A N E W E R A I N P E D I AT R I C R E S E A R C H
We’re seeking answers on behalf of children everywhere. Our researchers span the spectrum of pediatric research with the common goal of discovery and innovation to improve the health and quality of life for children and their families.
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Abigail Wexner Research Institute
Abigail Wexner Research Institute
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THE ABIGAIL WEXNER RESEARCH INSTITUTE AT NATIONWIDE CHILDREN’S HOSPITAL
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he Research Institute at Nationwide Children’s has been renamed in honor of Abigail Wexner, whose ongoing, passionate advocacy has ushered in a period of unprecedented transformation at the hospital. During her more than 25 years on the board of directors, Nationwide Children’s has become one of the leading pediatric health care systems in the United States, and the Abigail Wexner Research Institute has become one of the most preeminent centers of its kind. Ms. Wexner began serving on Nationwide Children’s board in 1993 and acted as board chair for seven years from 2005 to 2012. During her tenure as chair, Ms. Wexner led the hospital through the largest expansion in its 127-year history, including completion of a 12-story hospital building and a third research building, with more than $1.2 billion in regional economic impact.
“I am extraordinarily proud of the significant impact that Nationwide Children’s has, not only on the well-being of central Ohio’s children but also on the advances in research that support the health of children around the world. Impact of this magnitude doesn’t happen without visionary leadership, dedicated staff and a supportive community. It has been an honor to work alongside Dr. Allen and the team and witness firsthand the transformation of this institution. One simply cannot help but be inspired and want to do as much as possible to fuel further advances.” – Abigail Wexner Ms. Wexner was at the forefront of strengthening the central Ohio community’s response to family violence through the successful merging of the Center for Child and Family Advocacy with the Columbus Coalition Against Family Violence to create The Center for Family Safety and Healing on the campus of Nationwide Children’s. Since its inception in 2011, Mrs. Wexner has served as board chair. The Wexner family has provided crucial philanthropic support for Nationwide Children’s. With their most recent $20 million gift to The Center for Family Safety and Healing, in tandem with funds raised through the New Albany Classic, the family’s cumulative personal giving and philanthropic impact now exceed more than $80 million. This transformational funding has enabled Nationwide Children’s to expand clinical and research programs as one of America’s premiere pediatric leaders.
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Abigail Wexner Research Institute
THE ALLEN DISTINGUISHED SCHOLAR IN PEDIATRIC RESEARCH
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n nearly 13 years as CEO, Steve Allen, MD, helped build Nationwide Children’s into a renowned pediatric research institution, including overseeing an increase from $41.7 million to $105.9 million in external research awards. Nationwide Children’s is currently ranked fifth in the country for National Institutes of Health funding among freestanding children’s hospitals. In recognition of Dr. Allen’s role in the evolution of Nationwide Children’s as a leader in pediatric research and health care, Nationwide Children’s has established the Allen Distinguished Scholar in Pediatric Research. The award will be given to a preeminent Nationwide Children’s senior researcher who exemplifies the innovation at the Abigail Wexner Research Institute.
“Nationwide Children’s is a premier academic medical center creating world-renowned research because of Abigail Wexner’s leadership. I am honored by the creation of the Allen Distinguished Scholar in Pediatric Research as part of the hospital’s continuing efforts to support scientific pioneers in the Abigail Wexner Research Institute.” – Steve Allen, MD
GROWTH OF EXTERNAL RESEARCH FUNDING AT NATIONWIDE CHILDREN’S $120 105.9 $100
92.2 83.7
MI L L I O N S
$80 64.8 $60
79.2 81.7 70.7
69.4 57.9
66.3
49.4 $40 $20 $-
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Abigail Wexner Research Institute
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Abigail Wexner Research Institute
GROUNDBREAKING GENE THERAPY RESEARCH FOR NEUROMUSCULAR DISEASES Jerry Mendell, MD, Receives Inaugural Allen Distinguished Scholar Award
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he inaugural recipient of the Allen Distinguished Scholar in Pediatric Research, Jerry Mendell, MD, is a principal investigator in the Center for Gene Therapy and renowned researcher in neuromuscular disorders. Dr. Mendell has been a pioneer in the care of neuromuscular diseases for more than 40 years. He was the first to standardize and publish on the treatment of Duchenne muscular dystrophy with corticosteroids. In 2007, he led the first-ever phase 1 clinical trial using adeno-associated viral vector (AAV) based gene therapy in children with muscular dystrophy. He completed the first exon-skipping clinical trial in North America for selected genotypes of muscular dystrophy, which ultimately led to the U.S. Food and Drug Administration’s approval of eteplirsen. He is currently the clinical leader for a number of gene therapy trials for children with muscular dystrophies. The inaugural award includes $100,000 in support of Dr. Mendell’s work.
“For most of my career as a physician and researcher, we’ve had very little to offer families with neuromuscular disorders. Now, we’re starting to see that gene therapy can be a safe and effective treatment for some disorders. We’re on the cusp of a new era in targeted therapeutics, and it’s exciting to be part of it.” – Jerry Mendell, MD GENE THERAPY FOR SPINAL MUSCULAR ATROPHY TYPE 1 Harnessing the ability of a virus to deliver genetic material to a cell to treat, cure or prevent disease has been the long time goal of researchers working in gene therapy. Over the past 30 years, the journey to gene therapy has been fraught with challenges and roadblocks. But in 2017, after countless starts and stalls along the road, the field experienced many breakthroughs. No breakthrough received more attention than when researchers from the Abigail Wexner Research Institute at Nationwide Children’s and their colleagues at The Ohio State University published the astonishing results of the phase 1 clinical trial of gene therapy for spinal muscular atrophy type 1 (SMA1) in the New England Journal of Medicine. The SMA1 early phase trial, led by Dr. Mendell, demonstrated extended survival and increased achievement of milestones previously unseen in the natural course of the disease — a devastating, progressive neuromuscular disease that typically results in death by age 2. An intravenous injection of AVXS-101, a modified adeno-associated virus serotype 9 (AAV9), delivered the survival of motor neuron (SMN) gene. The study was the People’s Choice for Science Magazine’s Breakthrough of the Year in 2017. And Dr. Mendell received the Distinguished Clinical Research Achievement Award for the work from the Clinical Research Forum in 2018.
