Cincinnati Children's Research Annual Report-FY13
Rigorous, regular review our scientific priorities has helped make us a world leader in pediatric research. Our annual report highlights the achievements of more than 50 research divisions during FY13.
cincinnati childrenâ€™s research foundation annual report 2013 Research Breakthroughs ADVISORS Administrative Staff Arnold Strauss, MD Director Tracy Glauser, MD Associate Director Jeffrey Whitsett, MD Interim Associate Director Mitchell Cohen, MD Vice Chair, Clinical Affairs Sandra Degen, PhD Associate Chair, Academic Affairs Thomas DeWitt, MD Associate Chair, Education Michael Farrell, MD Associate Chair, Clinical Services James Heubi, MD Associate Chair, Clinical Investigation Jeffrey Robbins, PhD Associate Chair, Research Kenneth Campbell, PhD Director, Basic Surgical Research Michael Helmrath, MD Director, Translational Surgical Research John Maybury Vice President, Administration & Finance Jana Bazzoli Vice President, Clinical Affairs Kristine Justus, PhD Vice President, Research Operations & Management Nicole Robinson, PhD Assistant Vice President, Center for Technology Commercialization Jeremy Corsmo Senior Director, Office of Research Compliance and Regulatory Affairs 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 Community Advisors Steven Goldstein James Schwab Craig Young Thomas Boat, MD Christopher Wylie, PhD Harry (Hal) Dietz, MD CINCINNATICHILDRENS.ORG/RESEARCH 1 CONTENTS Division Accomplishments Adolescent and Transition Medicine Allergy & Immunology James A. Anderson Center for Health Systems Excellence Anesthesiology Asthma Research Behavioral Medicine & Clinical Psychology Biomedical Informatics Biostatistics and Epidemiology Cancer and Blood Diseases Institute Center for Career Development in Academic Pediatrics Center for Clinical and Translational Science and Training Clinical Pharmacology Critical Care Medicine Center for Technology Commercialization Dentistry Dermatology Developmental and Behavioral Pediatrics Developmental Biology Drug and Poison Information Center Emergency Medicine Endocrinology Every Child Succeeds Gastroenterology, Hepatology, and Nutrition General and Community Pediatrics 12 12 13 13 14 14 15 15 16 22 22 General and Thoracic Surgery Global Child Health Hospital Medicine Human Genetics Immunobiology Heart Institute Infectious Disease Mayerson Center for Safe and Healthy Children Nephrology and Hypertension Neurology Neurosurgery Ophthalmology Orthopaedics Otolaryngology Pathology and Laboratory Medicine Patient Services Pediatric and Adolescent Gynecology Physical Medicine and Rehabilitation Perinatal Institute Plastic Surgery Psychiatry Pulmonary Medicine Radiology Reproductive Sciences Rheumatology Sports Medicine Urology 33 38 38 39 39 40 42 42 43 43 48 48 49 49 50 50 51 51 52 58 58 59 59 60 60 61 61 ANNUAL REPORT 2013 4 6 8 From the Director Our growing research enterprise is transforming pediatric care. From the Board Our commitment to open inquiry and quality improvement continues. A Wise Legacy Regular scientific advisory reviews help investigators stay focused. 18 Small but Mighty Our Division of Infectious Diseases has grown into the top-funded research group at Cincinnati Children’s. 26 Changing Behaviors Members of Behavioral Medicine and Clinical Psychology delve into the interactions between child health, behavior, biology, family and community. 23 23 24 24 25 25 30 30 31 31 32 32 33 36 Prepared for Emergencies One of the nation’s top programs takes an unvarnished look at the challenges ahead for Emergency Medicine. 44 Finding the Right Dose Advances in mass spectrometry are helping clinicians match medication levels to a growing child’s unique metabolism. 54 Bright Ideas, Brilliant Products Our Center for Technology Commercialization helps translate discoveries into new medicines, devices and other tools to improve child health. 62 By the Numbers External funding, sources and faculty statistics. 2 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 3 From the Director C incinnati Children’s Hospital Medical markers and diagnosing rare disorders. The SAC review Center embraces the concept that dis- of our growing Center for Technology Commercializacovery through innovative research is es- tion (CTC) was prompted by our understanding that sential to develop medical and treatment the application of innovative discoveries into real-world breakthroughs that improve child health. Since the therapies and tools to improve clinical care can be faciliestablishment of our Cincinnati Children’s Research tated by forming start-up companies or licensing techFoundation (CCRF) by William Cooper Procter’s nologies to biotechnology and pharmaceutical industry 1931 gift, this philosophy has been incredibly success- partners. As our featured accomplishments, divisional brief ful and continues today. Mr. Procter required that CCRF review the qual- highlights, and “by the numbers” fact section illustrate, ity of our research and that is accomplished in part by these innovative research efforts are productive, with our comprehensive annual Scientific Advisory Commit- more than 1,900 peer-reviewed articles, chapters and other publications. Within tee (SAC) review process. The CCRF, more than 3,000 facSAC process and outcomes ulty, students, clinical and are the theme of this 2013 AnInnovative discovery post-doctoral fellows, and nual Report. In this report, you will drives change that improves dedicated staff ask and answer funded by more learn how our research stratechild health worldwide. questions, than $171 million in extergic plan, encouraged by SACCincinnati Children’s is nal sponsored research grants derived recommendations, and contracts and about $85 has shaped and supported our an international leader million in internal funding. research divisions. We focus dedicated to this Our successes allow continon several of our rapidly delofty goal. ued recruitment of clinical veloping research divisions, and research faculty, more including Infectious Diseases, than 100 in fiscal year 2013, led by Peggy Hostetter, MD, who was recruited in 2010 to lead the effort in microbial and demonstrate the need for expansion of our research pathogenesis, molecular virology, and vaccine develop- space through construction of our new Clinical Sciences ment. We highlight the well-established collaborative Building, slated to open in 2015. Innovative discovery, whether in the bench laboapproach within our Division of Behavioral Medicine and Clinical Psychology, led by Lori Stark, PhD, that ratory or in patient-oriented clinical and outcomes addresses critical issues related to patient adherence to studies, drives change that improves child health worldmedical treatments, chronic pain, and behavioral re- wide. Cincinnati Children’s is an international leader sponse to chronic and complex diseases. In Emergency dedicated to this lofty goal. We thank our Medical CenMedicine, long-time Director Richard Ruddy, MD, ter and Board leadership and all of the CCRF team for attests that SAC reviews have affirmed and altered the dedication and commitment to these critical discoveries. Division’s patient-oriented research and focus and have stressed the need for education and training. During the Pathology SAC review with Director Dave Witte, MD, the need to develop more specific, individualized therapies and to assess pharmacogenomics for this purpose Arnold W. Strauss was apparent. The review supported using rapidly evolving and highly sensitive mass spectrometry approaches toward these applications as well as for measuring bio- Arnold W. Strauss, MD Director of the Cincinnati Children’s Research Foundation, Rachford Professor and Chair of the Department of Pediatrics, University of Cincinnati College of Medicine CINCINNATICHILDRENS.ORG/RESEARCH 4 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 5 From the Board L From left: Nancy Eddy, PhD, Research Chair; Thomas Cody, Chairman, Board of Trustees; Michael Fisher, President and CEO of Cincinnati Children’s 6 CINCINNATI CHILDREN’S RESEARCH FOUNDATION eaders of great institutions know that success respected and accepted methods we use to assure that comes not from dwelling on past or even cur- our research is of the highest caliber. What has become rent achievements, but from anticipating the known as the Scientific Advisory Committee (SAC) review measures our research efforts against our own challenges ahead. So it was with Col. William Cooper Procter when strategic goals as well as the ever-rising standards of he donated $2.5 million in the early 1930s – a great excellence in the medical marketplace. No other pediatric academic research censum of money for the time ter has a self-review process – to launch the Cincinnati quite like this. Children’s Research FoundaWe offer our heartfelt tion. He was thinking not No other pediatric thanks to the Division Direconly of how research could academic research center tors at Cincinnati Children’s, serve the children of that has a self-review process and their teams, for the work time, but how it could conthey do to prepare for SAC tinue to meet the needs of quite like this. reviews. We also offer our generations to come. deepest gratitude to all the In this year’s annual rereviewers, especially those port, you will read about the groundbreaking work taking place in more than 50 re- from outside our organization, who share their time search divisions here at Cincinnati Children’s. You will and expertise in this process. This long-established commitment to open inlearn about discoveries that dig deeper than DNA to tease out secrets of human development and disease; quiry, collaborative discovery and ongoing quality imabout technologies that can detect the precise levels provement has been a major factor behind the growth of medication coursing through a child with cancer; of each of our divisions, and of this great institution. about child-sized artificial hearts, lab-grown organelles We think Col. Procter would be quite proud of the return on his investment. and tiny devices that change how bones grow. Most of these advances were unimaginable in Procter’s time. Many more amazing discoveries will In 2014, in honor of Col. Procter’s lasting influence, emerge in the years to come. But one concept has not Cincinnati Children’s plans to rename its research tower changed in the past 82 years. Col. Procter wisely want- known as “Location S” as the William Cooper Procter ed to ensure that his generous gift was being put to its Research Pavilion. intended use. And so do we. The scientific review process that began with Procter’s gift has become one of the most important, CINCINNATICHILDRENS.ORG/RESEARCH 7 sac review 2013 $788M 1935 $3M By 1935, the Cincinnati Children’s Research Foundation had a $3 million endowment. In 2013, its market value exceeded $788 million. The Wise Legacy of Scientific Review Rigorous and regular evaluation of our science has made us one of the world’s leaders in pediatric research “Our first SAC review in 1938 recommended that we get an immunologist and infectious disease specialist interested in vaccines. The result was the recruitment of Albert Sabin in 1939.” hen William Cooper Procter made a $2.5 million gift to Cincinnati Children’s in 1931, he attached some strings. Procter was a businessman, Chairman of the hospital’s Board of Trustees and grandson of William Procter, the co-founder of Procter & Gamble Co. His gift provided startup funding for the Cincinnati Children’s Research Foundation (CCRF) - $500,000 to construct the hospital’s first research building, and $2 million for its endowment. He had the foresight to understand the important role that research would play in the hospital’s growth. He also had the wisdom to ensure that the research was of the highest caliber. Procter specified that the Research Foundation undergo regular “critical review” of the funds every 20 years. If the research being conducted was found lacking, the funds would revert to the Southwestern Ohio Diocese of the Episcopal Church. Cincinnati Children’s traces its beginnings to the Church, which in 1884 converted a small house into a hospital for children. REVIEW GROWS AS WE DO Regular “critical review” has remained an important aspect of the Research Foundation’s operations, evolving as it grew to what is known today as Scientific Advisory Committee (SAC) review. With the expansive growth of the Research Foundation – there are now more than 50 research divisions – SAC reviews are more structured and more frequent, with most divisions undergoing review every five years. Tracy Glauser, MD, is one of three leaders within the Research Foundation who oversee the administrative aspects of the review each year. He notes that regular review helps strike a balance between scientific freedom and common purpose. W 8 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 9 WHAT SETS US APART Although SAC-style reviews might not be unique to medical research facilities, Glauser believes Cincinnati Children’s does take a different approach. “The review is not about rewards or punishment,” he says. “It’s designed to be an honest discussion of how to get from where we are to where we want to be in as short a time as possible.” Following their assessment, the reviewers meet with each division director, then with the research committee of the Board and medical center leaders to share their findings. Division directors respond to the reviewers’ findings within a month and report on their progress one year later. Although the review is not intended to be financially focused, it is held prior to constructing the next year’s budget so that any funding recommendations can be incorporated. THE GIFT OF WISDOM “The review is not about rewards or punishment,” says Dr.Tracy Glauser (left). “It’s designed to be an honest discussion of how to get from where we are to where we want to be in as short a time as possible.” Then vs. Now Since launching the Research Foundation, Cincinnati Children’s has expanded several times to make room for innovation. In 2007, the opening of our “Location S,” to be called the William Cooper Procter Research Pavilion, nearly doubled our research space to about 1 million square feet. By summer 2015, our new Clinical Sciences Building will add another 425,000 square feet, making Cincinnati Children’s the nation’s largest pediatric research center. “We encourage divisions to be innovative, collaborative and entrepreneurial,” says Glauser. “The SAC review process is an opportunity to make sure that each division has a strategy to accomplish their mission, that they are executing according to that strategy, and that their strategy and mission is consistent with the overall institutional mission.” THE IMPORTANCE OF AN OUTSIDE VIEW Each year, five divisions are invited to be reviewed. Each division has two reviewers from outside the medical center – respected experts in the division’s area of research. Division directors recommend one of the outside reviewers; medical center leaders choose the other. Additionally, two medical center leaders also attend the review. The external reviewers’ tasks include looking at the division’s strategy and execution, seeing how it aligns with the institution’s missions and goals, and determining how the division’s accomplishments compare to those of their national peers. “One of the key issues is to assess if the division’s strategy is on target for that given specialty,” says Glauser. “Every specialty is different and there is not a standard strategy that works for every division.” ASKING THE RIGHT QUESTIONS Divisions prepare a list of questions they want to ask the reviewers and an agenda for what they want to accomplish during the review. The review takes only one day, but preparation takes months. Divisions prepare binders of information so that the reviewers are fully acquainted with the divisions and the issues they face, even before they arrive. Peggy Hostetter, MD, recalls preparing the binder — hers contained some 750 pages — for her Division of Infectious Diseases review. She was only 18 months into her post as Director, and the preparation was a chance to learn about her division from top to bottom. “It was an opportunity to identify our divisional weaknesses,” she says. “We had a lot of strengths. But it was also important to know, what are my weaknesses, what do I need to improve?” Richard Ruddy, MD, Director of Emergency Medicine, went through his fourth SAC review this year. He says the review is a “positive experience” precisely because it points out issues that need to be addressed. “We try to spend time not on selling what we do well, but on saying, ‘Where are the gaps that need to be thought about for the next four or five years?’” he says. The gift that William Cooper Procter made in 1931 today generates some $50 million each year for research and education. And the regular scientific review he attached to that gift proved equally valuable. That single stipulation has likely played a role in our recruitment of many of the world’s top pediatric researchers, our breakthrough findings and treatments, and our place as the third-highest recipient of NIH funds for pediatric research. It was an idea that showed merit from the start. “Our first SAC review in 1938 recommended that we get an immunologist and infectious disease specialist interested in vaccines,” Glauser says. “The result was the recruitment of Albert Sabin in 1939.” William Cooper Procter 10 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 11 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Adolescent and Transition Medicine Transgender Health Program Launched Our new Transgender Health Program, led by Lee Ann Conard, RPh, DO, MPH, was launched this year to provide evidence-based, comprehensive services to this vulnerable group of adolescents and their families. Although some of our care providers were delivering these services in an informal manner, we worked with the Office of Diversity and Inclusion and the Divisions of Endocrinology and Child Psychiatry to formalize the program. The program also incorporates recommendations from several other medical organizations and transgender health programs. Allergy and Immunology Study Identifies Regulators of Eosinophilic Inflammation in Inflammatory Bowel Disease Simon Hogan, PhD, Research Director, identified an unexpected role for the innate inflammatory cell macrophage and NFκB signaling pathway in the regulation of eosinophilic inflammation in inflammatory bowel disease (IBD). NFκB signaling in inflammatory macrophages was required for secretion of the eosinophil-selective chemokine CCL11, eosinophilic inflammation and the histopathology of experimental colitis (DSS-induced murine model). The study, published in the Journal of Immunology, indicates that targeting myeloid cells and NFκB-dependent pathways may be of therapeutic benefit in treating IBD. James A. Anderson Center for Health Systems Excellence Health Services Research Supports Learning Health Systems The Health Services Research (HSR) Matrix encourages researchers, patients and clinicians to create practices and policies that improve care and outcomes for children, families, and communities. An integral part of the HSR Matrix is supporting “learning health systems,” which help patients and providers choose evidence-based care. One example is The Ohio Perinatal Quality Collaborative (OPQC), whose goal is to reduce preterm births and improve outcomes for babies in Ohio. Since 2008, the project has prevented an estimated 950 NICU admissions by lowering the number of scheduled deliveries, with a cost savings of approximately $19 million. Anesthesiology More Than 120 Papers and Presentations, 13 New Grants Our Department continued to be recognized nationally as a leader in pediatric anesthesia research. Faculty members delivered 70 lectures; authored 70 research papers, review articles and book chapters; presented 57 