128,670

Outpatient Mason

74,847

Outpatient Anderson

42,793

Outpatient Eastgate

23,706

Outpatient Harrison

15,008

Outpatient Fairfield

57,998

Outpatient Kentucky

49,704

Outpatient Kenwood

1,535

ADMISSIONS

30,579

Total Admissions DURING FY2012

Outpatient Drake

RESEARCH + P U B L I C AT I O N S

Medical

Surgical (I/P surgeries)

23-hour admissions

10,713

13,501

6,365

17,834

P U B L I C AT I O N S

SUMMER RESEARCH PROGRAMS

1,425

22

21

TOTAL:

161

80

425

PEER

NON PEER

ONLINE SITE

CHAPTERS

REVIEWED

REVIEWED

CONTRIBUTIONS

OF BOOKS

ARTICLES

ARTICLES

118

High School Interns Undergraduate Students

8

Total Publication Contributions in FY2012

Medical Students

84 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION

1,938

2012

A N N U A L R E P O R T

/////////////// RESEARCH BREAKTHROUGHS

PRODUCED BY Department of Marketing and Communications Cincinnati Children’s Hospital Medical Center MLC 9012 3333 Burnet Avenue Cincinnati, OH 45229-3026 Cincinnati Children’s is a teaching affiliate of the University of Cincinnati College of Medicine © 2012 Cincinnati Children’s Hospital Medical Center

Editorial Tim Bonfield Beatrice Katz Tanya Bricking Leach Nick Miller Mary Silva, Managing Editor Design Christina Ullman, Ullman Design Photography Michael Wilson Tine Hofmann

For a more detailed look at our research, publications and faculty, go to www.cincinnatichildrens.org/research12

Cincinnati Children’s Hospital Medical Center MLC 9012 3333 Burnet Avenue Cincinnati, Ohio 45229-3026

2012

A N N U A L R E P O R T

/////////////// RESEARCH BREAKTHROUGHS

2 // C I N C I N N AT I C H I L D REN’S RESEARCH FOUNDATION