Abigail Wexner Research Institute
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Abigail Wexner Research Institute
TAYLA’S STORY: BATTEN DISEASE “
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hen Tayla was diagnosed in Australia, we were told to take her home and love her while we could,” her mother says. “We were devastated and left without hope.”
But her family didn’t give up. They began scouring the research for more information about their daughter’s disease — Batten disease — and found a clinical trial for an enzyme replacement therapy in Columbus, Ohio. Batten disease is a congenital, progressive and terminal neurological disease. The most common form CLN2 (neuronal ceroid lipofuscinosis type 2) is caused by the lack of the TPP1 (tripeptidyl peptidase 1) enzyme. “I always told parents this is a brain disorder that will result in the early death of your child and that you may see your child melt before your eyes,” says Emily de Los Reyes, MD, neurologist and director of the Nationwide Children’s Batten Disease Center of Excellence. “Now, I can tell them that we have a treatment.” Tayla’s family moved across the world, hoping to find a place in the trial. “We were fortunate enough to be accepted into the clinical trial at Nationwide Children’s Hospital. I think most parents will do whatever they need to do to save their child,” says Tayla’s mom. “Travelling across the world is what we had to do.” “We made the call,” says Tayla’s dad. “And the rest, well, we’re here. We’re where we are because of the clinical trial that enabled her to get this drug.” To date, the drug cerliponase alfa, which was approved for use by children with CLN2 Batten disease by the FDA in April 2017, has an 84% response rate. For families like Tayla’s, that’s a miracle.
“Researchers are saving lives and giving us precious time with our children to create memories” Tayla’s mom says. “Our family can now look into the future and have hope.”
Abigail Wexner Research Institute
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LEADERSHIP
John A. Barnard, MD President
Lauren O. Bakaletz, PhD Vice President, Basic Sciences Research
Deena Chisolm, PhD Vice President, Health Services Research
William E. Smoyer, MD Vice President, Clinical Research
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Abigail Wexner Research Institute
Dennis R. Durbin, MD, MSCE Chief Scientific Officer
Amy J. Roscoe Vice President, Strategic Planning and Finance
Veronica J. Vieland, PhD Vice President, Computational Research
OUR STRATEGIC PLAN
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ationwide Children’s strategic plan is aptly named Journey to Best Outcomes. It is the journey that each clinician, researcher, family and patient strives for in and through every interaction with the institution. The Abigail Wexner Research Institute supports the pillars of the Journey to Best Outcomes. The plan involves recruiting the best people to oversee and improve the best programs to culminate in the best possible outcome for all children — even those who never set foot on our campus.
Nationwide Children’s aggressively supports the discovery of new knowledge to advance child health and well-being. Comprehensive integration of our pre-eminent clinical and research programs is the central goal for the strategic plan, with key areas of emphasis in genomic medicine, population health, quality and safety, and behavioral health.
“Unprecendented investment in our discovery mission at Nationwide Children’s has paved the way for tremendous progress. We have put into place a sophisticated infrastructure that supports facile movement of laboratory discoveries into the clinical arena. The impact on children who previously had little hope has been truly remarkable.” – John Barnard, MD
Abigail Wexner Research Institute
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Abigail Wexner Research Institute
THE SYLVESTER FAMILY STORY: RSV
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hen Sarah and Matt Sylvester’s infant daughter Addy tragically died of respiratory syncytial virus (RSV) infection, they were devastated.
Years later when their son Michael was born, Sarah noticed a flyer about a clinical trial for RSV at Nationwide Children’s Hospital that was enrolling healthy controls. “RSV is a very common infection in infants and young children — almost everyone will be infected by age 2. In the United States, 2-3% of all infants infected with RSV will be hospitalized,” says Octavio Ramilo, MD, division chief of Infectious Diseases and principal investigator in the Center for Vaccines and Immunity. Dr. Ramilo, Mark Peeples, PhD, and Asuncion Mejias, MD, PhD, and their collaborators are working to understand how the immune system responds to RSV so they can develop a safe and effective vaccine against it. “I never would have known what RSV was if it hadn’t been for Addy. And without being involved in anything medically, research didn’t really cross my mind,” says Sarah. “But the flyer caught my eye, and I knew this was something we could do so that someday no family would have to experience the loss that we felt.” They went on to enroll Michael as a healthy infant in the clinical trial when he was 5 months old, and have since become advocates for participating in clinical research — even when your child is healthy. In fact, they plan to enroll their youngest son Noah in the healthy baby study as well.
“Our passion for and personal connection to this research motivate us to participate,” says Sarah. “But the caring and understanding we experienced from the research staff have made it a really positive experience. Our children aren’t directly benefiting from this research – we’re doing it for someone else’s children. And that’s what the research community is doing, too. We’re all connected in that.”
Abigail Wexner Research Institute
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OUR CENTERS AND INSTITUTES The Abigail Wexner Research Institute is organized into centers of emphasis and the Institute for Genomic Medicine, all of which facilitate interdisciplinary team science by transcending traditional academic boundaries. The structure supports discovery, enabled by outstanding shared resources. Each center or institute is home to talented faculty members, staff, graduate students, residents, postdoctoral fellows and other students. • Battelle Center for Mathematical Medicine
• Innovation in Pediatric Practice
• Biobehavioral Health
• Institute for Genomic Medicine
• Cardiovascular Research
• Microbial Pathogenesis
• Childhood Cancer and Blood Diseases
• Perinatal Research
• Clinical and Translational Research
• Regenerative Medicine
• Gene Therapy
• Vaccines and Immunity
• Injury Research and Policy
At the Abigail Wexner Research Institute, collaboration and integration aren’t just ideals. They are our reality. In the pages that follow are stories about research made possible by our culture, resources and integration with our world-class clinical teams.