research abstracts; and were awarded 13 extramural research grants. Steve Danzer, PhD, Mike Jankowski, PhD, Andreas Loepke, MD, PhD, Mohamed Mahmoud, MD, Dave Richards, PhD, Senthil Sadhasivam, MD, and Anna Varughese, MD, MPH, led the research efforts. The Society for Pediatric Anesthesia awarded Raj Subramanyam, MD, and Vanessa Olbrecht, MD, first prizes for resident and faculty research for their studies on mortality after tonsillectomy and morphine pharmacogenetics. Our Transition Medicine program was developed to support the growing number of adult patients we care for. Our medical center had more than 38,000 patient encounters in FY 2010 with people ages 19 and older. Transition Medicine Program Supports Young Adult Patients Method Developed to Directly Evaluate Eosinophil Tracking In Vivo Cincinnati Children’s has a long history of continuing to work with young adults who have grown up with complex pediatric disorders. In fact, our medical center had more than 38,000 patient encounters in FY 2010 with people ages 19 and older. Our new Transition Medicine program was formed this year to further organize our expertise in this growing field. In collaboration with other divisions, we develop and monitor care plans for older patients. These plans integrate accessible and developmentally appropriate healthcare with health risk screening and promotion of self-management. Our program includes inpatient and outpatient services incorporating the biopsychosocial model for care. Our program includes care managers, social services, a research team and three faculty members: Abigail Nye, MD; Jennifer Shoreman, MD; and Darcey Thornton, MD. Most in vivo studies of granulocytes estimate their trafficking indirectly via steady-state tissue or blood levels rather than directly examining cellular trafficking. Ting Wen, PhD, and Marc Rothenberg, MD, PhD, Division Director, have developed a direct examination method that involves transferring genetically labeled, bone marrow-derived eosinophils into an elicited inflammatory site, the allergic lung. This unique cell transfer system is detailed in the Proceedings of the National Academy of Sciences. Faculty Reaches Goals Early Expanding ‘Decision Aids’ in Pediatrics Our faculty set records this year for general and regional anesthetics provided and for consultations in pain management and palliative care. These efforts helped us reach our strategic plan goal for faculty productivity one year early. Our faculty members recruited 12 outstanding fellows into the core pediatric anesthesiology fellowship program. We also recruited fellows into advanced programs for palliative care, pain medicine, quality and safety, neurophysiological monitoring, education, and cardiac anesthesia. Faculty Recognized For Research Endeavors The American College of Allergy, Asthma & Immunology (ACAAI) selected Amal Assa’ad, MD, Clinical Director, to receive its 2013 Woman in Allergy Award in recognition of her work in food allergy and science. Patricia Fulkerson, MD, PhD, was awarded the 2013 ARTrust Faculty Development Award by the American Academy of Allergy, Asthma and Immunology (AAAAI) for her eosinophil progenitor research. Joseph Sherrill, PhD, received the Thrasher Research Fund Early Career Award in recognition of his promise as an investigator. Evidence-based “decision aids” have been used with increasing success in adult medicine, but so far, their use has been limited in pediatrics. William Brinkman, MD, MEd, MSc, is leading efforts to prototype and test decision aids for shared decision-making (SDM) in pediatrics. Brinkman and colleagues have recently reported that parents of children with ADHD who received an SDM intervention were better informed and more involved in decision making. Other studies about decision aids for human papillomavirus vaccination and use of medications for juvenile idiopathic arthritis are showing great success. Continuing our role as a leader in pediatric anesthesia research, our faculty set records this year for providing anesthesia and consultations in pain management and palliative care. We reached our strategic goal for faculty productivity one year ahead of schedule. Faculty Members Play National Leadership Roles John McAuliffe, MD, was elected president of the Society of Neurophysiological Monitoring. Dean Kurth, MD, serves on the Boards for the Society for Pediatric Anesthesia and the journal Pediatric Anesthesia and is President of the Pediatric Anesthesia Leadership Council. Paul Samuels, MD, and Lori Aronson, MD, lead Board Exam review courses for the Society for Pediatric Anesthesia and American Physician Company. Mentoring Program Hosts Speakers and Events The HSR Matrix mentoring program promotes the career development of young investigators in health services research. In FY 2013, HSR Matrix hosted 12 speakers and two community learning events, at which national and international leaders spoke on topics ranging from methodology to community building and innovative care strategies. 12 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 13 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Asthma Research Examining the Factors that Influence Hospitalization for Asthma The new Ohio Pediatric Asthma Repository (OPAR), led by Gurjit Khurana Hershey, MD, PhD, and the Division of Asthma Research, began enrollment in December 2012. So far, 905 participants are enrolled in the study involving Cincinnati Children’s and five other pediatric hospitals in Ohio. The project will analyze outcome data to look for differences among patients, treatments and site pathways to see what factors influence re-hospitalization and length of stay. Behavioral Medicine and Clinical Psychology FIT Teens Program Aims to Reduce Juvenile Fibromyalgia Pain Through Exercise Susmita Kashikar-Zuck, PhD, recently completed the first multi-site clinical trial for juvenile fibromyalgia (JFM), which demonstrated that cognitive-behavioral therapy (CBT) produces strong improvements in daily functioning and coping. Now, through an NIH-funded pilot study, she is studying how to use exercise to further control JFM-related pain. The Fibromyalgia Integrative Training Program for Teens (FIT Teens), developed by Kashikar-Zuck and colleagues in Sports Medicine, Rheumatology and Pain Management, provides specialized neuromuscular training to improve gait, posture, balance and core strength. Biomedical Informatics Enhanced Registry for ImproveCareNow Our division has completed an enhanced registry for ImproveCareNow, a 54-center network of gastroenterologists, researchers, patients and families focused on improving outcomes in inflammatory bowel disease (IBD). Supported by a three-year, $12 million grant from the Agency for Healthcare Research and Quality (AHRQ), the enhanced registry has allowed ImproveCareNow to automate pre-visit planning, develop mobile applications for patients, conduct novel research and more. Now in its third year, the registry has grown to more than 10,000 participants. Next year, the registry will be extended to include adult patients. Biostatistics and Epidemiology Growth in Scientific Productivity Our faculty and staff contributed to 135 scientific articles, 20 percent more than in 2012. We participated in 100 active research projects, with annual direct costs totaling $38 million. Notable projects included “Extension of Censored Quantile and Empirical Likelihood,” Mi-Ok Kim, PhD; the biostatistical core of “Hemorrhagic and Ischemic Stroke Among Blacks and Whites,” Jane Khoury, PhD; and “Impact of Cognition on Language in Pediatric Hearing Loss,” Jareen MeinzenDerr, PhD; and “Neurobehavioral and Neuroimaging Effects of Traffic Exposure in Children,” Patrick Ryan, PhD, MS. Cincinnati Children’s Joins Largest Effort Yet to Study Asthma in Urban Setting Cincinnati Children’s is one of 10 research centers to join the nation’s largest effort to study asthma in the inner city. So far, we have been involved in three clinical trials: examining preventive omalizumab or step-up therapy to decrease fall asthma exacerbations, a phenotyping study to identify difficult-to-treat asthma in the inner city, and a study examining immunotherapy against exposure to German cockroach. Gurjit Khurana Hershey is the principal investigator for the Cincinnati site. New Fellowships Developed Continued NIH funding of behavioral studies underscores a growing recognition of the impact of human behavior on healing and overall health outcomes. Key Research Training Program Receives Renewal Patient Engagement and Community Our faculty members teach in several graduate programs and mentor post-doctoral fellows in Pediatrics and Environmental Health. This year, we developed the curriculum and selected initial candidates for new fellowships in Epidemiology and Biostatistics in Pediatrics. Registry Development and Sustainability QI and Chronic Illness Care Support Faculty and Staff Growth Continues The Role Of Epithelial Cell Genes In Allergic Response Finding New Uses for Established Drugs Hershey also is the principal investigator of an NIH-funded Asthma and Allergic Diseases Cooperative Research Center (AADCRC) and serves on the AADCRC steering committee. This center focuses on characterizing epithelial genes in allergic diseases, and delineating how they contribute to allergic response. Findings could lead to novel therapies for asthma, atopic dermatitis, and food allergy. Our Center for Child Behavior and Nutrition Research and Training received its second NIH funding renewal this year, providing continued research training opportunities for clinical fellows in behavioral medicine, nutrition science and pediatrics. The Center was established in 1999 and initially funded by the NIH under the directorship of Scott Powers, PhD. The renewal represents 15 years of investment by the NIDDK. This year, Meg Zeller, PhD, was named Co-Director of the training program. We are using the emerging tools of network medicine to identify more genes and drug targets related to rare and orphan diseases. We have designed algorithms and software systems that can help biomedical researchers systematically search for new indications for existing medications. With scarce funding available for new drug development, computational drug repurposing offers a hopeful approach for children with rare diseases. We recruited five new faculty: Lin Fei, PhD, a statistician; Shelley Ehrlich, MD, PhD, an obstetrician-gynecologist and environmental epidemiologist; Katherine Bowers, PhD, a genetic epidemiologist; Ping-I (Daniel) Lin, MD, PhD, a psychiatrist and genetic epidemiologist; and Nicholas Ollberding, PhD, a nutritional epidemiologist. We also added 17 staff professionals, including Vadim Tantsyura, MS, MA, our new Director of Data Management. Demand Grows for Data Management Support and Statistical Consulting Clinical Trial Will Focus on Improving Adherence to Epilepsy Treatment Reconstructing Critical Events of Embryonic Development Avani Modi, PhD, a member of the Adherence and Self Management Center, has received NIH funding to continue her studies of non-adherence to anti-epileptic drug regimens. Her previous research, published in JAMA, indicates that 58 percent of newly diagnosed patients exhibited some level of non-adherence and that there are five distinct patterns of adherence to treatment. The new clinical trial will monitor adherence electronically and offer targeted biobehavioral interventions when and if adherence falls below 95 percent. A research team led by Jun Ma, PhD, focuses on how an embryo develops the initial, elaborate patterns that later lead to the formation of organ structures. Using the fruit fly Drosophila as a model, the team explores how cells in the embryo interpret positional cues from the mother to form initial spatial patterns. The team has developed quantitative tools that allow high-resolution reconstruction of these critical events of early embryonic development. Their study — funded by the NIH and the National Science Foundation — could provide new insights into the molecular basis of birth defects, cancer and other diseases. Our Data Management Center supported 60 studies, up from 45 in 2012. Our Biostatistical Consulting Unit supported 120 projects while our Scale Development Unit supported 19 studies. We also acquired Medidata Rave, a leading electronic data capture system, to enhance data management support for multi-site research projects. 14 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 15 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Cancer and Blood Diseases Institute The CBDI includes the Divisions of Bone Marrow Transplantation and Immune Deficiency, Experimental Hematology and Cancer Biology, Hematology and Oncology. New Approach Targeting NF1 Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors that remain incurable. A group led by Nancy Ratner, PhD, found that NF1 mutation causes sustained extracellular signal-regulated kinases (ERK) activation in these tumors. They showed that an MEK inhibitor reduces aberrantly proliferating tumor cells, shrinks neurofibromas in mice, and prolongs survival of mice implanted with human cancer cells. This study, reported in the Journal of Clinical Investigation, demonstrates that deregulated ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provides a strong rationale for future clinical trials. Passing Through the Blood-Brain Barrier Dao Pan, PhD, and colleagues discovered a non-invasive procedure to deliver large-molecule therapeutic agents across the blood-brain barrier to treat neurological disorders. Findings were published online in February 2013 in PNAS. To accomplish this, they fused a receptor-binding peptide from apolipoprotein E with a potentially therapeutic protein; these were transcytosed into the central nervous system in a mouse model of a lysosomal storage disorder with central nervous system defects. They demonstrated the therapeutic potential of this approach by correcting brain glycosaminoglycan and b-hexosaminidase in the mice. Ware Named Hematology Director Russell Ware, MD, PhD, was selected this year to direct our Division of Hematology. Ware comes to Cincinnati Children’s from the Baylor College of Medicine in Houston. He has been involved in clinical and translational hematology research projects for more than 25 years, with a primary interest in sickle cell disease. Ware runs an NIH-funded project to investigate genetic modifiers of sickle cell disease. He also is the national principal investigator for the NIH-funded SWiTCH, TWiTCH and SCATE sickle cell clinical trials. Most recently Ware has started sickle cell screening programs in Angola, Uganda and other regions of Africa. Recently published findings from our investigators have advanced the understanding of cancer stem cell therapy, bone marrow transplantation, NF1 tumors and more. Stem Cell Regeneration Mechanism In a work published in Nature Communication, Jose Cancelas Perez, MD, PhD, and colleagues reported that Krüppel-like factor 5-deficient hematopoietic stem cells and progenitors fail to engraft after transplantation. They supplied evidence that Krüppel-like factor 5 is indispensable for adhesion, homing, lodging and retention of hematopoietic stem cells and progenitors in the bone marrow through Rab5-dependent regulation of b1/b2 integrins. No. 1 Pediatric Cancer Program in the Nation The Oncology Division had a successful year, which culminated in being named the top pediatric cancer program in the country by US News & World Report. This honor reflects successful team science, process improvement and clinical care initiatives. Key advances included faculty-led clinical trials using targeted small molecules to treat relapsed leukemia, brain tumors, advanced sarcomas and liver/renal tumors. These initiatives all involved close integration of effort between Oncology, Experimental Hematology, Blood/Marrow Transplant, Pathology, Clinical Pharmacology, and Biomedical Informatics. The G-protein-mediated Rho GTPase signaling axis has been implicated in human pathophysiology and is a potential therapeutic target. Yi Zheng, PhD, and colleagues reported in PNAS about a family of small-molecule inhibitors specifically targeting Rho activators that could benefit cancer stem cell therapy. Chemicals Targeting G-protein Coupled Receptor Signaling Our cancer center was named the top pediatric cancer program in the country by US NEWS & WORLD REPORT. CINCINNATICHILDRENS.ORG/RESEARCH 16 16 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 17 infectious disease 2013 $1.4M 2012 $700,000 2010 $350,000 In The Division of Infectious Diseases has more than tripled clinical revenues since 2010. Small but Mighty A small group of scientists aims to solve the mysteries of infections that have baffled us for decades. Their work has earned the Division of Infectious Diseases its place as our top-funded research group “Every one of us who contributes to the clinical and research missions can think of that one child who made us say, ‘I’ve got to figure this out.’” the weakened body of a hospitalized child, the common yeast Candida can quickly transform from a passive presence on the skin and in the GI tract to an invasive, destructive fungus. Gaining entrance often through a central venous line, the fungus travels through the bloodstream into the most remote recesses of the body, eating away at tissue and allowing toxins and bacteria to enter the system at an alarming rate. So it was with a young patient Peggy Hostetter, MD, recalls from some 25 years ago — a little boy undergoing chemotherapy for leukemia who developed a Candida infection from his central line. “I was a young attending in infectious disease at the University of Minnesota,” Hostetter recalls. “I’d seen lots of kids with Candida infections. I knew we could treat it and cure him with amphotericin, the only drug we had for the infection back then.” Hostetter explained this to the boy’s parents. The child died within 48 hours. Shocked by this turn of events, she searched the literature to see what was known about Candida. “There was nothing there,” she says. “So I decided, ‘I’ve got to study this.’” Study it she did. And now Hostetter, who is Director of the Division of Infectious Diseases at Cincinnati Children’s, has made a potentially game-changing finding that she believes could prevent infections like that young boy’s. Hostetter’s research revealed that the heparin fed through central lines to prevent clotting binds with the Candida yeast that lives on and in all of us. Candida uses this binding to elude the body’s defenses and to form biofilms within catheters. Biofilms are the first step in bloodstream infections with the yeast. The agent that Hostetter and her team developed prevents this binding; the discovery has been patented and the medical center is seeking licensing for human trials. CINCINNATICHILDRENS.ORG/RESEARCH 18 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 19 TOP-FUNDED RESEARCH DIVISION Such breakthrough research and discovery is the daily work of Hostetter’s division, and the reason the group of only eight extramurally funded research faculty is the highest-funded research group at Cincinnati Children’s at $10.5 million. The division has a history of discoveries, from the oral polio vaccine developed by Albert Sabin, MD, to the Rotarix rotavirus vaccine developed here by David Bernstein, MD, and Richard Ward, PhD, in 2004. Hostetter was aware of the legacy she inherited when she took her post in 2010. She was confident she could continue the tradition, even as she set a new course. “I’m not going to be the inventor of a tremendous life-saving vaccine,” she says, “but there were other ways I could contribute.” TRIAL BY FIRE She had the opportunity to demonstrate those contributions early on. Just 18 months after she arrived, Hostetter’s division would undergo Scientific Advisory Committee (SAC) review. The review is an intensive look by outside experts and medical center leaders at how the division is doing, and how it measures up to other such divisions nationally. During her recruitment to Cincinnati Children’s, Hostetter had prepared a business plan – a strategic vision for staff she wanted to recruit, space she would need, and budget. She had received everything she asked for. “I knew the SAC reviewers would say, ‘You have the vision and you got the resources. Now, can you execute?’” And after just 18 months, Hostetter was able to point to some significant achievements: steadily increasing external research funding and clinical activity. Her business plan had called for hiring six new investigators and starting two new clinical programs, one in transplant infectious disease and one in antimicrobial stewardship. As of SAC review time, she had signed commitments with three new faculty – Sing Sing Way, PhD, who studies the immunology of pregnancy, Joe Qualls, PhD, who works on the macrophage, and Lara Danziger-Isakov, MD, MPH, an expert in transplant infectious disease. CLINICAL INVOLVEMENT IS KEY The plan also called for increasing the division’s clinical activity; in just 18 months, their clinical consults increased to the point where clinical revenues doubled, topping $700,000 in billings. The division opened a general infectious diseases clinic at the hospital’s sub- urban Liberty campus and a travel medicine clinic at its main Burnet Avenue location. Clinical revenues at the close of FY13 topped $1.4 million - yet another doubling. “Our research is important, but as a clinical division within a major children’s hospital, we also have an important clinical mission,” Hostetter says. She believes this clinical involvement informs their research and expands the legacy of physician-scientists like Sabin and Bernstein. “The division’s previous research covered the map on norovirus, rotavirus, herpes, cytomegalovirus,” she notes. “It was vitally important work, and we have built on that legacy to cover areas beyond virology.” AN HONEST LOOK Hostetter was grateful to have SAC reviewers who were national leaders in Infectious Disease confirm that the division is on the right track – and corroborate what needs improvement. The reviewers agreed that the division’s fellows needed more protected research time, and that finding more research space and continuing to recruit should be priorities. Now, little more than one year after the review, growth continues. The division’s clinical volume has now tripled. Hostetter and Beverly Connelly, MD, fellowship director, have restructured clinical time for infectious disease fellows to give them protected time for research. And Hostetter recently hired David Halsam, MD, to develop an antimicrobial stewardship program. Hostetter credits much of the growth to unwavering support from medical center leadership, including members of the Board of Trustees who attended her SAC review and have shown keen interest in helping her build a successful research and clinical enterprise. But the single greatest factor in her division’s success, Hostetter believes, is its people. “Every one of us who contributes to the clinical and research missions can think of that one child who made us say, ‘I’ve got to figure this out.’” LEADING RESEARCH PROJECTS IN INFECTIOUS DISEASES Rhonda Cardin, PhD, studies viral/host interactions in cytomegalovirus and is currently working on the connection between cytomegalovirus and congenital deafness. explores Candida and central line infection, which has led to the discovery of an antibody that interrupts the binding of Candida to heparin. It has been patented; next steps are licensing and the move to human trials. Funding by the Gates Foundation has led to research finding that asymptomatic vaginal infection with Candida in pregnant women may be linked to preterm birth. Hostetter’s team has developed an inexpensive, easy-to-deliver agent that stops this process. It is now ready for testing in an animal model. Peggy Hostetter, MD, Nancy Sawtell, PhD, studies reactivation of herpes simplex virus in rodent models. Xi Jason Jiang, PhD, and Ming Tan, PhD, study enteric viruses and have produced a recently licensed vaccine against the human norovirus. David Bernstein, MD, is currently collaborating on a vaccine that shows promise for reducing the number of relapses in people suffering from herpes simplex genital infections. Dr. Peggy Hostetter and her team are unlocking the mysteries of infections that have puzzled science for years. examines the molecular aspects of macrophage biology during disease, specifically, how macrophages use amino acids and the effect on infection and inflammatory disease. Joseph Qualls, PhD, immunologic standpoint. 20 CINCINNATI CHILDREN’S RESEARCH FOUNDATION Sing Sing Way, MD, PhD, studies pregnancy from an CINCINNATICHILDRENS.ORG/RESEARCH 21 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Center for Clinical and Translational Science and Training Research Design and Implementation Services We had broad use of our Research Central service portal, which supports more than 900 faculty and staff at the University of Cincinnati (UC) and Cincinnati Children’s. Requests included 175 consultation requests for biostatistical study design support and 241 requests for Research Electronic Data Capture (REDCap) database/survey implementation. Our service integration meetings also have shown promise in early trials. In these meetings, CCTST methodologists and informaticians meet as a group with investigators to offer advice and strategies for developing and implementing projects. Center for Career Development in Academic Pediatrics Schmidlapp Program Produces Strong Return on Investment Since the start of the Schmidlapp Women Scholars Program, 12 Scholars have been promoted; four to professor and three awarded tenure. They have published 689 papers since becoming Scholars and have received 15 NIH R01 grants, five NIH K Awards and 15 foundation grants for a total of $32 million in direct costs. This is a 20-fold return on investment. Clinical Pharmacology Decision Support Tool Advances Personalized Therapeutics Our research seeks to identify pharmacokinetic, pharmacodynamic and pharmacogenetic factors to explain differences in clinical response to medications. In one of our focus areas, we worked with David Hooper, MD, Nephrology, Biomedical Informatics and the Adherence Center, to develop a webbased decision support system for managing immune-suppressing therapies in organ transplant patients. The system provides real-time patient data and can alert providers about toxicity and drug interaction risks as they adjust dosages. Critical Care Medicine Lifecenter Award Recognizes Compassionate Care Sue Poynter Wong, MD, was honored in November 2012 with the LifeCenter’s Champions for Life award. She was nominated for her kind and empathetic work with a donor family in our Pediatric Intensive Care Unit, which ultimately led to organ donations that saved four lives. 40 Donors Support Undergraduate Program Skills learned in the CCTST Community Leaders Institute helped participants obtain more than $3 million in grants. Over the past several years, faculty and parents of undergraduates supported by the Schmidlapp Program have donated more than $90,000 to support our future women researchers and clinicians, with 40 donors contributing almost $18,000 this fiscal year. Procter Scholar Award Supports Lung Research Work Senior Leadership Program Launched Training Leaders to Develop and Improve Community Research Initiatives The third class from the Community Leaders Institute (CLI) graduated 18 participants, with the first two classes obtaining more than $3 million in grants thanks to the skills provided by the CCTST. The six-week CLI program enhances research and capacity-building competencies among agency directors, administrators, advocates and other community leaders. The long-term goal is to improve community research capabilities to address social, educational, environmental and physical health disparities in Greater Cincinnati. The Office for Faculty Development (OFD) has provided a variety of seminars, networking opportunities, and career development resources for faculty members. More than 650 faculty attended OFD events in FY 2013. A new senior leadership program was launched this year with the Harvard School of Public Health, a second cohort of faculty participated in the Core Leadership Program, new Core Leadership Program Booster Sessions were offered, a mentorship brochure and templates were published and a diversity promotional video was created. Brian Varisco, MD, received the Procter Scholar Program Award in December 2012. The program supports highly skilled pediatric fellows who are committed to pursuing careers in academic research. Varisco studies lung development and injury, focusing on the mechanisms that govern alveolar growth and regeneration and the remodeling of pulmonary vasculature. Leadership Changes in Critical Care Medicine Derek Wheeler, MD, was appointed this year to Associate Chief of Staff and Erika Stalets, MD, was named Medical Director. Predicting the Right Dose Improving the IRB Process for Multicenter Studies As part of the personalized pain initiative, we worked with Anesthesia to identify important factors for setting effective doses of morphine and related drugs while reducing the risk of adverse events. In a joint effort with the Center for Bariatric Research and Innovation, we developed a new dosing algorithm for providing propofol to obese patients. We also worked with the Cancer and Blood Diseases Institute to study genetic and developmental factors that can influence the ideal dose of sirolimus when treating children with NF1 and plexiform neurofibromas. A reciprocal agreement was developed among the three clinical and translational science award (CTSA)recipients in Ohio to accept reviews from any of their eight institutional review boards (IRBs) for multicenter studies. This collaborative effort will accelerate research by streamlining human subject protection processes when participating institutions partner on research requiring IRB approvals. The first of its kind in Ohio, this agreement will foster collaborative efforts among investigators, increase efficiency and reduce the regulatory burden on researchers. One of Three US Training Programs We are one of three sites awarded a pediatric clinical and developmental pharmacology training grant from the National Institutes of Health. Our program provides research support to evaluate drugs for pediatric use and to expand therapeutic applications of pharmacokinetics and pharmacogenetics. Dawn Pinchasik, MD, a third year fellow in Pediatric Hematology-Oncology, is our first 2013 graduate. Other fellows are Jason Wiles, MD, Andrea Hahn, MD and Kevin Downes, MD. 22 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 23 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Center for Technology Commercialization Commercialization Revenue Nears $5 Million Cincinnati Children’s received more than $4.9 million in commercialization revenue this year, up nearly 25 percent from the previous year. The revenue included $2.4 million from licensing activity, $1.2 million from industry-sponsored research, $900,000 in patent reimbursement and $400,000 in commercialization grants. Our grant support included awards from the Greater Cincinnati Foundation, the Third Frontiers Technology Validation and Start-Up Fund and the CincyTech Imagining Grant program. Dentistry Pediatric Sedation for Dental Procedures Stephen Wilson, DMD, MA, PhD, Director, was guest lecturer at the annual meeting of the International Association of Pediatric Dentistry in June 2013. He spoke on oral sedation of children for dental procedures. Wilson also helped develop an international sedation interest group to meet each year at future conferences. Wilson also was a principal writer of “Guidelines 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. He is Director of the American Academy of Pediatric Dentistry-sponsored sedation course presented twice a year in the US. Dermatology Pigmented Lesion Center Launched We launched the Pigmented Lesion Center, which comprises physicians representing Dermatology, Pediatric General Surgery, Pediatric Plastic and Reconstructive Surgery, and Pediatric Oncology. All specialize in treating congenital melanocytic nevi (moles), atypical melanocytic tumors, and melanoma. Developmental and Behavioral Pediatrics O’Leary Center Plays Leading Role in Autism Treatment Network The Kelly O’Leary Center for Autism Spectrum Disorders (ASD) remains the leading enrollment site for the 17-site Autism Speaks Autism Treatment Network, enrolling 565 of the 6,380 patients in the network’s national registry. We recently contributed to the network’s special supplement on ASD care, published in November 2012 in Pediatrics. Our center has collected blood and urine samples from more than 150 children with ASD and their parents in support of a national biorespository. We also provided training to more than 1,600 providers and family members in FY2013. In-Room Registration Begins Our Center focused this year on fostering partnerships to develop pediatric medical devices, advancing our discoveries in rare diseases, and winning award funding that will further innovative discoveries within the medical center. Rare Disease: Big Opportunity, Big Impact Our rare disease research expertise, coupled with strong interest from industry, led the CTC to actively pursue rare disease collaborations. This year, the CTC partnered with four other leading pediatric research institutions to host the first-ever Rare Disease Partnering Summit at the Biotechnology Industry Organizations international conference. The Summit, sponsored by Shire, brought together leading investigators from Cincinnati Children’s, Boston Children’s, Los Angeles Children’s, Toronto SickKids and Chicago Comer Children’s who have active research in the rare disease arena. The Summit resulted in our pursuing several collaboration opportunities. We have implemented a new in-room registration process, which allows patients to be taken directly back to their exam room and be registered. This new process has improved clinic flow and has eliminated excessive waiting room time. First Fellow Recruited to New Program We implemented our pediatric dermatology fellowship program and are training our first fellow this year. The one-year fellowship, approved by the American Board of Dermatology, aims to train physicians in all aspects of pediatric dermatology, including clinical care, research, scholarly activity, resident and medical student education, and administration and office management. A new genotyping assay may help predict how children with ADHD will respond to medication. Guiding the Research Agenda Cincinnati Children’s is one of the largest of 12 sites in the Developmental-Behavioral Pediatrics Research Network, funded by the federal Maternal and Child Health Program. The network guides key research agendas, identifies clinical practice variations and advances the use of electronic health records in clinical research. Advancing the Understanding of ADHD Funding Programs Drive Innovation and Collaboration Advanced Training in Pediatric Dentistry Two internal funding programs managed by the CTC — the Cincinnati Children’s Innovation Fund and the Ben-Gurion Cincinnati Children’s Collaborative (BG3C) — have invested $1.3 million in the past year in 15 projects. The Innovation Fund, now in its second year, provides up to $200,000 per project to further develop discoveries with market potential. The BG3C program, which focuses on developing pediatric medical devices, involves a partnership with Ben-Gurion University of the Negev in Israel. The BG3C funded three projects in its first round and plans to launch a second round. A new member of the Division this year, Sarat “Bobby” Thikkurissy, DDS, MS, also teaches the sedation course of the American Academy of Pediatric Dentistry. Thikkurissy became Program Director of the Advanced Pediatric Dentistry training program on July 1, 2013. The training program began a collaborative effort with the Division of Anesthesiology to provide intravenous sedation of patients, supplementing our reputation for performing oral sedations for dental restorative procedures. Five of our residents presented posters at the annual session of the American Academy of Pediatric Dentistry annual session in Orlando, Florida in May 2013. Research led by Tanya Froehlich, MD, MS, is contributing substantially to our understanding of attention-deficit/hyperactivity disorder (ADHD). Her work includes elucidating the effects of dopamine gene variants on methylphenidate response in children with ADHD and collaborating on a genotyping assay for the enzyme that metabolizes methylphenidate. The new test may help predict how children with ADHD will respond to medication. Froehlich also studies the effects of pesticide exposure on ADHD and has examined national datasets to explore how poverty, race and other disparities affect ADHD prevalence rates and treatment patterns. 