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Abigail Wexner Research Institute
A Path for Tissue Engineered Vascular Grafts
I CENTER FOR REGENERATIVE MEDICINE OFFICE OF TECHNOLOGY COMMERCIALIZATION CARDIOTHORACIC SURGERY RADIOLOGY 3D PRINTING CLINICAL MANUFACTURING FACILITY
n the first clinical trial of tissue engineered vascular grafts (TEVGs) Christopher Breuer, MD, pediatric surgeon and director of the Center for Regenerative Medicine, and Toshiharu Shinoka, MD, PhD, principal investigator and cardiothoracic surgeon, successfully implanted TEVGs in patients undergoing the Fontan procedure for complex congenital heart disease. TEVGs are superior to other options for pediatric congenital heart patients for several reasons — the most important of which is the graft’s growth capacity. TEVGs don’t require immunosuppression or anti-rejection medications because they are made of the patient’s own cells. And they grow with the child, decreasing the number of follow-up surgeries needed. Now, they are developing a second trial funded by the National Institutes of Health, using what they’re learning along the way to develop new strategies for TEVGs. Some of those strategies are designed to reduce or eliminate narrowing in the graft. Others are aimed at increasing access to the technology by developing a closed disposable system — essentially a portable clean room. And still others are aimed at using three-dimensional printing to develop scaffolds customized to a patient’s individual anatomy. “To take advantage of patient-specific modeling and customized regenerative implants to yield an optimized patient-specific TEVG is a natural extension of the progress in both fields,” says Dr. Breuer. “The implementation of the closed disposable system takes the concept a step further and would increase the accessibility of TEVG.”
Christopher Breuer, MD
Toshiharu Shinoka, MD, PhD Abigail Wexner Research Institute
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Looking for the Genetic Clues to Congenital Heart Disease
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multidisciplinary group of researchers including Vidu Garg, MD, director of the Center for Cardiovascular Research, Kim McBride, MD, MS, division chief of Genetic and Genomic Medicine, and Peter White, PhD, senior director of Computational Genomics in the Institute for Genomic Medicine, published the first study to demonstrate that data from whole exome sequencing (WES) can be applied to clinical testing of congenital heart disease (CHD).
CENTER FOR CARDIOVASCULAR RESEARCH
Using next generation sequencing technology, combined with advanced data techniques, the researchers looked for places in the genome where affected family members’ DNA differed from that of their healthy relatives. The study identified the genetic cause of CHD in three of the nine families tested, despite having only limited genetic information from affected family members in some cases.
INSTITUTE FOR GENOMIC MEDICINE RESEARCH INFORMATION SOLUTIONS AND INNOVATION
“This study demonstrates the benefits of utilizing previously identified causative genes in combination with modern sequencing techniques to diagnose the genetic cause of CHD in patients with familial CHD,” says Dr. Garg. In an effort to bridge the gap between the genomics lab and the cardiology clinic, Drs. Garg, McBride and White also worked with Simon Lin, MD, MBA, chief research information officer in Research Information Solutions and Innovation, and his team to develop CardioGX, a free cloud-based platform that empowers clinicians and researchers to find new genetic mutations that cause heart disease. The interactive web application enables users to upload, explore and analyze de-identified data generated through genomic sequencing.
Vidu Garg, MD
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Kim McBride, MD, MS
Abigail Wexner Research Institute
Peter White, PhD
Simon Lin, MD, MBA
Building a Genomic Protocol for Pediatric Cancer
T INSTITUTE FOR GENOMIC MEDICINE CENTER FOR CHILDHOOD CANCER AND BLOOD DISEASES HEMATOLOGY, ONCOLOGY & BMT
he Cancer Protocol, developed through a collaboration between the Institute for Genomic Medicine’s leadership team and leaders in the Division of Hematology, Oncology & Blood and Marrow Transplant, reviews patient candidates for genomic profiling submitted by hospital oncologists. In most cases, the nominees have tumors that did not respond to prior rounds of therapy or that came back after remission. Selected patients are invited to consent to have a full genomic analysis performed. “Many centers utilize a small gene panel or test about 100 to 500 genes,” says Elaine Mardis, PhD, co-executive director of the IGM and president of the American Association for Cancer Research for 2019-2020. “We look at both tumor and normal cells for all patients and do a thorough comparison across all known human genes. We look for susceptibility genes for their cancer risk by studying normal cells, and we look across the entire cancer genome plus their RNA for clues to what might be driving their cancer. That level of comprehensive study is not very common.” Although this is still a research-based study, the team identifies potentially clinically important findings that are then subjected to existing clinical testing options. By doing so, if they validate the findings, the relevant clinical information can be recorded in the medical record and, ideally, may identify alternative treatment options or offer a clue to likely outcomes. “We want to get to the point where a comprehensive genome analysis is available to every patient who comes here with a cancer diagnosis,” says Dr. Mardis.
Elaine Mardis, PhD
Abigail Wexner Research Institute
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A Newborn. A Virus. A Novel Treatment. A Life Saved.
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ver the course of just six days last year, Nationwide Children’s clinicianscientists conceptualized a treatment that had never been tried on a preterm infant before, received an emergency federal approval, and used the treatment to save a life in the Newborn Intensive Care Unit (NICU).
CELLULAR THERAPY AND CANCER IMMUNOLOGY PROGRAM BLOOD AND MARROW TRANSPLANT NEONATOLOGY DRUG AND DEVICE SERVICES HOST DEFENSE PROGRAM
The infant, born at 29 6/7 weeks gestation, was diagnosed with disseminated adenovirus infection at two weeks postpartum. Given the high mortality associated with this infection in a neonate, Jeffery Auletta, MD, director of the Host Defense and Immunocompromised Infectious Diseases Program in the Division of Infectious Diseases and director of the Blood and Marrow Transplant Program, looked outside the box for answers. So, he called Dean Lee, MD, PhD, director of the Cellular Therapy and Cancer Immunology Program at Nationwide Children’s and The Ohio State University Comprehensive Cancer Center, and together they developed a plan. They wanted to take T cells from the mother — who had successfully cleared the infection — and isolate as many of the ones specific to the virus infecting the infant as possible. They would then give the cells to the infant intravenously. They reached out to Kevin Bosse, PhD, RAC, regulatory operations manager in Drug and Device Development Services, to pave the way for the emergency investigational new drug designation. Most IND applications take months to prepare. But with an all-hands-on-deck approach, the team — pulled everything together that they needed for the EIND application in less than 36 hours. After receiving the novel treatment, the infant’s viral load dropped dramatically and the child’s clinical condition improved. The infant was ultimately discharged home and has been doing well ever since.