24 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 25 Behavioral Medicine 2013 $9.3M 2009 $4.6M 2004 $1.5M On Research support at the Division of Behavioral Medicine has soared to more than $9.3 million in direct funds in 2013. Changing Behaviors Growing recognition of the impact of behavior on health brings unprecedented expansion to the Division of Behavioral Medicine and Clinical Psychology “Our growth reflects a long-term commitment from senior leadership who had the foresight to see behavioral health as being independent from and equal to other specialties.” any given day at Cincinnati Children’s, you can find teens in a laboratory using a driving simulator to measure the effects of shortened sleep on their reflexes and concentration. In another, children connected to biofeedback devices practice how to manage chronic pain. Meanwhile, hundreds of miles away, a boy with Crohn’s disease receives a text alert reminding him to take his next dose of medication. These kids are taking part in just a few of the many research projects happening in the Division of Behavioral Medicine and Clinical Psychology (BMCP) at Cincinnati Children’s — one of the largest groups of its kind in the US. The division’s faculty has grown to more than 70 members in the past 15 years. Its investigators received more than $12 million in the past year in external grant funding — the second highest total of any of the medical center’s 56 research divisions. “There is no place like Cincinnati Children’s in terms of the appreciation for what psychology can bring to the research enterprise or to patient care,” says Lori Stark, PhD, Director of BMCP since 1998. Research within BMCP focuses on the interactions between child health, behavior, biology, family and community. The division includes nationally recognized research centers for ADHD, childhood obesity and treatment adherence. Other important research programs include nutrition and eating, sleep problems, pain disorders, childhood abuse, migraine headaches, cystic fibrosis, sickle cell disease, and the neuropsychology of brain tumors and traumatic brain injuries. Meanwhile, clinical psychologists provide expert assessment and treatment services and work with children facing anxiety, sadness, difficulties with parent-child interactions, or peer relationship problems. BUILDING UPON STRENGTHS The BCMP was one of five divisions that recently underwent a Scientific Advisory Committee review at CINCINNATICHILDRENS.ORG/RESEARCH 26 26 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 27 Dr. Lori Stark leads a growing division that includes nationally recognized research centers for ADHD, childhood obesity and treatment adherence. simulator paired with an eye tracking device to improve the driving skills of teens with ADHD by reducing distractability. Epstein also led development of a web portal that allows pediatricians to collect and interpret parent and teacher ADHD rating scales, communicate with parents and teachers about patients, track patient outcomes and more. Susmita Kashikar-Zuck, PhD, leads a team of investigators in sports medicine, BMCP and rheumatology in developing a neuromuscular training program to increase functioning and reduce pain for teens with fibromyalgia. Our faculty members also play an important role in cystic fibrosis(CF)-related research. Scott Powers, PhD, Director, Center for Child Behavior and Nutrition Research and Training, leads a project to encourage children with CF to eat, even when they do not want to. Research has shown that children with CF have better lung function if they can stay close to the 50th percentile of body mass index. Kevin Hommel, PhD, is leading and participating in more than a dozen adherence-related studies, including innovative work that uses social media and telehealth approaches to help children with inflammatory bowel disease (IBD) stick to their treatment regimens. Managing growth OUR TEAM APPROACH INCLUDES Collaboration Collaborations with 18 specialized programs at Cincinnati Children’s from international adoptions to liver transplantation to epilepsy. Access Access to quantitative psychologists at our Data Core, who are experts at designing studies and developing mathematical models to measure psychological processes. Peer Review Senior-level peer review of all grant applications, which gives division projects better odds of securing funding. Training One of the largest postdoctoral fellowship training programs in the US, which admits seven to eight new pediatric psychology fellows each year. Cincinnati Children’s. The external reviewers, who included two past presidents of the Society of Pediatric Psychology, said they have seen no other behavioral medicine programs like this in the US. “Very few hospitals have assembled their psychologists all in one division,” Stark says. “That’s particularly attractive for recruiting strong researchers. They know if they come here they will receive comprehensive support for their work, plus the opportunity to collaborate with others in their own discipline as well as with world-class researchers in many other fields.” Our team approach includes: • Collaborations with 18 specialized programs at Cincinnati Children’s from international adoptions to liver transplantation to epilepsy. • Access to quantitative psychologists at the BMCP Data Core, who are experts at designing studies and developing mathematical models to measure psychological processes. • Senior-level peer review of all grant applications, which gives division projects better odds of securing funding. • One of the largest postdoctoral fellowship programs in the US, which admits seven to eight new pediatric psychology fellows each year. Collaborations expand In one of its largest collaborations to date, the BMCP is working with the Cancer and Blood Diseases Institute to launch a program to support more children with cancer as they face treatment adherence problems and other coping issues. Ahna Pai, PhD, directs the program, which is expected to grow to include nine clinicians and three research faculty. In epilepsy-related research, Avani Modi, PhD, Co-Director of the New Onset Seizure Clinic at Cincinnati Children’s is working with Tracy Glauser, MD, and others to improve treatment adherence. This project involves supplying patients with pill bottles fitted with electronic caps that monitor how often and when the bottles were opened. Clinicians can use the data to zero in on why a particular patient is missing his medication doses. Dean Beebe, PhD, Director of our Neuropsychology Program, uses a driving simulator to study the risks of sleep deprivation on the driving behaviors of teens. In ADHD research, Jeff Epstein, PhD, Director of our Center for ADHD, plans to use the driving The wide range of projects within BMCP reveals the interconnected role child psychology plays in understanding and treating many types of diseases and conditions. However, SAC reviewers and senior leaders agree the division faces some challenges, most of which are byproducts of its size and growth. As accomplished faculty members land research funding and gain prominence, they also become more attractive to other research centers. Stark and other senior leaders are working on ways to enhance retention to prevent potential disruptions to ongoing research. Meanwhile, as concern about the future of government grant funding continues, leaders are studying how to provide gap funding to continue strategic projects should research budget cuts occur. “Longer term projects can be affected by dry spells and shifts in funding priorities,” Stark says. “One of our goals is to develop ways to support our most productive investigators in these situations.” Stark predicts the role that behavioral health plays in maintaining and improving children’s overall health will not waver. “Our growth reflects a long-term commitment from senior leadership who had the foresight to see behavioral health as being independent from and equal to other specialties,” she says. Dr. Dean Beebe uses a driving simulator to test how lack of sleep affects teenage driving. CINCINNATICHILDRENS.ORG/RESEARCH 28 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 29 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Developmental Biology Long-Time Director Retires Christopher Wylie, PhD, retired in March 2013 after 13 years as our Division Director. Under his leadership, our faculty grew from 11 members in 2000 to 22 primary faculty and 22 secondary appointments, making our Division one of the largest groupings of developmental biologists in the world. Wylie understood that establishing a center for model organism developmental biology could provide tremendous value to a pediatric medical center. The research enterprise he built is well-positioned to play a major role in changing the outcome for children for years to come. Drug and Poison Information Center 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. We serve 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. Our Health Alert Network sends alert faxes to 60 regional hospitals on subjects ranging from blue green algae in local rivers to fentanyl-contaminated heroin. The Center’s Pharmacovigilance Medical Communication Unit continues to gather and evaluate safety data on public health issues such as poisoning, water quality, common household detergents, alcohol sanitizers, and terrorism preparedness. Emergency Medicine Prevention Research Ranges from Suicide to Smoking Our faculty made several contributions to prevention research in the past year. Jacqueline Grupp-Phelan, MD, MPH, leads a multi-center study on suicide screening with Nationwide Children’s Hospital. Melinda Mahabee-Gittens, MD, MS, co-authored two papers regarding smoking prevention. Lisa Vaughn, PhD, studies cross-cultural health issues. Mike Gittelman, MD, and Wendy Pomerantz, MD, MS, lead ongoing studies in injury prevention while Jennifer Reed, MD, and Kari Schneider, MD, focus research on preventing sexually transmitted diseases. Endocrinology Growth Factor Replacement Therapy Proves Safe and Effective A study led by Philippe Backeljauw, MD, published in July 2013 in Hormone Research in Paediatrics, reports that twicedaily injections of recombinant human insulin-like growth factor-1 (IGF-1) safely and effectively helps certain children with severe short stature due to growth hormone resistance reach significantly improved heights. Previous reports from this long-term study have led to US and European approvals for using IGF-1 to treat children who are resistant to other growth hormone therapies. This study reports final height data after tracking participants into adulthood. Kopan Becomes New Director Raphael Kopan, PhD, a world-renowned developmental biologist, took over as Division Director in August 2013. Kopan had been the Wolff Distinguished Professor of Developmental Biology at the Washington University School of Medicine in St. Louis, where he had worked since 1994. His research focuses on the role of Notch signaling in development and disease. Kopan’s strong international reputation will help to maintain the high visibility of our division and his collaborative instincts will dovetail nicely with the Cincinnati Children’s culture of teamwork. Improving Growth for Boys with Duchenne Muscular Dystrophy PECARN Projects Focus on Head Injury, Alcohol Screening and More Retreat Features 62 Poster Presentations Our annual two-day research retreat, held this spring, was the largest and most diverse to date. We had 175 participants from 16 divisions at Cincinnati Children’s who presented 62 posters. The scale of this internal retreat nearly matches the size of a regional meeting of the Society of Developmental Biology. Led by Richard Ruddy, MD, Division Director, and Lynn Babcock, MD, MS, several faculty members contribute to multisite studies through the Pediatric Emergency Care Applied Research Network (PECARN). Ongoing projects include studying RNA biosignatures in febrile infants and ASSESS, a study to validate an alcohol screening process for teens. Publications this year include findings on abdominal trauma, mild head injury, ED patient safety and cervical spine injury. Backeljauw and Meilan Rutter, MD, FRACP, Endocrinology, also worked with James Collins, MD, PhD, and Brenda Wong, MD, MBBS, Neuromuscular Center, to study IGF-1 as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Traditionally, DMD is treated with glucocorticoids (GC), which improve motor function, but also can result in growth failure and insulin resistance. They found that six months of once-daily IGF-1 injections significantly improved linear growth. Markers of insulin resistance also improved. There was no difference in motor functional outcomes. Research has shown that insulin-like growth factor (IGF-1) safely improves growth in children with certain conditions. Functional Hormone Production in Human Intestine Derived from Pluripotent Stem Cells Jonathan Howell, MD, PhD, works with James Wells, PhD, to study intestinal hormones that play important roles in regulating blood glucose levels. Wells’ lab has developed a method to grow intestinal organoid tissue from human pluripotent stem cells, which could serve as a novel model for studying intestinal development. Howell has detailed how the stem cells can be prompted to become small intestine or large intestine tissue. His work confirms that the lab-grown tissue mimics critical elements of normal human intestinal development, which further validates using this tissue to develop and test new treatments for diabetes, cystic fibrosis and other disorders. Research Improves Outcomes Community Outreach and Education Our Center continued to educate citizens and health professionals about poison hazards while implementing programs to promote healthy, drug-free lifestyles. Our staff includes prevention specialists, health educators, pharmacists, other health care professionals and law enforcement officers working as positive role models. Last year, more than 27,000 people in Hamilton County benefitted from our services. As a founding member, we also continue to support the People of Color Wellness Alliance Coalition and the Grassroots Urban Mobilization Benefitting Ohio initiatives, to respond to health disparity issues among minorities in Hamilton County. Benjamin Kerrey, MD, Matthew Mittiga, MD, Gary Geis, MD, and Andrea Rinderknecht, MD, continue innovative work on rapid sequence intubation and have reduced adverse events in children. Tara Rhine, MD, received the Willis Wingert Award for best presentation at the 2012 American Academy of Pediatrics Section on Emergency Medicine, for balance testing in concussion. Gregory Faris, MD, is using an Academic Pediatric Association young investigator award to assess a new decision rule to predict post-concussion symptoms. In quality research, substantial progress has been made managing fever and neutropenia in immunocompromised children and in screening patients for HIV and syphilis. 30 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 31 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Every Child Succeeds Moving Beyond Depression Program Expands Maternal depression affects up to 250,000 mothers a year, which can be devastating to mothers and harmful to their children. Moving Beyond Depression, a program we developed to provide in-home therapy to depressed mothers, has been demonstrated locally to be an effective approach. This year, with support from The Health Foundation of Greater Cincinnati, we partnered with Flywheel Cincinnati to develop a business plan to accelerate disseminating the program to other states. So far, Moving Beyond Depression has been implemented in Connecticut, Kentucky, Kansas and Massachusetts. Gastroenterology, Hepatology, and Nutrition Digestive Health Center One of 17 Core Research Centers The Digestive Health Center (DHC) directed by Jorge Bezerra, MD, and managed by Cynthia Wetzel, PhD, is one of only 17 Silvio O. Conte Digestive Diseases Research Core Centers in the US, and the only one dedicated to pediatric diseases. Our center engages 102 investigators from 21 divisions within the Department of Pediatrics. This year, the DHC launched the Pluripotent Stem Cell and Organoid Core, under the leadership of James Wells, PhD, and Chris Mayhew, PhD, to advance translational research in digestive diseases. Collectively, DHC investigators have received $32.5 million in grants and have published more than 140 peer-reviewed articles in the past year. General and Community Pediatrics Defining Standards of Bone Growth Children with chronic medical conditions such as cerebral palsy and kidney disease often lose bone strength with increased risk of fractures. Identifying children with compromised bone requires that we first understand normal bone accrual and bone density in healthy children. Heidi Kalkwarf, PhD, and a national team of investigators have published eight papers in the past six years detailing bone accrual and density reference standards for older children and adolescents. This year, they published findings for infants and toddlers up to age 3, including data documenting the impacts of growth, breastfeeding, gender and racial differences in bone accrual. General and Thoracic Surgery Projects Explore Intestinal Rehabilitation Michael Helmrath, MD, Director of Surgical Research, studies the adaptive response of stem cells following surgical loss of the bowel. NIH-funded projects in the laboratory examine the expansion of intestinal stem cells and the ability to culture and expand both murine and human intestinal epithelium. Helmrath also is surgical director of the intestinal rehabilitation center and is actively involved in the intestinal failure registry and outcome trials in this patient population. Biliary Atresia Replicates Better in Newborn Cells Exploring a Program to Better Engage Fathers Every Child Succeeds is using a grant from the National Institute on Child Health and Development to evaluate an inhome version of Family Foundations, an innovative program developed at Penn State University to help fathers become more involved in co-parenting children; many of these children live in single-mother households. Reducing Immunosuppression Dose Levels Our Community Impact Grows Every Child Succeeds is leading local community engagement efforts for Best Babies Zone, an initiative to reduce infant mortality and racial disparities in birth outcomes. Cincinnati’s program, one of three nationwide, focuses on the urban Price Hill neighborhood. Our staff members helped train 280 Hamilton County child protection workers to screen families for domestic violence issues as part of the local Futures Without Violence team. During FY2013, our home visitors served 2,762 low-income, first-time parents. Among families we have visited, 90 percent of infants are born weighing at least 2,500 grams, 46 percent of mothers report breastfeeding for at least one month, and 86 percent of infants receive at least three of five well-child visits expected by 6 months of age. John Bucuvalas, MD, is site principal investigator and protocol chair for the IWITH trial, a 12-center study of immunosuppression withdrawal for children receiving liver transplants. Clinicians have known for years that long-term immunosuppression can lead to substantial complications. Results from the study will help guide clinical decision-making to achieve safe immunosuppression withdrawal. Gregory Tiao, MD, continues to study biliary atresia with the help of an NIH grant and research team Sujit Mohanty, Bryan Donnelly and Ashley Walther. They recently published data showing that the temporal nature of biliary atresia may be due in part to the virus’s ability to replicate better in newborn cholangiocytes than mature cholangiocytes. Further study has shown that a specific gene/protein on the rhesus rotavirus strain is necessary to induce obstruction in the murine model by activating T- and NK cells. More than 700 children from 25 states were treated for IBD at Cincinnati Children’s in the past year. Inflammatory Bowel Disease Program Grows Transforming Pediatric Primary Care More than 700 children with inflammatory bowel disease (IBD) from 25 states were treated at Cincinnati Children’s in the past year. Our volume of second opinion patients has quadrupled in the past three years. Our IBD research efforts this year include leading the first multi-center trial of a telemedicine intervention to improve medication adherence; helping to launch the multi-center PROTECT study, which will evaluate a model for predicting therapeutic responses among children with ulcerative colitis; contributing to an international study seeking to identify genes linked to pediatric-onset IBD; and working with colleagues at MIT to use gut microbial data from 1,600 children to define novel pathogenic mechanisms and patient sub-groups. Anticipating dramatic changes in healthcare, Mona Mansour, MD, leads a team focused on redesigning primary care for low-income children. The goal is to achieve measurable improvements in health outcomes and quality of care while reducing costs for this population. The initiative includes our Pediatric Primary Care Center, the Hopple Street Health Center, and Fairfield Primary Care sites, which had 60,000 visits last year. Bundling Preventive Services As part of this redesign work, the team focused last year on improving delivery of preventive services. Although many practices improve single measures of preventive care, delivering a bundle of care measures requires significant systems change. Our primary care practices developed a bundle of preventive services for children up to 2 years old that includes immunizations and flu vaccination as well as screening for lead exposure, developmental delays and other risk factors. Our percentage of children receiving this bundle has jumped from a baseline of 58 percent to sustained performance above 95 percent. Trauma Collaborative Shows Results Richard Falcone, MD, MPH, and Trauma Services developed the Pediatric Trauma Transformation Collaborative (PTTC) to support trauma centers in providing the highest level of pediatric trauma care. The PTTC currently supports three institutions; each site has shown improvements that include reduced radiation exposure, shorter length of stay, fewer transfers, increased patient volumes and American College of Surgeons trauma verification. The results of this program will be presented at national trauma association meetings, and new partners are being identified. 32 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 33 emergency medicine 2013 75 2009 36 2004 6 director of the Division of Emergency Medicine at Cincinnati Children’s for 22 years, Richard Ruddy, MD, knows how to make things better. Whether working to improve systems within the hospital, leading the Section of Emergency Medicine of the American Academy of Pediatrics or reviewing operations at other emergency departments around the country, Ruddy has developed a keen sense of what it takes to transform emergency services for children. He also knows that earning a place as one of the nation’s top pediatric emergency medicine divisions requires regular checkups. Which is why he has looked forward to each of the four Scientific Advisory Committee (SAC) reviews he has gone through during his time here. “I actually like the process,” Ruddy says. “It has led to important changes in the growth and goals of the Division of Emergency Medicine, and it parallels the ability of the division to do its own strategic and tactical planning. It’s a very positive experience.” An unvarnished look As The Division of Emergency Medicine has dramatically increased it’s peer reviewed publications since 2004. Prepared For Emergencies Review helps Emergency Medicine prepare for a future filled with uncertainty “It’s not clear we will have the financial resources in the future, but we will not and should not turn away patients needing care.” Every five years or so, SAC review requires that a division presents a comprehensive overview of what it is doing and learns what it needs to do to be at the top of its game. The process “involves everyone,” Ruddy says, including research, clinical care, education, advocacy and work that crosses division lines. And the process is not intended only to showcase what is working well. “It has really become critical to think about the problems to solve, as opposed to the accomplishments that have been made,” says Ruddy. “I like the fact that it addresses all the important questions and gets us closer to being the best we can be.” Jacqueline M. Grupp-Phelan, MD, MPH, Research Director in the Division of Emergency Medicine, says she appreciates the perspective provided by the review. “Because of the reputation and experience of our SAC reviewers, we are able to understand where we fall CINCINNATICHILDRENS.ORG/RESEARCH 34 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 35 with respect to other top programs nationally. The serial nature of the review process is essential in understanding where we have come from, where we are now and most importantly, where we need to go. We are lucky to have the SAC review to push on our strengths and improve on our weaknesses.” The division sends the visiting reviewers electronic binders of documentation in advance. “The information gives reviewers an overview of our current state, where we believe we are headed with our strategic planning and the key questions we want them to address,” says Ruddy. Involving everyone Ruddy’s team had definite ideas about what they wanted to focus on in this year’s review. “We knew our need to be the best pediatric ED would include looking at the physical plant of the ED for the next 20 years, how to develop areas that could put us in the lead nationally, and what it would take to develop people, our most important resource.” Ruddy works to create an environment in which all staff feels comfortable talking with the reviewers. “It is an opportunity for junior staff and trainees to describe things that should happen in the next several years, in a non-threatening environment.” Joseph Luria, MD, Associate Director of the Division and Medical Director of the Clinical Services, says this approach provides more honest feedback. “The reviewers had time to spend with our staff without leadership present,” Luria says, adding that the resulting suggestions offered new ideas ranging from telehealth systems and facility upgrades to shift schedules and work-life balance. “We are now going through the process of prioritizing projects so we can address the feedback in a meaningful way,” Luria says. “I think this will set the stage for the development of our ED clinical practice over the next three to five years.” Preparing in the face of uncertainty Even the best SAC review generates some anxiety, says Ruddy – primarily concerns about how staff will be involved and what the future will bring. In preparation for this year’s review, Ruddy did something he had not done for previous reviews – he asked peers from around the country what challenges they face. Research funding, health care system change and the stress on the medical education system came up again and again. The challenge of research funding Concerns about research funding topped everyone’s list. “We’ve had great research funding for the last five years, but like other departments, we’re nervous about the funding difficulties the NIH is feeling right now,” Ruddy says. Although the division has $5.6 million in research projects currently underway, Ruddy worries that future funding will be a challenge for young and mid-level investigators. Reform and what it means Another issue that came up frequently in Ruddy’s poll of his peers was how healthcare payment reform and the pressing need to provide higher quality, integrated care will affect the face and future pediatric emergency care. “Everyone is wondering about the Affordable Care Act and the expense of care issue,” he says. “It’s not clear we will have the financial resources in the future, but we will not and should not turn away patients needing care.” Ruddy says change will not happen quickly, and in the meantime, emergency departments need to plan for the future. “You can’t tell people not to go to the ER if they don’t have access to what we would call the ‘ideal medical home.’ We are the front porch of the medical home, always open. We need to be creative about how we can do what is best for patients in the new environment of the next five to 10 years in healthcare.” Educating future providers, educators and leaders The third concern is the stress on training programs for pediatric emergency medicine specialists. “Federal funding for training is at significant risk. And changes in training program requirements could reduce the face time with patients that is so important to becoming the kind of provider patients and families deserve,” Ruddy says. The SAC reviewers agreed for the most part that the issues identified by Ruddy and his colleagues were the right ones to be thinking about. And although the review cannot resolve all the questions, it goes a long way toward helping the division be as prepared as possible for the coming changes. “By taking stock of our methods, goals and strategies on a regular basis, the Division of Emergency Medicine will be well prepared to accept the challenges that we anticipate and those we don’t,” Ruddy says. “The most important thing is, we have to be ready for whatever comes our way.” For Dr. Richard Ruddy, SAC review is an opportunity to focus on problems needing to be solved. “I like the fact that it addresses all the important questions and gets us closer to being the best we can be.” 36 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 37 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Global Child Health High-Dose Vitamin D Most Effective for Mothers and Infants Research led by Adekunle Dawodu, MBBS, reports that high-dose supplements worked best at helping pregnant Arab women achieve optimal vitamin D status. Dawodu’s team randomly assigned 192 women at approximately 12 weeks of pregnancy to receive 400, 2000 or 4000 IU/day of vitamin D3 until delivery. The 4000 IU/day dose was most effective and safe. The team also found that 400 IU/day — the currently recommended level for pregnant women in the US — proved inadequate at preventing vitamin D deficiency in this study. Hospital Medicine Improving Care Following Pediatric Surgeries Our Hospital Medicine Surgical Service (HMSS), led by Erin Shaughnessy, MD, offers many opportunities to improve care of children who have received surgery. This year, we developed a postoperative care protocol with Orthopaedic Surgery for posterior spinal fusion surgery. We also created a respiratory care protocol for major hip or spine surgery. These efforts have reduced the need for extra oxygen and shortened hospital stays. Division member Joshua Schaffzin, MD, PhD, received a PLACE Outcomes Research Award to further his work to reduce surgical site infections. We also lead a group of physicians developing guidelines for pediatric venous thromboembolism (VTE) prophylaxis. Human Genetics Advance in Genomic Analyses Lisa Martin, PhD, Co-Director of the Cincinnati Genomic Control Cohort, published a methods paper entitled, “Variant Impact on Linkage Effect Test,” which identifies a critical mismatch in the way linkage results are followed up. This novel approach overcomes the issue of the overlap of linkage and association when looking for disease-causing variants among complex traits. Immunobiology Studies Demonstrate Ways to Control Inflammation Investigators in our Division published four papers that suggest improved ways to control dangerous disease-related inflammation. In a paper published in Nature Medicine, Jörg Kohl, PhD, and colleagues report on a potent anti-inflammatory mechanism that shows how artificially galactosylated IgG can be used to inhibit inflammatory diseases mediated by the anaphylatoxin C5a. Marat Khodoun, PhD, Fred Finkelman, MD, and colleagues reported in the Journal of Allergy and Clinical Immunology that increasing doses of a monoclonal antibody can safely suppress IgE-mediated allergy in mice. The findings suggest a similar approach could be used to treat human food and drug allergies, insect venom sensitivities and asthma. In a paper published in Blood, Michael Jordan, MD, and C.E. Terrell used a mouse model to define a critical feedback loop that leads to the fatal inflammatory disorder hemophagocytic lymphohistiocytosis (HLH). Their findings suggest interventions that could treat HLH by limiting antigen-presenting dendritic cells. Julio Aliberti, MS, PhD, and colleagues reported in PLoS One that anti-inflammatory lipoxins can protect against lethal inflammation in experimental malaria in mice. Their findings suggest that lipoxins may be useful for treating children with cerebral malaria. More Timely Hospital Discharges Flu Vaccine Given in Pregnancy Protects Breastfed Infants Patient discharge delays can slow admissions and delay or cancel surgeries. A multidisciplinary team led by Christine White, MD, MAT, and Angela Statile, MD, has developed new discharge criteria for 11 common inpatient diagnoses, with positive results. The rate of patients discharged within two hours of meeting their discharge goals has grown from 42 percent to 80 percent and hospital lengths of stay were reduced by 10 percent, saving almost $6 million per year. Elizabeth Schlaudecker, MD, MPH, and Mark Steinhoff, MD, in collaboration with colleagues in Bangladesh, demonstrated that influenza-specific Immunoglobulin A (IgA) levels in breast milk were significantly higher for at least 6 months postpartum when women received influenza vaccines during pregnancy. Breastfed infants of influenza-vaccinated mothers also experienced significantly fewer respiratory illnesses with fever compared to breastfed infants of pneumococcalonly vaccinated mothers. New discharge criteria for 11 common inpatient diagnoses have reduced hospital stays by 10%, saving almost $6 million per year. Improving Care Through Regional Partnerships Progress in Pulmonary Hypertension Study in China Evaluates Medical Cost Burden of RSV Infections In Suzhou, China, respiratory syncytial virus (RSV) infections were a significant cause of hospitalization for children, with rates much higher than for influenza infections. These findings were from a study led by Steven Black, MD, and Mark Steinhoff, MD, in collaboration with investigators at Fudan University in Shanghai and Suzhou Children’s Hospital. Given the income levels of Suzhou residents, the costs of RSV-related hospital care represented a significant burden to families. This was the first population-based study in China to evaluate the economic burden of RSV infections. 38 CINCINNATI CHILDREN’S RESEARCH FOUNDATION Our Division recently helped Cincinnati Children’s establish an affiliation with Niswonger Children’s Hospital and related organizations in Johnson City, TN. The affiliation includes a hospital medicine program led by a Cincinnati Children’s-employed director to provide more evidence-based, data-driven patient care. Division member Craig Gosdin, MD, MSHA, led this work and partnered with Niswonger staff to improve inpatient asthma care. William Nichols, PhD, has established the National Heart, Lung and Blood Institute-funded National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH). To date, the repository has received samples from more than 600 patients. The goal is to gather samples from 3,000 patients during the five-year funding period. Data on these patients will be distributed to researchers worldwide for genetic and other studies of this devastating disease. Halting the Growth of Leukemia Cells Genetic Counseling Program Earns High Rating Our Genetic Counseling Graduate Program (GCP) received an A rating of excellence from the University of Cincinnati Graduate School Review and was reaccredited by the Accreditation Council for Genetic Counseling for the maximum period of eight years. Melanie Myers, PhD, Director, and Carrie Atzinger, MS, CGC, Associate Director, also successfully transitioned the GCP from quarters to semesters with students meeting academic requirements and finishing research projects in a timely manner. James Phelan, H. Leighton Grimes, PhD, and colleagues reported in Cancer Cell that acute lymphoblastic leukemia (ALL) cells rely on growth factor independence 1 (Gfi1) to escape the tumor-suppressing protein, p53. Removing Gfi1 from human ALL cells implanted in the mice stopped the progression of leukemia without any harmful effects. This suggests a potential new approach for treating human ALL and, possibly, other malignancies. New Leadership Harinder Singh, PhD, was chosen as our new Division Director. He joins us after having led Immunology programs at the University of Chicago and at Genentech. Also, the German Federal Republic approved funding for an integrated immunology graduate program between the University of Lübeck and Cincinnati Children’s. CINCINNATICHILDRENS.ORG/RESEARCH 39 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Heart Institute Program Focuses on Links Between the Brain and Heart Research shows that children with complex congenital and acquired heart disease are at a greater risk for neurodevelopment issues. The new Heart Institute-Kindervelt Neurodevelopmental and Educational Clinic (HI NDEC) at Cincinnati Children’s is an innovative program established by Bradley Marino, MD, MPP, MSCE, and now headed by Haleh Heydarian, MD. It provides individualized follow-up care to help each child reach their full potential. Our team provides comprehensive neurodevelopmental screening, evaluation and treatment for infants, toddlers, children and adolescents. Our developmental assessments help maximize school preparedness by evaluating children for behavioral and emotional problems as well as problems with attention, task management and organization. Our clinic experts come from an array of specialties, including Pediatric Cardiology, Developmental-Behavioral Pediatrics, Pediatric Psychology, Education, Pediatric Neurology, Occupational/Physical Therapy, Pediatric Nutrition, Cardiac Nursing, and Social Work. The Heart Institute includes the Divisions of Cardiology, Cardiothoracic Surgery and Molecular Cardiovascular Biology Gene Discovery Could Improve Treatment for Cardiac Fibrosis Systems, HeartWare, Thoratec, Berlin Heart, and Levitronix are producing new pediatric ventricular assist devices and total artificial hearts. The Heart Institute has formed relationships with several of these companies to serve as an international reference and training center for physicians. In the past year, we trained physicians from Japan and South America, and have hosted several training symposia for these companies at Cincinnati Children’s. As a result, our surgical team has become the primary investigator and coordinating center for the first clinical trial of a pediatric total artificial heart. Cardiac fibrosis refers to the thickening or scarring of heart muscle tissue, which can lead to heart failure and death. Studying the genes and mechanisms that promote cardiac fibrosis will help produce new therapies to stop or slow this process. In a recent paper published in Developmental Cell, Jeffery Molkentin, PhD, and colleagues showed how the gene TRPC6 works to convert fibroblasts into myofibroblasts, thereby promoting cardiac fibrosis and heart disease. Mice lacking TRPC6 had defective generation of myofibroblasts, with a lessening of the fibrotic response in vivo. Their work suggests new therapies with existing experimental drugs might have an anti-fibrotic effect, possibly reducing the progression of heart failure in select disease states. Since forging relationships with several device manufacturers, we have become an international training center for pediatric mechanical circulatory support systems. Regional ECMO Transport Program Launched Training Physicians in Pediatric Mechanical Circulatory Support Mechanical circulatory support for children is an emerging and quickly changing field. Several companies including SynCardia We have worked with Transportation to create an Extracorporeal Membrane Oxygenation (ECMO) transport program, which enables us to treat critically ill children while transferring them to Cincinnati Children’s. The Heart Institute is the only program in the country to provide third-party ECMO transport. A $2 million gift from Kindervelt helped us launch a Neurodevelopmental Clinic to address the psychosocial and education needs of children with complex heart problems. 