Kevin Bosse, PhD, RAC | 18 |
Abigail Wexner Research Institute
Dean Lee, MD, PhD
Jeffery Auletta, MD
New Use of a Biomarker Predicts Severity of Community-Acquired Pneumonia
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ommunity-acquired pneumonia (CAP) is a leading cause of hospitalization and mortality in children.
CENTER FOR VACCINES AND IMMUNITY INFECTIOUS DISEASES
“When a child comes to the emergency department with CAP, we often don’t know what’s causing it. And we can’t predict if that patient is going to get worse and have to go to the intensive care unit or if we can send them home with antibiotics,” says Rebecca Wallihan, MD, physician in Infectious Diseases and vice-chair for Education in the Department of Pediatrics. “We know a lot about CAP, but the reality is that we still don’t know enough to be practical.” To address these unknowns, clinicians need a way to quickly and accurately predict disease severity in children with CAP. Octavio Ramilo, MD, division chief of Infectious Diseases and principal investigator in the Center for Vaccines and Immunity, and Dr. Wallihan initiated a clinical study to determine if they could use transcriptional profiling to identify better markers of disease severity in children hospitalized with CAP. They used a novel metric called Molecular Distance to Health (MDTH) — a single numerical score that summarizes the overall change in expression of immune-related genes in a patient compared to a healthy, age-matched control. “Our approach gives us a detailed sense of how the immune system is responding to each case of CAP, and this score directly correlates with the severity of disease,” says Dr. Ramilo. “Looking at the host in addition to the pathogen is a key aspect.” “We are trying to build a database of the knowns, and use that data to reveal the unknowns,” he adds. “This study has been the first return on an investment that we hope will eventually lead to best outcomes for children with CAP worldwide.”
Rebecca Wallihan, MD
Octavio Ramilo, MD Abigail Wexner Research Institute
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Could Antimicrobial Peptides Be Biomarkers for Obstructive Uropathy?
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CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH NEPHROLOGY UROLOGY
ntimicrobial peptides (AMPs) may play a role in obstructive uropathy. Upon investigating the urine of children undergoing surgery for ureteropelvic junction obstruction (UPJO), a team of researchers and physicians at Nationwide Children’s identified a significant increase in the expression of AMPs compared to age- and sex-matched healthy controls. “Currently, our methods for diagnosing urinary tract obstruction rely on imaging techniques that are at times nonspecific and can subject the patient to radiation. Other potential less-invasive means of diagnosing urinary tract obstruction in the form of biomarkers are needed,” says Christina Ching, MD, urologist and principal investigator in the Center for Clinical and Translational Research. A significant and sensitive relationship between AMP expression and obstructive uropathy could result in numerous potential clinical applications for AMP tests, including prediction of the clinical course of congenital hydronephrosis, confirmation of obstructive kidney injury requiring surgery, prediction of risk for UPJO-related infections, indication of the degree of recovery after surgery and much more. “The next step is to look longitudinally rather than taking a cross-sectional approach. That will help us understand how AMP levels vary over time and among patients with different ages, sex, ethnicity, disease severity, surgical and disease outcomes and other clinical differences,” says Brian Becknell, MD, PhD, a nephrologist and principal investigator in the Center for Clinical and Translational Research. “That information will help tell us whether the AMP levels have predictive value and how specific they can be for a variety of pathologies.” The joint Urology and Nephrology research team at Nationwide Children’s has several AMP-related investigations planned or underway, including basic research to understand the role of AMPs in infectious and non-infectious injury to the urothelium and their potential clinical utility.
Brian Becknell, MD, PhD | 20 |
Abigail Wexner Research Institute
Christina Ching, MD
Investigating the Benefits of Supplements for Cognitive Development in Toddlers Born Preterm
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esearch from the Center for Perinatal Research and the Center for Biobehavioral Health aims to overcome some of the challenges to studying dietary and supplementary omega fatty acids that have plagued investigators in the past.
CENTER FOR PERINATAL RESEARCH CENTER FOR BIOBEHAVIORAL HEALTH
“One of the biggest challenges this area of research faces is inconsistencies among previous studies,” says Lynette Rogers, PhD, interim director of the Center for Perinatal Research. “If you look at the research on omega fatty acid supplementation in neurodevelopmental disorders alone, the methodologies and supplements used are so diverse that a meta-analysis is nearly impossible.” Dr. Rogers is part of a multi-institutional team investigating the use of docosahexaenoic acid (DHA), an omega-3 fatty acid, to prevent preterm birth in a project called the ADORE (Assessment of DHA On Reducing Early preterm birth) clinical trial. The ADORE trial aims to determine the impact of supplementation in pregnant women. The overall goal is to determine whether omega-3 fatty acid supplementation will lengthen gestation in women who give birth preterm. Investigators are tracking preterm births, inflammation biomarkers and collecting detailed information about the women’s diet. Sarah Keim, PhD, principal investigator in the Center for Biobehavioral Health, has been working with Dr. Rogers to study the impact of omega fatty acid supplements on developmental outcomes in toddlers born prematurely through two studies focused on specific patient populations. Another trial examines how omega fatty acid supplements impact biomarkers related to inflammation and autism spectrum disorder. “Our key areas of focus are on populations and health outcomes where there are no other interventions,” says Dr. Keim. “We’re trying to offer something that is, first and foremost, evidence-based and, secondly, fairly accessible and easy to do.”