40 40 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 41 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Infectious Diseases Top-funded Research Division Our division became the top-funded research division at Cincinnati Children’s this year. Our total external funding reached $10.5 million, from sources including the NIH, CDC, Burroughs Wellcome, Bill and Melinda Gates Foundation, NASA and industry. We also had the highest increase in grant funding among all Cincinnati Children’s research divisions - at 25 percent. Our funded research projects include studies of the pathogenesis of cytomegalovirus, herpes simplex virus, norovirus/calicivirus, and Candida infections; vaccine response; macrophage biology; normal and aberrant immune responses in pregnancy; and surveillance for community-acquired infections. Mayerson Center for Safe and Healthy Children The National Crisis of Child Abuse Each week, the Mayerson Center for Safe and Healthy Children evaluates more than 30 children for concerns of child abuse or neglect. We perform multi-disciplinary, collaborative clinical evaluations in an environment that minimizes child and family stress. Our team includes Cincinnati Children’s physicians, social workers, researchers, and nurses; Hamilton County Department of Job and Family Services caseworkers; City of Cincinnati and Hamilton County law enforcement officers; and members of the Hamilton County Prosecutor’s office. We provide a variety of specialized services, including forensic interviewing, medical-legal examinations, trauma screening, evidence collection and testimony. Nephrology and Hypertension Improving Survival for Children on Dialysis In a study published in the Journal of the American Medical Association, lead author Mark Mitsnefes, MD, MS, found that death rates among children and adolescents undergoing dialysis for end stage kidney disease (ESKD) in the United States have declined significantly over the past two decades. The study of 23,401 children and adolescents noted a significant decrease in mortality between 1990 and 2010, along with a decline in cardiovascular and infection-related mortality. Improved pre-dialysis care, advances in dialysis technology and greater experience of clinicians providing dialysis care may each have contributed. Neurology Comprehensive Neuromuscular Program Over the past year, we have continued to lead in the care and research of children with neuromuscular disease. We are a Center of Excellence for the care of patients with pediatric neuromuscular disorders, with 80 percent of our Duchenne muscular dystrophy (DMD) patients coming from around the country and the world. We are becoming known for our care of patients with dystrophinopathy. Over the past year, we launched a “one stop” interdisciplinary neuromuscular clinic, with providers from as many as nine specialties available to patients at one time. Transplant Infectious Disease Program Launched Controlling Cholesterol in Kidney Transplant Recipients Our Research in Neuromuscular Disease We launched the Transplant Infectious Disease Program under the direction of Lara Danziger-Isakov, MD, who was recruited from the Cleveland Clinic. Danziger-Isakov collaborates with clinicians and investigators in solid organ transplant and the bone marrow transplant unit. Overall, our clinicians provided consultative expertise to 691 inpatients and 1,695 outpatient visits in 2012. Billings reached $1.49 million. These numbers represent a three-fold rise in clinical activity since 2010. Inventions That Improve Child Health A study published in Pediatrics by David Hooper, MD, MS, and Jens Goebel, MD, showed that for 95 percent of their patients who received kidney transplants, using health information technology and reliable systems of care for cholesterol monitoring dramatically improved outcomes. One hundred percent of their patients with high cholesterol received appropriate medical treatment; 97% of their kidney transplant patients controlled their LDL cholesterol below a recommended target of 130 mg/dl. The study demonstrated powerful techniques for improving outcomes for children and adults with many chronic illnesses. We participate in ongoing industry-sponsored clinical trials as well as in a transcriptomics and proteomics study in DMD. This has been attained through training of residents and fellows and collaboration with multiple divisions, including Endocrinology, Cardiology and Radiology. Breakthrough Research in Headache Jason Jiang, PhD, and Ming Tan, PhD, have licensed the technology for a norovirus vaccine to Ligocyte. The Center for Technology Commercialization patented an antibody from the Hostetter laboratory that prevents Candida albicans biofilm formation. Our Headache Center is in its 16th year. Research highlights of the past year include an NIH-sponsored study that showed cognitive behavioral therapy for treating chronic migraine to be comparable to pharmaceutical treatment in adults. Our CHAMP study of the comparative effectiveness of amitriptyline and topiramate for pediatric and adolescent migraine continues to proceed well. Addressing Behavioral Aspects of Abuse In a collaborative effort between the Mayerson Center and Behavioral Medicine and Clinical Psychology, psychologists Heather Bensman, PsyD, and Erica Pearl Messer, PsyD, now provide trauma-informed mental health services. Children evaluated for abuse and neglect through the Mayerson Center can now receive therapy at the center to address symptoms associated with trauma and maltreatment. A new system for cholesterol monitoring has resulted in 100% of kidney transplant recipients receiving appropriate treatment for high cholesterol. Reducing Harm from Nephrotoxic Medication Tuberous Sclerosis Program is the World’s Largest Earning National and International Recognition Two of our exceptional staff received special honors this year. Kathi Makoroff, MD, was elected President of the Ray Helfer Society, an international honorary society for child abuse physicians. Mary Greiner, MD, was invited to join the National Committee for Quality Assurance’s National Collaborative for Innovation in Quality Measurement (NCINQ) Foster Care Expert Advisory Panel. This group sets the national standard for quality of care for children in the child welfare system. A study published in Pediatrics by Stuart Goldstein, MD, Director, Center for Acute Care Nephrology, demonstrated that the electronic health record can be programmed to identify patients at risk for acute kidney injury from nephrotoxic medication. When kidney function was assessed, the research team found that 25 percent of at-risk patients developed AKI. The team also observed a 42 percent reduction in nephrotoxic medication-associated AKI days, which translates to 900 AKI-free days over a one-year period. Our Tuberous Sclerosis (TSC) Program, now designated a Center of Excellence, is the largest in the world, and the only one that manages every aspect of TSC in adults and children. Research conducted or led by our physicians resulted in 15 peer-reviewed publications over the past year. We started the TSC Autism Center of Excellence, an NIH-sponsored, multi-site study into the pathophysiology of TSC. One of the highlights of our support to children and families is our TSC summer camp, the only one of its kind in the world. 42 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 43 Pathology 2013 14,000/yr 1985 4,500/yr growing. “Our institutional goal of providing more personalized medicine requires a great deal of support – in technology and personal expertise,” says David Witte, MD, Director, Division of Pathology. “Pathology fits into the picture by helping clinicians manage treatment in a more effective way.” A CULTURE OF GROWTH When Witte joined the division in the mid-1980s, the tiny department was staining and analyzing about 4,500 surgical specimens a year. Now, it handles 14,000 surgical samples a year and its viral PCR (polymerase chain reaction) laboratory – established from scratch a decade ago – now conducts more than 60,000 assays a year. When Witte became division Director in 1998, Pathology had three full-time faculty members; it now has 18 and counting, and has significantly expanded its range of work. THE MASS SPECTROMETRY ADVANTAGE Earlier this year, during the division’s Scientific Advisory Committee (SAC) review, the reviewers zeroed in on one service they consider especially rare among pediatric medical centers – its Mass Spectrometry Laboratory. While other institutions may have one, two or three mass spectrometers in service, Cincinnati Children’s has 10. “We have invested millions over the years in the mass spec lab to add and upgrade equipment. We now have much broader capabilities and state-of-the-art technology,” Witte says. Mass spectrometry offers a new way to address an old problem in pediatric medicine. Clinicians have long known that absorption and excretion rates for medicaCINCINNATICHILDRENS.ORG/RESEARCH As advancing technology allows doctors to match treatments to individual patients, the role to be played by hospital pathology services is evolving and The Pathology Division has grown from analyzing 4,500 specimens a year in the 1980s to handling 14,000 surgical samples in 2013. Paving the Way to a Perfect Dose An unprecedented investment fuels Pathology’s new role in providing personalized medicine “Now, we can go beyond simply determining what type of tumor a child has. Using gene sequencing and mass spectrometry analysis, we can say, ‘This is your tumor. Here’s how we predict it will behave.’” 44 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 45 MASS SPECTROMETRY AT CINCINNATI CHILDREN’S The laboratory uses 10 mass spectrometers to perform hundreds of tests a day to measure thyroid function, complex lipids, steroid levels and more. For years, the Mass Spectrometry Laboratory has been testing samples from children around the world to determine if defects in bile acid metabolism are causing their liver faliure. For some, the test results can prevent the ordeal of receiving a liver transplant. Six of these rare genetic defects were discovered here by Kenneth Setchell, PhD, the laboratory’s Director. (Below) As the laboratory added mass spectrometers, testing has expanded to include measures of thyroid function, complex lipids, steroid levels and genetic defects involving organic acids and acylcarnitine deficiencies in infants. Now, its fastest-growing service is measuring therapeutic drug levels for organ transplant recipients and children with cancer and other serious conditions. This work also provides data for a variety of clinical trials. Under the leadership of Dr. David Witte, our Division of Pathology has invested millions in technology and expertise that enable clinicians to predict the course of illness and treatment. tions can vary widely between full-term newborns and preterm newborns, between children and adolescents and between adolescents and adults. Metabolism rates also vary among individuals even when they share the same age and body mass. But there have been few practical ways to put that knowledge into practice. “Until recently, drug dosing in children has been educated guesswork,” Witte says. “Clinicians traditionally use weight and sometimes body surface area to calculate a starting dose based on a percentage of the normal adult dose. But this approach was never very accurate because it could not take individual metabolism into account. Now, with mass spectrometry we can.” Better, faster technology Years of resolution improvements have made mass spectrometers much more effective at distinguishing between compounds of similar molecular weights, which makes them more useful for analyzing complex biological samples such as lipids, organic acids and the metabolites of small-molecule drug compounds. “If all you know is that the molecular weight of a target sample is 368 daltons, that could describe 3,000 compounds,” says Kenneth Setchell, PhD, Director of the Mass Spectrometry Laboratory. “Our newest 46 CINCINNATI CHILDREN’S RESEARCH FOUNDATION machines can get down to four decimal places, where the probability of different molecules having the same mass is dramatically less, which means the elemental composition and the structure of the molecule can be determined with accuracy.” Results also can be obtained much faster than in years past. For example, the laboratory at Cincinnati Children’s produces same-day results for children receiving chemotherapy and immunosuppressive therapy, which can allow doctors to promptly adjust dosages to keep treatments within narrow therapeutic windows. This reduces the risks caused by overdoses and underdoses. NEW TESTS With demand rising for personalized analysis to help guide treatment, the division plans to add two more PhD-level experts in mass spectrometry in the coming year, Witte says. The additional help will be needed as mass spec analysis expands into new areas, such as precision dosing for antibiotics and pain medications. The technology also will help the medical center carry out its role in a new regional policy, which took effect Sept. 1, to perform drug tests for all expectant mothers. “We are developing methods for monitoring morphine, codeine, oxycodone and other related drugs. Eventually we will have a panel that will simultaneously monitor the levels of 42 pain medications,” Setchell says. Even as their usefulness expands, mass spectrometers themselves are getting smaller. Some older mass spectrometers had to be installed in basements because they can weigh several tons. But most newer devices are small enough to sit atop a laboratory bench. Looking forward, researchers in Pathology are working with a device maker to perfect an even smaller mass spectrometer -- small enough to be carried into a patient’s room and fast enough to produce results in minutes. Between device development and other projects, Witte predicts Cincinnati Children’s will be a leading center for establishing best practices for the use of mass spectrometry in pediatric medicine. “When I started out in pathology, nobody talked about mass spectrometry because nobody saw the link with clinical care,” Witte says. “But now, we can go beyond simply determining what type of tumor a child has. Using gene sequencing and mass spectrometry analysis, we can say, ‘This is your tumor. Here’s how we predict it will behave.’” Dr. Kenneth Setchell and colleagues are developing a test panel that will simultaneously measure blood levels for 42 pain medications. CINCINNATICHILDRENS.ORG/RESEARCH 47 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Neurosurgery Diverse, Collaborative Clinical and Research Activities Our faculty has undertaken a variety of clinical and research programs this year. Ellen Air, MD, leads the surgical arm of the Dystonia and Surgical Movement Disorders Clinic and is principal investigator of a study evaluating low-frequency electrical activity in response to traumatic brain injury in adults and children. Karin Bierbrauer, MD, is site principal investigator for a national registry studying children with Chiari I malformations and syringomyelia. Bierbauer recently presented research on syringomyelia cavities in fetuses with spina bifida. Ophthalmology A Link Between Fetal Light Exposures and Retinopathy of Prematurity A study published in Nature in February 2013 by researchers in the laboratory of Richard Lang, PhD, and David Copenhagen, PhD, University of California, San Francisco, first showed that light response in the fetal eye of mice regulates the number of retinal neurons and, in turn, the pattern of retinal vascularization. Michael Yang, MD, followed this study by showing that reduced light exposure during the first trimester is strongly associated with severe forms of retinopathy of prematurity. This was published in the journal Ophthalmology. His findings suggest that many cases of retinopathy of prematurity might be prevented if newly pregnant mothers received sufficient daily light exposure. Orthopaedics Clinical Trial of HemiBridge Spine Clip Advances We successfully completed the Phase I clinical safety trial of the HemiBridgeTM spine clip. The device immediately decreased curvature for the six patients enrolled in the study and spine deformities are either stable or improved. Four patients have completed one-year follow-up visits, including one patient with a curve correction of 70 percent. The device has been approved in Europe and a Phase II trial has been approved in the US. Results of the device on spine biomechanics in an in vitro model were accepted for publication in the journal Spine. Results also have been presented at three major orthopaedic conferences. Otolaryngology/ Head and Neck Surgery Choo Becomes Division Director In October 2012, Daniel Choo, MD, was named Director of the Division, assuming a post held by Robin Cotton, MD, for 37 years. Cotton helped build the Division into the premier center for diagnosis and treatment of pediatric airway abnormalities. Cotton also is one of only nine scientists since 1960 to be awarded the William Cooper Procter Medallion, Cincinnati Children’s highest honor. Choo takes the helm of one of the nation’s busiest otolaryngology practices, which includes more than 33,000 outpatient visits and 11,000 procedures a year. Focus on Hydrocephalus Breakthrough Study in Usher Syndrome June Goto, PhD, has generated new genetic models of neurological disorders such as hydrocephalus and tuberous sclerosis complex and has performed pre-clinical trials targeting epilepsy, developmental delay, and brain malformations. Francesco Mangano, DO, Division Director, focuses on surgical treatment of intractable epilepsy in children and techniques that improve outcomes while minimizing morbidity. He is co-principal investigator with Weihong Yuan, PhD, Department of Radiology, on a multi-site NIH study of advanced MR imaging techniques in hydrocephalus. Sudhakar Vadivelu, DO, and Timothy Vogel, MD, recently joined the division. Vadivelu studies cerebrovascular neurosurgery and the effect of medications on the blood brain barrier. Vogel focuses on targeting neural progenitor cells in treating congenital hydrocephalus. Kenneth Campbell, PhD, studies molecular mechanisms that control normal brain development. Campbell and Mangano are working to establish a hydrocephalus research program. Already approved in Europe, the HemiBridge spine clip is moving into Phase II clinical trials in the United States. PRECICE Device Revolutionizes Limb Lengthening Treatment Saima Riazuddin, PhD, and colleagues published “Alterations of the CIB2 Calcium- and Integrin-binding Protein, Cause Usher Syndrome Type 1J and Nonsyndromic Deafness DFNB48” in Nature Genetics. This breakthrough work has been highly cited and is featured in the Editor’s Choice of Science Journal. The PRECICE™ device is a remote controlled, magnetic intramedullary nail that can lengthen leg bones without the need for an external device or fixator. James McCarthy, MD, is piloting this new FDA-approved device in a multi-center post-market study to evaluate its safety and effectiveness in children. So far, the device has been successfully implanted in two patients. Eye Genetics Clinic Established Brachial Plexus Research Coming to Fruition Battling Brain Tumors, Studying Neural Circuits Charles Stevenson, MD, leads our brain tumor program, which participates in clinical trials as part of the Pediatric Brain Tumor Consortium. Stevenson and colleagues in the Fetal Care Program also perform in utero repair of myelomeningocele defects, one of only a few programs in the country offering this surgery. Steven Crone, PhD, studies neural circuits that control motor behavior and how they are altered by disease or injury. He received an Emerging Investigator Award from the FightSMA! and Gwendolyn Strong Foundations and a starter grant from the Amyotrophic Lateral Sclerosis Association. In October 2012, we joined with Human Genetics to establish an Eye Genetics Clinic to provide diagnosis for rare and unique eye diseases. So far, we have provided ophthalmologic and genetic evaluation to more than 20 families. The clinic is led by Constance West, MD, Director of Pediatric Ophthalmology and Howard Saal, MD, Director of Clinical Genetics and Cytogenetics; with assistance from Virginia Utz, MD, and Robert Hufnagel, MD, PhD. The clinic’s genetic research is led by Zubair Ahmed, PhD, Associate Professor of Pediatric Ophthalmology and Human Genetics. So far, 70 people have been enrolled in his effort to identify new disease genes. Identifying these genes will provide new questions for research in animal models, to be answered in the Visual Systems Group led by Lang, which studies the mechanisms of familial eye disease and its treatment. Roger Cornwall, MD, received a three-year Career Development Grant from the Orthopaedic Research and Education Foundation (OREF) to study “The Role of Muscle Satellite Cells in Contracture Formation Following Neonatal Brachial Plexus Injury.” He also received the Goldner Pioneer Research Award from the American Society for Surgery of the Hand for his study, “Afferent Denervation and Contractures Following Neonatal Brachial Plexus Injury.” Pediatric Sports and Injuries Study Shital Parikh, MD, presented research at the American Academy of Orthopaedic Surgeons Annual Meeting that shows sports injuries in children and adolescents have decreased over the past decade. Parikh attributes the reduction to a decrease in children’s physical activity as well as education and preventive programs. 