Sarah Keim, PhD
Lynette Rogers, PhD Abigail Wexner Research Institute
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Solving the Challenges of Probiotic Applications
O CENTER FOR MICROBIAL PATHOGENESIS CENTER FOR PERINATAL RESEARCH OFFICE OF TECHNOLOGY COMMERCIALIZATION ANIMAL RESOURCE CORE
ne of the problems with traditional approaches to probiotic therapy is the delivery system. For probiotics to work, they must survive the acidity of the stomach and the host immune system, and then take root in the gut, where they are expected to compete with pathogenic bacteria and flourish. All probiotic clinical studies to date have used free-living (planktonic) probiotic formulations, which do not optimally display these required characteristics. Gail Besner, MD, chief of Pediatric Surgery and principal investigator in the Center for Perinatal Research, and Steve Goodman, PhD, Michael Bailey, PhD, and Lauren Bakaletz, PhD, all principal investigators in the Center for Microbial Pathogenesis, recently licensed a technology that solves this problem — administering a probiotic in a biofilm state provides near elimination of necrotizing enterocolitis (NEC) with one dose in preclinical studies. Their probiotic of choice, Lactobacillus reuteri, is incubated with maltose-filled dextranomer microspheres (Lr-DM-M-malt). In one study, the administration of a single dose of Lr-DM-Malt reduced the incidence of NEC from 70% to 21% in the animal model. In a follow-up study, the investigators filled the microspheres with sugars that promoted increased biofilm formation, making the probiotic formulation even more effective. “We know that bacteria are stronger and more resistant in the biofilm state,” says Dr. Goodman. “They are in their optimal physiologic state in a biofilm, and this gives them a better chance to affect the digestive tract.” While studies to date have been focused on the application to NEC, Drs. Besner and Goodman acknowledge that the applications of this probiotic technology are far reaching.
Gail Besner, MD | 22 |
Abigail Wexner Research Institute
Steve Goodman, PhD
Ingestion of Foreign Items, Including Dangerous Button Batteries, on the Rise in Young Children
R CENTER FOR INJURY RESEARCH AND POLICY DIVISION OF GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION
OTOLARYNGOLOGY
esearchers in the Center for Injury Research and Policy and the Division of Gastroenterology, Hepatology and Nutrition analyzed data from the National Electronic Injury Surveillance System (NEISS) for children younger than 6 years who were treated in a U.S. emergency department from 1995 through 2015 due to concern of a foreign body ingestion. The study found that the rate of foreign body ingestions per 10,000 children increased by 91.5%, from 9.5 in 1995 to 18 in 2015. The number of estimated cases among children under 6 nearly doubled from about 22,000, or about 61 per day in 1995 to nearly 43,000, or 118 per day in 2015. “The dramatic increase in foreign body ingestions over the 21-year study period, coupled with the sheer number and profundity of injuries is cause for concern,” says Danielle Orsagh-Yentis, MD, lead author of this study and motility fellow in the Division of Gastroenterology. “Continued advocacy and product regulations are needed to keep children safe, and the data shows that vigilance, advocacy and regulations are effective.” While batteries represented only 7% of all cases, they can do considerable damage when ingested. Even more concerning, battery ingestions increased 150-fold over the study period. Button batteries, found in everyday items like toys, key fobs, and greeting cards, represented 86% of battery ingestions. Kris Jatana, MD, pediatric otolaryngologist and member of the American Academy of Pediatrics’ National Button Battery Task Force, recently published a study that showed honey could attenuate esophageal damage in the case of button battery ingestion. This study influenced new guidelines from the National Capital Poison Center.
Danielle Orsagh-Yentis, MD
Kris Jatana, MD Abigail Wexner Research Institute
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Parents of Chronically Ill Teens in Medical Homes Report Higher Health-Related Quality of Life
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hen teens with special health care needs receive care through a “medical home” — often a primary care provider with overall responsibility for a child’s health — their parents can benefit.
CENTER FOR INNOVATION IN PEDIATRIC PRACTICE PARTNERS FOR KIDS
“A medical home has a lot of benefits for children — we know that from a lot of research — but it has additional benefits for the family as well,” says Laura Chavez, PhD, MPH, a postdoctoral fellow in the Patient-Centered Pediatric Research Program in the Center for Innovation in Pediatric Practice. For this study, researchers recruited and surveyed caregivers of 488 children aged 15 to 18 who have one or more of the 16 most common health conditions reported in the National Survey of Children with Special Health Care Needs (NS-CSHCN). Conditions include allergies, asthma, emotional problems, mental retardation, seizure disorder, heart and blood problems, cerebral palsy, muscular dystrophy and cystic fibrosis. The families surveyed live in urban and suburban areas of central Ohio and rural regions of southeastern Ohio. Investigators identified them through Nationwide Children’s Medicaid accountable care organization, Partners For Kids. “This study shows the value of care coordination and the value of good communications with the family,” says Dr. Chisolm. “The spillover effect may reduce medical related costs for the whole family and may potentially make it worth the investment to expand medical home care.” She suggests prospective studies evaluating the associations could build a case for further investing in the medical home model for vulnerable children and their families.
Laura Chavez, PhD, MPH | 24 |
Abigail Wexner Research Institute
Deena Chisolm, PhD
DNA Variations Associated With Prolonged Walking in Duchenne Muscular Dystrophy
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ome boys who have Duchenne muscular dystrophy may stop walking at age 9, while others may stop walking at 12. Recent research has shown for the first time that two DNA variants are associated with that difference.
CENTER FOR GENE THERAPY BATTELLE CENTER FOR MATHEMATICAL MEDICINE
Kevin Flanigan, MD, director of the Center for Gene Therapy, led what the research team believes is the first genome-wide association study to identify singlenucleotide polymorphisms (SNPs) influencing ambulation in boys with DMD. Veronica Vieland, PhD, director of the Battelle Center for Mathematical Medicine, led the statistical analysis of about 2.5 million SNPs distributed across the entire genome that showed two SNPs to be associated with a delay in loss of ambulation, suggesting the variants are protective. Drs. Flanigan and Vieland, along with their collaborator, Robert Weiss, PhD, of the University of Utah, are now looking for modifiers that influence breathing, heart function and muscle performance in more than 650 DMD patients. “We believe there are other modifiers that will prove important, by both identifying new pathways to target for therapies and by helping to expand our understanding of responses to the gene restorative therapies under development here at Nationwide Children’s and elsewhere,” Dr. Flanigan says. In addition, the findings may inform clinical trials, Dr. Vieland says. “If genetic background is influencing phenotype, we need to know this going in. You may get most of the kids who you expect to do well in one arm of the study — getting the medication or the controls — and that could skew the outcome.”