48 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 49 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Pathology and Laboratory Medicine Progress Against Pediatric Lung Disease Kathryn Wikenheiser-Brokamp, MD, PhD, has identified key genes and molecular pathways controlling development of the pediatric lung tumor pleuropulmonary blastoma (PPB), chronic obstructive pulmonary disease and lung cancer. She identified critical biologic functions for the Rb/p16 and p53 pathways in pulmonary epithelial stem cell growth relative to lung development, repair after injury and carcinogenesis. Wikenheiser-Brokamp also leads the basic science research for a multi-institutional team of researchers that recently discovered DICER1 mutations in a familial tumor predisposition syndrome defined by PPB. Patient Services Research Research Staff to Expand Rita Pickler, PhD, was named scientific director for nursing this year, and will focus on expanding research staff and funding in our Division. Pickler’s own research focuses largely on the care of preterm infants. In a recently completed randomized control trial, she confirmed the benefits of an intervention that shortens transitions from tube to oral feeding and can reduce hospital lengths of stay. Pickler also studies the effect of maternal well-being on pregnancy outcomes and the transition to home from the NICU. Pediatric and Adolescent Gynecology Improving Care for Sexually Transmitted Diseases Jill Huppert, MD, was awarded $625,000 over five years to collaborate with Johns Hopkins University on a study titled “Center for Point-of-Care Technologies Research for Sexually Transmitted Diseases.” Over the same period, Huppert also secured more than $86,000 from industry-sponsored funding for sexually transmitted disease (STD) diagnostic tests. Her quality improvement work on improving STD care was published in Pediatrics. Physical Medicine and Rehabilitation Research Advances Understanding of Brain Injury Brad Kurowski, MD, MS, and Shari Wade, PhD, recently published results in the Journal of Head Trauma Rehabilitation and Pediatrics of a multi-center study evaluating the efficacy of web-based, counselor-assisted problem solving for managing the cognitive and behavioral effects of pediatric traumatic brain injury (TBI). Kurowski also is using a five-year grant from the NIH to study the use of methylphenidate for managing attention problems in children with TBI. He also has collaborated with several colleagues at Cincinnati Children’s to obtain a grant from the Ohio Department of Public Safety to study the benefits and biologic correlates of aerobic exercise in managing pediatric post-concussion syndrome. Revolutionary Hearing Test Studied Here Breakthrough Findings in Liver Disease Kenneth Setchell, PhD, has identified and described six genetic defects in the pathway for bile acid synthesis, which manifest as progressive neonatal liver disease. His research group is an international center for the diagnosis and treatment of liver disease caused by genetic defects in cholesterol and bile acid syntheses. Setchell and colleagues recently published findings in Gastroenterology on the clinical, biochemical, molecular and morphologic features of a genetic defect in bile acid conjugation. They identified the defect using mass spectrometry analysis of urine bile and serum samples and sequence analysis of the gene. Mass Spectrometry Expands The Division of Pathology now has 10 mass spectrometers, including technology that will serve as the cornerstone of our developing metabolomics program. We perform more than 17,000 clinical assays a year and are developing a personalized therapy drug management program with Clinical Pharmacology. By developing new ‘speech-in-noise’ (SiN) tests of hearing, and by analyzing the results of the SiN hearing test in more than 160,000 people, David Moore, PhD, and his colleagues helped develop the next generation of diagnosis and intervention for hearing impairment. The SiN test improves on the audiogram, which does not predict well the ability to hear in real-life conditions. Their results highlight the close interaction between the ear and the brain in processing complex speech signals. Moore and his team have published seven peer-reviewed papers this year, plus two articles in professional society newsletters and two book chapters. They have presented at more than 10 international invited lectures. The team also represented Cincinnati Children’s as part of a consortium, ‘Auditory Cognitive Neuroscience’, which was recently awarded €1 million by the European Union Erasmus Mundus. Our Division is enrolling patients in the Ovarian Tissue Cryopreservation Project to protect the fertility of young women receiving cancer treatments. Preserving Fertility For Patients With Cancer We continue to collaborate with Hematology /Oncology to build our Oncofertility program, which focuses on protecting future fertility for patients being treated with chemotherapy or radiation. Leslie Ayensu-Coker, MD, is enrolling patients in the innovative Ovarian Tissue Cryopreservation Project, which collects and freezes ovarian tissue before treatment with gonadotoxic drugs. For this work, Ayensu-Coker was awarded the ACOG/Merck Research Award in Adolescent Preventive Services. Neuropathology Program Grows Under the direction of Lili Miles, MD, we have built a comprehensive neuro-oncology program that evaluates more than 100 new brain tumor cases a year. With funding from The Cure Starts Now Foundation, we also operate the Diffuse Intrinsic Pontine Glioma International Repository, which gathers tumor samples for research purposes. Miles provides the pathology review for this important tumor repository. Miles also provides pathology support to the Pediatric Brain Tumor Consortium, a national NIH-funded consortium for which Maryam Fouladi, MD, is site principal investigator for the medulloblastoma protocol study. Our faculty members have played important roles in developing new Speech-In-Noise tests, which represent the next generation of diagnostic tools for hearing impairment. Evaluating Post-Concussion Rehabilitation Three Studies Explore Brain Injury Recovery Catherine Quatman-Yates, PT, DPT, PhD, in her first year as a faculty member, completed two pilot grants that supported her work in post-concussion diagnosis and rehabilitation. The work from these grants culminated in scientific presentations, multiple manuscripts and a series of preliminary studies for her recently funded grant, “Clinical Detection of PostConcussion Impairments in Children and Adolescents.” Our Rehabilitation Research and Training Center on Interventions for Pediatric TBI continues to enroll patients in three large clinical trials addressing cognitive and behavioral consequences post-TBI. Kurowski and Wade also are collaborating with Lynn Babcock, MD, Emergency Medicine, to develop a web-based intervention to facilitate recovery following mild TBI. Outpatient Care Volume Up 34% Visits to our outpatient TBI program increased to more than 1,900 this past year, a 34 percent increase. Collaboration across the medical center has improved outpatient care for TBI and continued work to bridge research and clinical initiatives will further optimize care. 50 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 51 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Perinatal Institute The Perinatal Institute includes the Divisions of Neonatology, Perinatal and Pulmonary Biology, Developmental Biology, Reproductive Sciences, the Center for Prevention of Preterm Birth and the Fetal Care Center of Cincinnati. March of Dimes Funds Statewide Collaborative The March of Dimes Prematurity Research Center Ohio Collaborative was formed to bring together investigators from 20 disciplines to intensify the search for the fundamental causes of preterm birth. We believe this collaborative will become a world leader in preterm birth research and prevention. The March of Dimes has pledged $10 million over five years to fund this initiative. The project includes Ohio’s leading health research institutions – Cincinnati Children’s, the University of Cincinnati (UC), the Ohio State University, Nationwide Children’s Hospital, Case Western Reserve University, and University Hospitals/MetroHealth. Cincinnati Children’s will be the coordinating site; codirected by Louis Muglia, MD, PhD; James Greenberg, MD, Jeffrey Whitsett, MD, and SK Dey, PhD. Collaborative for Infant Mortality Reduction The Perinatal Institute facilitated the creation of a public/private collaborative to reduce our region’s infant mortality rate. Based at Cincinnati Children’s, the collaborative brings together leaders from Hamilton County, the City of Cincinnati, the UC Colleges of Medicine and Nursing, Cincinnati Children’s, all regional hospital maternity providers, and several local nonprofit agencies. The collaborative has a five-year $1.25 million funding commitment based upon an agreement between the Hamilton County Commission, UC Health and the Drake Center. Greenberg and Elizabeth Kelly, MD, provide operational leadership along with newly appointed Director, Ryan Adcock. County Commissioner Todd Portune and City Councilmember Wendell Young Co-Chair the Advisory Board. Three Major Grants for Lung Disease Research Our faculty received three new awards this year from the National Heart, Lung, and Blood Institute (NHLBI). Whitsett, Bruce Trapnell, MD, MS, and Frank McCormack, MD, are co-principal investigators for a T32 training grant entitled “Pulmonary and Cardiac Development and Disease.” Whitsett is collaborating with Biomedical Informatics and the UC College of Engineering on a K12 grant, “Omics of Lung Diseases.” Whitsett also will lead a new R01 grant, “Transcriptional Programming of Asthma Related Pathology in Respiratory Epithelia.” The March of Dimes has pledged $10 million over five years to a statewide collaborative to intensify studies of preterm birth. 52 52 CINCINNATI CHILDREN’S RESEARCH FOUNDATION The Collaborative for Infant Mortality Reduction will use $1.25 million in funding to bring together local leaders to reduce our region’s high infant mortality rate. CINCINNATICHILDRENS.ORG/RESEARCH 53 Center for Technology Commercialization 2012 202 2011 118 2010 93 2009 88 Be Scientists at Cincinnati Children’s have more than doubled their invention disclosures since 2009. From Bright Idea to Brilliant Product Our Center for Technology Commercialization helps scientists’ discoveries make the leap from laboratory to marketplace Currently, more than 200 new medicines, devices, diagnostic tests, software tools and other products are in our pipeline preparing for market. it designing an infant-sized MRI scanner, developing a gene therapy for sickle cell disease or coming up with a better test for inflammatory bowel syndrome, clinicians and researchers at Cincinnati Children’s are constantly coming up with ways to improve pediatric medicine. The challenge for our Center for Technology Commercialization (CTC) is to help translate a growing volume of innovative ideas into real-world products that benefit children – and to do it as quickly as possible. “Our mission is clear: to be the leader in the commercialization of pediatric innovations,” says Niki Robinson, PhD, an Assistant Vice President at Cincinnati Children’s who leads the CTC. Our need for expertise in technology transfer has grown in concert with the rapid expansion of our research enterprise. In the past 13 years, the medical center has pumped more than $1.5 billion in public and private grants into pursuing new discoveries. In fact, annual external research funding has more than tripled from about $50 million in 2000 to more than $171 million in FY2013, which ended June 30. Recent investments have spawned more than 200 new medicines, medical devices, diagnostic tests, software tools and other products now pushing their way through the development pipeline towards market. Hundreds more innovations are being disclosed every year. The vital role the CTC plays in translating research into new therapies made the division the ideal candidate for becoming the first non-faculty division to participate in the medical center’s unique Scientific Advisory Committee (SAC) review process. (see page 8 for more about the process). In the CTC review, experts from the Cleveland Clinic and Boston Children’s Hospital joined senior leaders at Cincinnati Children’s to analyze the division’s CINCINNATICHILDRENS.ORG/RESEARCH 54 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 55 progress and strategic plans. The rigorous review produced two important outcomes: “The first thing we learned was that we are moving in the right direction at the right velocity,” Robinson says. “The second was that if we want to be the best at developing innovation, there is still more we can do.” STAFF TO GROW WITH DEMAND Seven years ago, the CTC had a professional staff of three. Now, its staff of 15 includes specialists in technology management, marketing and business development – and the CTC has six openings to fill. Plans include adding specialists with expertise in medical devices, healthcare information technology and other key fields. Expanding external engagement In addition to working directly with industry on a wide range of licensing and partnership arrangements, the CTC is expanding formal collaborations with other entities at regional and global levels. A year ago, the division helped forge a new venture with Ben-Gurion University of the Negev in Israel to accelerate pediatric medical device development. Future collaborations may include leading a long-discussed statewide network for pediatric health innova- tion and joining an international rare diseases research consortium that was launched in 2011. “Collaborating with industry and other research centers on product development is especially important in pediatrics because the research itself so often requires a non-traditional approach,” Robinson says. Enhancing internal engagement Cincinnati Children’s made a strong statement last year by launching an Innovation Fund to accelerate marketable projects. The fund plans to invest $500,000 to $1 million a year in promising projects that need proof-of-concept funding to attract commercial partners. Very few pediatric centers are large enough to make such investments, but such funding is becoming more important, Robinson says. Large pharmaceutical companies and device makers have become less willing to take financial risks to develop products for rare childhood disorders with inherently small market potential. Now that the Innovation Fund has been established, it is encouraging an entrepreneurial spirit among our faculty, Robinson says. The proof? The number of proposals was twice as high for our second round of Innovation Fund awards compared to the first round. INNOVATION FUND PICKS 6 Gastroenterology – To develop a novel diagnostic tool that uses genetic signatures and computer algorithms to more accurately determine whether patients have Crohn’s disease or ulcerative colitis. These researchers were selected from more than 30 applications in FY13 to receiving support to prepare their recent discoveries for commercialization. Lee (Ted) Denson, MD, Experimental Hematology/ Cancer Biology – To continue study of an improved y-globin gene developed by Malik’s research team for a Phase I/II clinical trial of gene therapy for sickle cell disease. Punam Malik, MD, Charles (Chuck) Dumoulin, PhD, Radiology – To continue developing a novel small-scale MRI scanner that will provide quieter, improved images of newborns – especially fragile premature infants – without removing them from the neonatal ICU. Senthil Sadhasivam, MD, MPH, Anesthesia – To develop a rapid genetic test and decision support tool that would allow physicians to precisely tailor the use of opioids for pain management. – To further develop an oral therapy that would reverse pulmonary fibrosis – a potentially fatal complication of several adult and pediatric diseases -- by targeting a specific molecule (P70S6K). William (Bill) Hardie, MD, Pulmonary Medicine Critical Care Medicine – To continue validating a novel diagnostic biomarker (IL-27) for rapid, early identification of sepsis, which could prevent potentially fatal septic shock by allowing earlier intervention with antibiotics. Hector Wong, MD, Discovery The Pipeline to Market Agreement Management The CTC monitors and assists as needed while new technologies move through several years of pre-clinical and clinical development. The CTC actively manages about 100 licenses. Cincinnati Children’s researchers disclosed more than 180 new innovations in FY13 including new therapeutics, diagnostics, medical devices and software. Patent Process The CTC filed 66 patent applications in FY13. It can take up to seven years for a patent to issue. For existing projects, 20 patents were issued in FY13 Revenue Distribution Assessment The CTC assesses all disclosures to determine if the technologies require that a patent application be filed or if they need further development. In some cases, the CTC will seek industry partners to fund additional development. Commercialization Support The CTC seeks out industry partners to forge licensing agreements that include license fees, milestones and other terms. In some cases, the CTC advises forming a start-up company. The CTC completed 23 license and option agreements in FY13. As fees, royalties and other payments are received the CTC distributes the funds to the research foundation, investigators and their divisions according to the terms of Cincinnati Children’s IP policy. The CTC distributed more than $2.4 million in FY13. Cincinnati Children’s Innovation Fund invests nearly $1 million a year to support promising projects, says Dr. Niki Robinson, who leads the Center for Technology Commercialization. 56 57 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Plastic Surgery The Genetic Roots of Craniofacial Development Samantha Brugmann, PhD, studies the function of primary cilia and the role of the Hedgehog (Hh) pathway during craniofacial development. She also studies the role the protein Kif3a plays in forming the mandibular prominence. Christopher Gordon, MD, and visiting research scientist, Armando Uribe-Rivera, are collaborating with Bruce Aronow, PhD, to investigate microRNAs as master controllers of craniofacial development. Donna Jones, PhD, focuses on the influences of ontogeny, function and evolution on craniofacial morphology. Yu Lan, PhD, has established a new mutant mouse model to provide insight into the mechanisms that cause cleft palate.Lan also worked with Rulang Jiang, PhD, Developmental Biology, and researchers at Sichuan University in China to describe a critical role played by the gene Smad7 in regulating cranial suture development. Psychiatry Improving Our Understanding of Aggression in Children Drew Barzman, MD, has created a unique pediatric aggression research database that includes more than 3,000 patients. Recent studies are evaluating the use of fMRI and salivary biomarkers as tools for predicting aggressive behavior in children and adolescents. Pulmonary Medicine Lung Transplantation to Begin by Spring 2014 In collaboration with the Heart Institute, we are developing Cincinnati’s first Lung Transplant Program. We anticipate beginning lung transplants and lung-heart transplants by spring 2014. Radiology Safety Initiatives Expand Our “Right Patient, Right Exam” initiative, designed to decrease inappropriate imaging from order entry errors, prevented more than 750 errors from reaching patients in fiscal 2013. Our “What, When, Where” initiative empowered our technologists to fill in the missing components of patient histories, resulting in 95 percent of all studies having an appropriate history, which allows our physicians to make more accurate and complete interpretations. This year’s efforts to minimize pediatric imaging radiation exposure focused on radiography, which accounts for 70 percent of all imaging studies in children. Adjustments in techniques allowed us to cut our already low doses by 50 to 75 percent without compromising diagnostic quality. Upper-Airway Center Established Our new Upper-Airway Center was formed to provide innovative treatments to patients with persistent upper-airway obstruction who have not responded to standard therapy. This multidisciplinary program includes expertise from Pulmonology, Human Genetics, Plastic Surgery, Radiology, the ENT Outpatient Treatment Center and The Jane and Richard Thomas Center for Down Syndrome. Research to Improve Reconstruction Gordon has worked with Alessandro DeAlarcon, MD, and Michael Rutter, MD, to create a tissue-engineered trachea. He also studies tissue-engineered mandible reconstruction as an alternative to traditional surgery. Ann Schwentker, MD, Brian Pan, MD, and Scott Rapp, MD, in collaboration with Bruce Aronow, PhD, are investigating the impact of adipocyte injections in a porcine model of hypertrophic burn scarring. Our team also studies how muscle forces influence mandible development, which eventually could lead to reduced need for surgeries and long hospital stays for children with lower jaw abnormalities. Fragile X Center Studies New Treatments In collaboration with the Heart Institute, we are developing Cincinnati’s first Lung Transplant Program. No. 2 in the Nation Our Division was ranked No. 2 in the nation for Pulmonology by US News & World Report for the second year in a row, with an overall score of 96.8 out of 100. We ranked “superior” in categories including asthma-management success, commitment to best practices and quality improvement, and efforts to involve families. Advances in Airway and Pulmonary Imaging Protecting Skin Integrity Our Skin Sciences Program, led by Marty Visscher, MD, works on several studies to enhance skin integrity for premature infants and to improve healing processes in other skin conditions. Visscher studies infection risks for premature infants who lack vernix caseosa, the development of stratum corneum barriers in premature infants, and collaborates with colleagues at Johns Hopkins University to evaluate the effect of topical massage oils on neonatal skin integrity. Visscher also uses high-resolution color imaging, thermal imaging and three-dimensional surface scans to characterize disease processes and treatment effects for hemangiomas, pressure ulcers and other skin conditions. Craig Erickson, MD, has established the Fragile X Research and Treatment Center and started several new translational research projects. The center is using a four-year, $1 million grant from The John Merck Fund to conduct a clinical trial to evaluate the effectiveness of acamprosate in youth with Fragile X. The center also has three other industry contracts to study investigational drugs for youth and adults with Fragile X Syndrome. Tori Schaefer, PhD, leads a study funded by the FRAXA Research Foundation to evaluate a novel modulator of GABA neurotransmission in Fragile X knockout mice. Our Fragile X Center also has begun collaborating with the National Fragile X Foundation and the Centers for Disease Control and Prevention on a longitudinal behavior tracking study. We have developed an integrative approach that uses both CT and MRI to make more precise, non-invasive diagnoses of airway disease. Working with engineering partners at the University of Cincinnati, we have developed modeling that improves outcomes by allowing surgeons to assess proposed interventions prior to actual surgery. Jason Woods, PhD, joined us this year bringing with him an entirely new area of pulmonary magnetic resonance research -- hyperpolarized gas imaging. This allows detailed functional and structural lung assessments that may ultimately replace CT (and its attendant radiation) in the evaluation of the pediatric chest. New Faculty Bring Research, Clinical Strength Psychiatric Care Expands to Green Township We have opened a partial psychiatric hospitalization program at Cincinnati Children’s new campus in Green Township. The program provides five to 10 days of intensive therapy while allowing patients to continue residing at home. Thanks to a generous donation from the Pichler family, our Green Township program brings our partial hospitalization capacity to about 4,000 patient days a year. Overall, our outpatient services grew to more than 29,000 visits this year. Jason Woods, PhD, was appointed Director of the Center for Pulmonary Imaging Research. Woods is a leading expert on using hyperpolarized-gas MRI to measure lung function. Anjaparavanda Naren, PhD, recently joined our faculty. His research focuses on understanding the structural and functional aspects of cystic fibrosis transmembrane conductance regulator (CFTR) ion-channel biology. Satish Madala, PhD, was promoted to assistant professor and was awarded a Parker B. Francis Fellowship to initiate his research program on the “Molecular Mechanisms of TGFα-driven Pulmonary Fibrosis.” Expanded Informatics Capability Our Radiology Informatics team has extended the capabilities of the PACS system by increasing the archive space, implementing disaster recovery capabilities, and creating a method for secure, remote access to the research system. These enhancements have allowed Cincinnati Children’s researchers to lead multi-institutional research trials. Our team also was recognized this year with a second place Innovation Award from the Society of Imaging Informatics in Medicine. 58 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 59 DIVISION ACCOMPLISHMENTS DIVISION ACCOMPLISHMENTS Reproductive Sciences How Testosterone Affects Fetal Development Tony DeFalco, PhD, published a study, “Testosterone levels influence mouse fetal Leydig cell progenitors through Notch signaling” in April 2013 in Biology of Reproduction. The journal also used an image from the paper as its cover image for that issue. Following publication, the NICHD chose the cover image as part of their hallway dedicated to various grantees and NICHD investigators. Rheumatology New Therapies for Juvenile Idiopathic Arthritis (JIA) Phase III clinical trials were published by Daniel Lovell, MD, MPH, and Hermine Brunner, MD, MSc, MBA, as contributors to large multi-center studies. They found canukinumab and tocilizumab to be highly effective treatments of the systemic form of JIA that block the cytokines IL-1 and IL-6, respectively. The systemic form of JIA is responsible for 75 percent of the deaths associated with JIA. Sports Medicine Research Team Earns Neuromuscular Training Awards Greg Myer, PhD, Sports Medicine Research Director, continues to lead a team of successful researchers in neuromuscular training. His team won the 2013 American Journal of Sports Medicine Systematic Review Award and the 2013 Clint Thompson Recognition for Clinical Advancement award in the Journal of Athletic Training. Myer also collaborated with Eric Wall in Orthopedics to win the 2012 AOSSM Innovative Outcomes Assessment Grant for “Optimization and External Validation of Non-invasive Outcome Prediction Algorithm for Knee Osteochondritis Dissecans in Children.” Urology Clinical Services Rise to No. 3 in Nation We moved up to third in the nation in the US News & World Report ranking of pediatric urology programs. Our ranking reflects unique services such as our Center for Disorders of Sex Development (DSD), which provides care for children with congenital chromosomal, gonadal or anatomical variations of sex development; and our Urogenital Center, which treats highly complex genitourinary conditions involving abnormalities of the bladder, urethra, vagina and anorectum. We also have established the Stone Center to offer coordinated care management of patients with stone disease of the urinary system. Top Ten Project in Reproductive Medicine A paper from the laboratory of S.K. Dey, PhD, was chosen as one of the “Top Ten Projects in Reproductive Medicine: Debating Breakthrough Basic and Clinical Papers with their Authors,” presented at the Serono Symposia International Foundation in Italy on Sept. 20, 2013. The paper, “Aberrant cannabinoid signaling impairs oviductal transport of embryos,” was published in Nature Medicine in 2004. It was selected as one of the “Top 5 in Basic Science” by the conference expert panel. Two Phase III clinical trials find canukinumab and tocilizumab to be highly effective treatments for systemic form of JIA. New Informatic Tools Expanding Staff and Programs Transcription factors are very important in the coordination of gene expression, making possible nearly all cellular processes. Understanding the precise sequence that they bind in DNA is important to explaining how healthy cellular processes occur (growth, division, differentiation) as well as pathological processes such as cancer, anemia and inflammation. Matthew Weirauch, PhD, with colleagues in Toronto, evaluated the relative merit of alternative ways of evaluating transcription factor binding, leading to important methodologic advances for understanding these enigmatic and critically important proteins. Adam Kiefer, PhD, a researcher in virtual reality and postural coordination, joined us this year. We also added clinical faculty Kate Berz, DO, Greg Walker, MD, and new Division Director Kelsey Logan, MD, MPH, all of whom share research interests in concussion. Over the past year, a new Sports Medicine Outreach Program has been funded and staffed to provide training coverage and services to local high schools, clubs, organizations and local tournaments. Our division rose from 4th to 3rd in the nation in the US News & World Report ranking of pediatric urology programs. Surgeons Share Expertise Overseas Pramod Reddy, MD, traveled to India and Eugene Minevich, MD, traveled to Israel to perform complex urological surgeries. Several faculty members also were invited to present at international pediatric urology conferences: W. Robert DeFoor, Jr., MD, MPH, in England; Minevich in England and Italy; Reddy in India, Hungary and the United Arab Emirates; and Paul Noh, MD, in South Korea. Micro-RNAs in Inflammation Outstanding Accomplishments for Graduate Student Leading Basic and Clinical Research Jeeyeon Cha, MD, PhD, completed her PhD this June. She was the first graduate student from the Division, and was awarded her PhD “with outstanding accomplishments.” Cha was lead author on a major paper in preterm birth, “Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions,” which was published in the Journal of Clinical Investigation in August 2013. This study also was highlighted by Biology of Reproduction in its “World of Reproductive Biology” section. Micro-RNAs appear to inhibit the expression of specific genes in cells. Nan Shen, MD, and John Harley, MD, PhD, collaborated with scientists in China to explore the properties of these molecules in inflammation. They found that microRNA 31 contributes to the impaired production of the cytokine IL-2 in systemic lupus erythematosus. They also show that the cytokine IL-17 contributes to autoimmune pathogenesis by suppressing the expression of micro-RNA 23b, which in turn inhibits expression of IL-17, TNFα, and IL-1β making a complex web of gene expression control. Reddy has focused on studying changes in bladder function and morphology induced by social stress in a mouse model. He also leads a clinical trial to evaluate festerodine as a treatment for neurogenic detrusor overactivity. Joo-Seop Park, PhD, investigates nephron progenitors during nephrogenesis. DeFoor is principal site investigator on an NIH clinical trial, “Randomized intervention for children with vesicoureteral reflux (RIVUR).” DeFoor and Minevich are evaluating the use of Deflux for VUR patients receiving endoscopic correction. DeFoor also is in a clinical trial using Botox to treat urinary incontinence. Elizabeth Jackson, MD, is studying “Nocturnal Enuresis: Comparison of Buzzer and Voice Alarms on the Rate of Resolution of Bedwetting.” 60 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 61 2013 FACULTY & CLINICAL STATISTICS 2013 FACULTY & CLINICAL STATISTICS AWARDS & FUNDING by the numbers awards, funding, and statistics for 2013 62 62 CINCINNATI CHILDRENâ€™S RESEARCH FOUNDATION Overall Sponsored Program Awards $171,185,001 National Institutes of Health Awards $122,073,374 140,000,000 140,000,000 120,000,000 120,000,000 100,000,000 100,000,000 80,000,000 80,000,000 60,000,000 60,000,000 40,000,000 40,000,000 20,000,000 20,000,000 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2013 2010 2011 2012 2007 2008 2009 2004 2005 2006 0 Indirect Funds Direct Funds Approximately $6.8 million of ARRA awards received in FY10 were awarded for a two-year period. All are shown in FY10. Approximately $13.7 million of ARRA awards received in FY11 were awarded for a three-year period. All are shown in FY11. CINCINNATICHILDRENS.ORG/RESEARCH 63 2013 FACULTY & CLINICAL STATISTICS 2013 FACULTY & CLINICAL STATISTICS EXTERNAL FUNDING Distribution of Funding FY2012 STATE 1% OTHER 8% INDUSTRY 10% FEDERAL 81% Sources of Federal Funding National Institutes of Health (NIH) Health Resources & Services Administration(HRSA) Agency for Healthcare Research and Quality(AHRQ) Department of Defense Army (DOD) Centers for Disease Control (CDC) US Department of Education US Department of Agriculture Department of Health and Human Services(DHHS) Food & Drug Administration (FDA) National Science Foundation(NSF) Department of Veteran Affairs USAF/AFMC Department of Justice Foundation & Other Agency Awards 122,073,374 3,013,974 2,808,821 2,166,980 1,719,926 948,517 478,151 475,770 450,467 384,016 107,343 56,483 48,087 31,440 24,669 $ 134,788,018 Ohio Children’s Hospital Association Fdn Bill & Melinda Gates Foundation Ohio Department of Jobs & Family Services Ohio Department of Health American Heart Association Miscellaneous Other (115) Total 4,103,146 3,091,072 1,220,286 875,361 670,001 11,823,075 $ 21,782,941 FY 2012 Distribution of Funding FY2013 STATE 1% OTHER 11% INDUSTRY 9% FEDERAL 79% US Department of Housing & Urban Development (HUD) US Army Total NIH $122,073,374 FY 2013 Federal funding sources shown right to left as listed above 64 64 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 65 2013 FACULTY & CLINICAL STATISTICS 2013 FACULTY & CLINICAL STATISTICS OUR FACULTY TRAINING Students Triple Board Pediatrics/Neurology Senior Medical Students entered Medicine/Pediatric Training Senior Medical Students entered Pediatric Training 1 3 9 13 168 194 Pediatrics FULL-TIME 642 PART-TIME 87 Surgery FULL-TIME 84 PART-TIME 10 Junior Medical Students in the Pediatric Clerkship Total 194 Residents Psychology 6 6 7 7 10 12 13 21 28 34 117 140 401 729 94 Pediatric Physical Medicine and Rehabilitation (PM&R) Dermatology Human Genetics/Pediatrics Dental Anesthesia Psychiatry/Child Psychiatry/Pediatrics Neuro/Pediatrics Medicine/Pediatrics Radiology Pediatrics Surgery * 401 Anesthesia FULL-TIME 37 PART-TIME 13 Radiology FULL-TIME 43 PART-TIME 9 Total *Includes General Surgery, Pediatric Adolescent Gynecology, Cardiothoracic, Neurosurgery, Otolaryngology, Ophthalmology, Plastic, Orthopedic & Urology Pediatric House Staff Recruitment HG Pediatrics Interviewed PM&R Candidates Interviewed Neuro/Pediatrics Interviewed Psychiatry/Child Psychiatry/Pediatrics Interviewed Medicine/Pediatric Candidates Interviewed Pediatric Candidates Interviewed Total 50 52 7 9 29 29 70 276 420 420 Categories appear in clockwise order as listed to the left. 66 66 CINCINNATI CHILDRENâ€™S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 67 2013 FACULTY & CLINICAL STATISTICS 2013 FACULTY & CLINICAL STATISTICS FELLOWS Research Postdoctoral Fellows / 158 Research Fellows / 55 PROCTER SCHOLARS 213 TOTAL Year Adolescent Medicine + Transition Medicine Allergy/Immunology Anesthesia + ABA Alternate Pathway Cardiology + Fetal Cardiology + Heart Failure, Cardiomyopathy & Transplant + Interventional Cardiac Cath Child Abuse Critical Care Developmental Disabilities Emergency Medicine Endocrinology Gastroenterology +Pediatric Transplant Hepatology Division of General Pediatrics + Pediatric Master Educator + Pediatric Primary Care Research Hematology/Oncology + Clinical Immunodeficiency + Neuro-Oncology 3 2 1 Tanya Kowalczyk Mullins, MD Adolescent Medicine Adolescent Sexual Behavior and Incident Sexually Transmitted Infections Kasiani Myers, MD BMT & Immune Deficiency Leukemogenesis and Genomic Instability in Fanconi Anemia Elizabeth Schlaudecker, MD Infectious Diseases Influenza Infection and Immunization in Pregnancy 3 0 4 12 1 11 1 1 1 2 12 4 11 9 12 1 2 2 14 1 1 Hospital Medicine Infectious Disease Medical Genetics + Clinical Biochemical Genetics + Clinical Cytogenetics + Clinical Molecular Genetics Neonatology Nephrology + Acute Care Nephrology & Dialysis Neurology + Clinical Neurophysiology + Clinical Neurosciences + Pediatric Epilepsy + Pediatric Neuromuscular Neurosurgery Ophthalmology Orthopaedics + Hand & Upper Extremity Surgery + Surgery of the Spine Otolaryngology Pathology Plastic Surgery 3 5 0 1 1 2 12 5 1 0 1 1 1 1 0 2 1 1 6 0 1 Psychiatry Psychology Pulmonary Quality Scholars in Transforming Health Care Radiology + Body MRI + Pediatric Neuroradiology Rehabilitation Medicine Rheumatology Sleep Disorder Medicine Sports Medicine Surgery + Pediatric and Adolescent Gynecology + Colorectal Surgery + ECMO + Fetal Surgery + Pediatric International Surgical Fellow + Trauma Surgery + Vascular Anomalies Urology + International Pediatric Urology Fellow 5 16 7 1 8 0 2 2 5 2 2 2 1 2 0 1 1 1 1 2 2 Stephanie Merhar, MD Neonatology Safety, Tolerability and Efficacy of Levetiracetam as Initial Monotherapy for the Treatment of Neonatal Seizures Year Jonathan Howell, MD, PhD Endocrinology Investigating the Regulatory Pathways that Control Endocrine Cell Function within the Pancreas and Intestine Amy Shah, MD, MS Endocrinology Exploring HDL’s In Vitro Functions in Youth with Type 2 Diabetes Brian Varisco, MD Critical Care Medicine Chymotrypsin Like Elastase-1 Regulates Pulmonary Vascular Morphogenesis Year Benjamin Mizukawa, MD Oncology Targeting CDC42 in Leukemia Stem Cells Andrew Beck, MD, MPH General & Community Pediatrics Bringing Neighborhood Phenotypes and Geomarkers to the Bedside for Children with Asthma 68 68 CINCINNATI CHILDREN’S RESEARCH FOUNDATION CINCINNATICHILDRENS.ORG/RESEARCH 69 2013 FACULTY & CLINICAL STATISTICS 2013 FACULTY & CLINICAL STATISTICS CLINICAL ACTIVITY Clinical Activity & Outpatient Visits Admissions Breakdown 23 HOUR ADMISSIONS 12,560 MEDICAL 12,007 SURGICAL (I/P SURGERIES) 6,237 RESEARCH & PUBLICATIONS Publications 30,804 admissions in 2013 1,141,420 1,694 Peer-reviewed articles 126 Chapters of Books 79 Non-peer-reviewed articles 21 Online site contributions 1 Books (edited or authored) outpatient visits in 2013 TYPE Sub-specialty Care Burnet NUMBER 504,358 Total Publication Contributions in FY2013 Summer Research Programs 1,921 Outpatient Liberty 136,642 Emergency Room Visits Primary Care (PPC) Burnet, Hopple, Batesville & Fairfield Outpatient Mason Outpatient Kentucky Outpatient Anderson Outpatient Fairfield Surgical procedures Outpatient Eastgate Outpatient Drake Outpatient Harrison Outpatient Green Township Outpatient Kenwood 70 70 CINCINNATI CHILDREN’S RESEARCH FOUNDATION 127,376 78,905 23 HOUR ADMISSIONS 74,348 51,136 42,538 40,076 25,951 HIGH SCHOOL INTERNS / 15 UNDERGRADUATE STUDENTS / 142 16,187 10,938 7,207 1,639 MEDICAL 24,119 SURGICAL 183 TOTAL MEDICAL STUDENTS / 26 CINCINNATICHILDRENS.ORG/RESEARCH 71 2013 Annual Report 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 © 2013 Cincinnati Children’s Hospital Medical Center Editorial Tim Bonfield, Managing Editor Tanya Bricking Leach Mary Silva Design & Illustration The Fairview Agency Photography Michael Wilson Julie Kramer For a more detailed look at our research, publications, and faculty, go to www.cincinnatichildrens.org/research13 About the cover: This confocal microscope image of an intestinal cell comes from the laboratory of James Wells, PhD. His team is one of several nationwide working on a large, federally funded project to develop tissue chips for improved drug testing. Cincinnati Children’s leads an effort to develop 3-D organoids that can mimic human intestinal function. CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER 3333 BURNET AVE, MLC 9012 CINCINNATI, OH 45229-3026 Cincinnati, Ohio Permit No. 4167 PAID Nonprofit Org. US Postage