Veronica Vieland, PhD
Kevin Flanigan, MD Abigail Wexner Research Institute
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Abigail Wexner Research Institute
LAUREN’S STORY: LEUKEMIA AND LATE EFFECTS OF CANCER
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auren survived pediatric leukemia with spirit, style and determination to help others. She staked her claim as an ambassador for kids with cancer in her video diaries chronicling her journey through treatment in the 4th grade. Now, an 8th grader, she remains cancer-free and outspoken about the need for more research into better therapies for pediatric cancer. “Research saved Lauren’s life,” says her father. “When we were at Nationwide Children’s Hospital that first night, the doctors were honest with us that she might not make it through the night. But because of the research that advanced medical care to that moment, she was able to receive treatments that ultimately put her into remission.” Now, on her journey of life after cancer, the late effects of cancer are part of her day-to-day. “I have some effects of chemo and radiation on my brain that affect my ability to do math and remember formulas,” Lauren says. “I also have annual follow-ups with a cardiologist to monitor my heart, as well as regular checks of my liver and kidneys.” “We know that late effects of cancer can impact survivors in many ways throughout their lives,” says Timothy Cripe, MD, PhD, chief of the Division of Hematology, Oncology & Blood and Marrow Transplant. “Research is a critical pathway to better therapies that are more effective and less toxic than traditional chemotherapy and radiation.” Ever the activist, Lauren is well versed on what it takes to make new therapies available to children.
“Every time I get a chance, I encourage people to give to pediatric research. Only 4% of the national research budget goes to kids’ cancer. And most therapies used in kids were developed for adults,” she says. “We need researchers to look for new treatments specifically for kids.”
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RESOURCES AND INFRASTRUCTURE
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he Abigail Wexner Research Institute at Nationwide Children’s Hospital has a wealth of resources available to ensure researchers have the tools they need to advance the hospital’s mission. From core facilities to computational resources and regulatory offices, researchers have the support to enhance the health of children by engaging in high-quality, cutting-edge research according to the highest scientific and ethical standards.
CLINICAL RESEARCH SERVICES
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linical Research Services is designed to be a portal through which clinical investigators access streamlined coordination of services necessary to initiate clinical research projects, regardless of funding source. Support is provided for all clinical research studies from initiation to completion according to Good Clinical Practice and federal, state and institutional regulations and policies. Nationwide Children’s is accredited by the Association for the Accreditation of Human Research Protection Program (AHRPP). This accreditation highlights clinical study participant safeguards that surpass state and federal requirements.
Through the National Institutes of Health Clinical and Translational Science Award, Wexner Medical Center at The Ohio State University, OSU’s seven health science colleges and Nationwide Children’s comprise the OSU Center for Clinical and Translational Science (CCTS). Grace Wentzel, CCRP, director of Clinical Research Services at Nationwide Children’s and Rose Hallarn, program director for Recruitment and Retention Services at the OSU Center for CCTS, work to coordinate shared resources, including clinical trial recruitment and retention services, and funding opportunities for clinical researchers at both institutions.
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GOOD MANUFACTURING PRACTICES CLINICAL MANUFACTURING FACILITY
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he Abigail Wexner Research Institute at Nationwide Children’s is home to a current Good Manufacturing Practices (cGMP) Clinical Manufacturing Facility that operates according to FDA cGMP guidelines to ensure the safety of manufactured biologic products. The CMF is 9000 square feet. It consists of a 7,500 square foot clean room suite with ISO Class 5/7/8 spaces and 1500 square foot of quality control lab
and research production spaces. The biological drug substances are manufactured according to the FDA Guidance for Industry cGMP for Phase I Investigational Drugs, to ensure product safety, identity, purity and strength. The Clinical Manufacturing Facility at Nationwide Children’s is a leading cGMP production facility dedicated to advancing the field of Gene and Cellular Therapy.
“Our mission is to apply our knowledge, resources, technology, and experience to move the field of translational and regulatory science forward, in collaboration with our clients, to develop new, safe and effective treatments for diseases once thought untreatable. Our approach and commitment within the cGMP facility is that there are no diseases too rare and no challenges too difficult to make a difference and give hope to every patient and their family.” – Wade Macedone, executive director and general manager of cGMP The CMF is accredited by both Health Canada and the European Medicines Agency (EMA), in addition to the FDA.
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TECHNOLOGY COMMERCIALIZATION: BRINGING INNOVATION TO PATIENTS EVERYWHERE
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he Office of Technology Commercialization, led by Matthew McFarland, RPh, PhD, facilitates the transfer of new technologies, research and innovations to outside partners to benefit pediatric care, the local community and the general public. Technology Commercialization staff work closely with Nationwide Children’s physicians, nurses, researchers and others to translate ideas and innovations into the commercial sector, bringing new patents, startup companies and inventions. The Office of Technology Commercialization provides financial and administrative support for faculty and staff to make inventions more attractive and less risky for potential licensing and business partners.
STARTUP COMPANIES BASED ON NATIONWIDE CHILDREN’S DISCOVERIES INCLUDE:
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GROWTH IN TECHNOLOGY COMMERCIALIZATION AT THE ABIGAIL WEXNER RESEARCH INSTITUTE 2014
2015
2016
2017
2018
LICENSES/OPTIONS
DISCLOSURES 24
120
22 20
100
18 16
80
14 12
60
10 8
40
6 4
20
2 0
0
Disclosures
U.S. PATENTS ISSUED 60
Licenses/Options
PATENTS FILED 90 80
50 70 40
60 50
30
40
20
30 10 0
20 Patents Issued
10
Patents Filed
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SCIENTIFIC RESOURCES AND CORES
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he Animal Resources Core facilitates preclinical research by providing the highest quality animal husbandry, veterinary care and technical support in an ethical and compliant manner. The Behavioral Outcomes Core assists investigators incorporating behavioral assessments in their research, which can add a practical or applied aspect to research by defining meaningful outcomes from a patientcentered perspective. The Biopathology Center (BPC) serves as a biorepository for projects sponsored by Nationwide Children’s Hospital investigators as well as a large number of national cancer research consortia. The BPC is the repository for many National Cancer Institute-sponsored biorepository-based efforts, including the Children’s Oncology Group, the Gynecologic Oncology Group, SWOG (formerly the Southwest Oncology Group), and the Cooperative Human Tissue Network. The Biospecimen Core Resource (BCR) provides a variety of services including biospecimen processing, banking, distribution and virtual microscopy. The BRC can assist investigators in the planning stages of projects to create budgets, review feasibility and offer biobanking options to ensure quality outcomes. The Biostatistics Resource at Nationwide Children’s Hospital (BRANCH) provides assistance to researchers in study design, data analysis and interpretation of statistical results. The Cell Line Core processes human subject samples and provides the researcher with cell lines or DNA appropriate for applications in human and molecular genetic studies.
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Clinical Research Services (CRS) provides clinical investigators access to streamlined coordination of services necessary to initiate clinical research projects, regardless of funding source. CRS supports all clinical research studies, enabling researchers to manage their studies from beginning to end according to Good Clinical Practice and federal, state and institutional regulations and guidelines. CRS can also facilitate survey research, large data set analyses and psychometrics. Advanced computational expertise in biostatistics, high performance computing and innovation technology solutions are available through Computational Resources. Drug and Device Development Services assist medical faculty and investigators in traversing the process of preclinical and clinical trials while guiding teams through the regulatory landscape. The goal of Drug and Device Development is to guide and smooth the way to FDA approval for investigators involved in therapeutic development. The Flow Cytometry Core offers several platforms for performing flow analysis and cells sorting. Genomics Services offers advanced sequencing technologies to provide high quality genomics as a critical clinical and research resource. The High Resolution Imaging Facility provides a centralized imaging suite for in vivo studies in small animals. The Morphology Core provides services in histology, electron microscopy, confocal and laser scanning microscopy and atomic force microscopy.
ADMINISTRATIVE SUPPORT FOR RESEARCH
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he Institutional Animal Care and Use Committee reviews all research activities involving the use of animals and operates in full accordance with the Animal Welfare Act and the Health Research Extension Act to ensure the humane treatment of animal subjects in research. The Institutional Biosafety Committee is responsible for evaluating and approving all research involving infectious or potentially infectious agents, recombinant DNA or RNA, and biological toxins. The committee ensures compliance with current safety regulations and guidelines as issued by the U.S. departments of Health and Human Services and Agriculture, the NIH, and the Centers for Disease Control and Prevention. International Employee Resources provides expertise in key regulations and procedures, international paperwork and green cards required for employment to ensure a mutually productive and valuable experience.
The Institutional Review Board (IRB) provides oversight of all research involving human subjects. For more than a decade, the IRB has received full accreditation from the Association for the Accreditation of Human Research Protection Programs. The Office of Finance and Sponsored Projects supports grant and contract funding from the start of a search through the closeout of a project, offers expertise in federal and state regulatory requirements, experience negotiating for the maximum award and spending cycle, and assistance with purchasing needs and financial information. The Office of Research Compliance and Integrity ensures all research is conducted according to the highest scientific and ethical standards and in compliance with regulations from the National Institutes of Health, Food and Drug Administration and all other government agencies with authority over research activities.
“The breadth and impact of our researchers’ discoveries would not be possible without the support of many research cores and services and our outstanding research administration team holding it all together. From basic science to clinical research core services and cutting edge regulatory and administrative support that ensure the highest level of ethical and scientific standards are met, we have a framework for discovery that allows our researchers to excel.” – Dennis Durbin, MD, MSCE
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PARTNERSHIPS
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ife-changing research is a team effort. Collaboration is as essential outside of our institution as it is within it. Some key partnerships between the Abigail Wexner Research Institute and other entities include the following. OHIO STATE UNIVERSITY CCTS The Ohio State University’s Wexner Medical Center and seven health science colleges and Nationwide Children’s have come together to form the OSU Center for Clinical and Translational Science. Researchers at Nationwide Children’s receive funding annually in support of CCTS activities and are eligible to compete for pilot and training grants through CCTS. Shared resources, including clinical trial recruitment and retention services, help researchers achieve trial goals. OHIO PERINATAL RESEARCH NETWORK (OPRN) The Abigail Wexner Research Institute, Nationwide Children’s, Wexner Medical Center and OSU have developed the OPRN, a research collaborative dedicated to better understanding preterm birth and its complications. A major effort of OPRN is a research repository for clinical data and specimens from infants delivered preterm and their mothers. Additional collaborating institutions include OhioHealth, Mt. Carmel and community partners in the Ohio Better Birth Outcomes (OBBO) project. OBBO is a community outreach program aimed at mothers and physicians to prevent preterm births. REV1 VENTURES Nationwide Children’s is a sustaining member of Rev1Ventures, an organization created to accelerate innovation, business growth, job creation and prosperity in the 15-county region of central Ohio. Rev1Ventures works to create new companies, strengthen existing businesses, open doors to technology resources and support the attraction and retention of technologybased businesses.
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NATIONWIDE PEDIATRIC INNOVATION FUND Established in 2014 by the Nationwide Foundation, the Nationwide Pediatric Innovation Fund at Nationwide Children’s Hospital has now contributed $50 million. This fund supports pediatric research and innovative projects to advance the science and practice of pediatric health care. Innovation Fund investments are directed long-term to both clinical and research program development and recruitment in areas of greatest priority. THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER – ARTHUR G. JAMES CANCER HOSPITAL AND RICHARD J. SOLOVE RESEARCH INSTITUTE A collaborative agreement among Nationwide Children’s Hospital and The Ohio State University Comprehensive Cancer Center broadens the study of childhood cancers and accelerates the transfer of key research findings to the clinical setting. The unique relationship among the institutions is stimulating novel research and developing collaborations in pediatric cancer-related studies that will also have applications to adults. Among the innovative outcomes of this collaboration are the Cellular Therapy and Cancer Immunology Program and the proton therapy facility that is expected to open in 2021. AND MANY MORE Each center and specialty is actively involved in growing and fostering collaborative relationships within Nationwide Children’s and throughout the world. Researchers in the Abigail Wexner Research Institute are actively presenting at national meetings, publishing in highly respected journals and earning research grants to further their fields of study.
“We know that increasing our work to discover new knowledge, and the push to create new treatments and better outcomes, has actually driven collaboration, accountability and innovation — at Nationwide Children’s and far beyond our walls.” – Steve Allen, MD
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TRAINING AND EDUCATION
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esearch education and training are vital to the mission of Nationwide Children’s, with the outstanding faculty at the Abigail Wexner Research Institute dedicated to training and mentoring the next generation of scientists in pediatric research. Investigators at the Abigail Wexner Research Institute are teaching faculty in various departments at The Ohio State University College of Medicine. As a result, a large number of students and trainees are based at the Abigail Wexner Research Institute. This includes undergraduates, residents and fellows in pediatrics and pediatric surgery, graduate students, postdoctoral fellows and high school students. Instruction occurs in informal and formal didactic sessions, one-on-one interactions and hands on laboratory training. RITA In 2013, the Research Institute Trainee Association (RITA) formed to help better train and prepare young scientists for careers in research. All trainees are welcome to participate, including graduate students, postdoctoral scientists and fellows. It is modeled after guidelines established by the National Postdoctoral Association, of which the Abigail Wexner Research Institute is a member.
“RITA provides camaraderie among trainees regardless of what lab they belong to, what their ultimate career goals are or what stage of training they find themselves in. We are invested in supporting the academic and professional endeavors of our trainees. Our faculty is supportive, but there’s nothing quite like having a community of peers who you can rely on.” – Adrianna Matos, PhD candidate in the Center for Cardiovascular Research and Community Outreach Officer for RITA
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RITA is led by a team of trainees nominated and elected by their peers. They receive guidance and assistance from an advisory committee of faculty co-advisors and administrators. FUTURES MATTER PROGRAM The Futures Matter Program is an eight-week, paid summer research experience on the campus of the Abigail Wexner Research Institute. High school student with an interest in biomedical research careers have an opportunity to work with a researcher for a hands-on science experience, while learning about different professional pathways in biomedical research. During the program, participants also engage in discussions and seminars led by faculty and trainees.
ACCOMPLISHMENTS
2018 ANNUAL PERFORMANCE INDICATORS 2018 EXTERNAL AWARDS BY SOURCE
$105.9
MILLIONS
Program $0.5 Industry $13.5 Other $17.9 Federal Other $20.4 NIH Prime
$53.6 2018
RESEARCH BY THE NUMBERS
2016
2017
2018
Principal Investigators* Research Fellows Graduate Students Employees Publications
182 188 195 75 70 81 34 37 42 1075 1310 1238 1067 1171 1583
*Includes faculty from the Abigail Wexner Research Institute and faculty from Nationwide Children’s Hospital with $50,000 or more in research funding support.
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OUR CAMPUS
RESEARCH FACILITY HIGHLIGHTS • Wexner Institute for Pediatric Research (Research Building I) contains 136,580 square feet of dedicated research space contiguous with Nationwide Children’s clinical facilities.
CAMPUS HIGHLIGHTS • 1,184,473 square feet of inpatient space on Main Campus
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Research Building II provides 164,016 square feet of additional space including a 200-seat amphitheater. It is also contiguous with the clinical facilities.
• Busiest pediatric surgery program in the nation
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Research Building III is 238,914 square feet and includes a 75-seat conference facility. Research Building III is LEED certified for sustainable green building design.
• Research Building IV is in planning, and it is currently expected to open in 2021.
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• 406,751 square feet of outpatient space • Largest neonatal network in the United States
• The Big Lots Behavioral Health Pavilion — expected to be largest such facility on a pediatric campus — is scheduled to open in 2020.
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TARYN’S STORY: PREMATURITY AND CEREBRAL PALSY
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aryn was born at just 27 weeks gestational age. She experienced the most severe type of intraventricular hemorrhage and was diagnosed with bronchopulmonary dysplasia, retinopathy of prematurity, apnea of prematurity and, ultimately, cerebral palsy.
Taryn received her official CP diagnosis at about 12 months of age during her visit with the Nationwide Children’s NICU Follow-up Program. Her parents later enrolled her in the “Early Childhood Constraint Therapy in Cerebral Palsy” clinical trial led by Nathalie Maitre, MD, PhD, director of the NICU Follow-up Program and principal investigator in the Center for Perinatal Research. “Participating in the trial was personally rewarding because of the benefit we saw for Taryn,” says Taryn’s mom. “But it was also really important to know that we were contributing to something bigger. We knew that we could help change things for future generations of children with cerebral palsy.” The trial was focused on the use of soft-restraint therapy to encourage the use of the nondominant side of the body. This is beneficial both physically in strengthening the weaker side and neurologically in helping to build new neural pathways in her developing brain. “The research is important on its own, but it also helps ensure that a clinic is using the most up-to-date, evidencebased care,” says Dr. Maitre. “We are not just a research program that documents outcomes. We are a clinical program that fully integrates research into our patients’ journeys.” The practicality and application-focus of the trial and clinical education was also much appreciated, says Taryn’s parents.
“We understand more now about how we can help her, how we can advocate for her, and what resources are available to her,” her dad adds. “We’ve learned so much from the therapists and other clinic staff. We went from feeling scared and intimidated to knowing that there’s something we can do. That’s empowering.”
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