Bench to Bedside

January 2015

Raymond G. Perelman Donates $50 Million to Support Research at CHOP


The Children’s Hospital of Philadelphia (CHOP) recently announced a $50 million gift from businessman and philanthropist Raymond G. Perelman. This gift, equal to the largest ever received by CHOP, will directly support a wide range of pediatric research, tackling the toughest and most challenging pediatric illnesses and establishing CHOP as a global center for innovative pediatric study.

In recognition of this extraordinary gift for research, CHOP will establish the Raymond G. Perelman Campus, an eight-acre area that will serve as a hub of pediatric research and clinical innovation at CHOP.

“The significant research funding associated with this gift underscores the commitment of Raymond Perelman to world-class pediatric research and medicine,” said Mortimer J. Buckley, chair, Board of Trustees at The Children’s Hospital of Philadelphia. “Through his generosity, Mr. Perelman is first and foremost improving the lives of children for generations to come and we will always be grateful for his altruism,” he said.

Born in Philadelphia, Raymond G. Perelman was raised in the Feltonville and Olney sections of the city and attended the University of Pennsylvania. After serving in World War II, he began a 50-year career with American Paper Products Co., and is currently CEO of RGP Holdings. Mr. Perelman has served on many boards of directors, and has been active in numerous civic organizations, including the Philadelphia Museum of Art, Penn Medicine, and the Albert Einstein Health Center.

“We know first-hand the tremendous resource that CHOP represents to families in the Philadelphia region, across the country and around the world,” said Raymond G. Perelman. “This gift will help to ensure that critically important pediatric research, conducted on this campus, remains second to none; in addition to making a tangible difference in the lives of children around the globe for many years to come, it is my hope and expectation that advances in medical research funded by this gift will benefit us all,” he said.

“The Philadelphia community has long benefited from the generosity and commitment of Raymond Perelman,” said Steven M. Altschuler, MD, chief executive officer of The Children’s Hospital of Philadelphia. “The impact of Mr. Perelman’s gift will be felt long into the future, helping generations of children live healthier lives. Raymond’s kindness and vision are truly remarkable,” he said.

The significance of the Perelman gift was noted by two other donor families whose past generosity place them among the most significant supporters of CHOP’s clinical and research endeavors: Ruth and Tristram Colket, Jr.; and the Buerger family, Constance and Alan Buerger, Krista and Reid Buerger, and Grant Buerger.

“Raymond Perelman’s commitment to advancing healthcare is truly extraordinary. We have long believed that the most powerful research happens when scientists and clinicians work closely together, and the Raymond G. Perelman Campus will unite them like never before. Children and families the world over will benefit from the transformative discoveries made possible by this generous gift,” the Colkets said.

“So many parents — in this area and far beyond — have a ‘CHOP story’: A story of how the work done by the wonderful physicians and scientists at CHOP changed their child’s life. By forging an even stronger connection between research and clinical care, the Raymond G. Perelman Campus will ensure that we will hear many more of these stories in the years to come,” Reid Buerger said.

The gift also establishes the “Raymond G. Perelman Research Fund,” that will provide direct support for:

The newly named Raymond G. Perelman Campus comprises an eight-acre portion of the CHOP site located on Civic Center Boulevard just south of the main hospital and encompasses its most state-of-the-art research and clinical centers, including the Ruth and Tristram Colket, Jr. Translational Research Building, which opened in 2009; the new Buerger Center for Advanced Pediatric Care, under construction and slated to open this summer; and a 2.6-acre landscaped plaza.

To learn more about this extraordinary gift, see the full press release.

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Short Observations Not Enough to Detect Autism Risk


Identifying autism spectrum disorder (ASD) risk early is imperative, because the earlier autism is detected the earlier clinicians will be able to intervene. In general, the younger the patient, the more effective ASD interventions are. However, according to a new study published in Pediatrics, short 10 to 20-minute observations — such as an office visit — may be insufficient when it comes to assessing autism risk.

Led by The Children’s Hospital of Philadelphia’s Judith S. Miller PhD, MS, a senior scientist at the Center for Autism Research (CAR), the researchers studied a group of children aged 15 to 33 months with autism, speech delays, and typical development. The researchers asked two licensed psychologists with toddler and autism expertise — who were unaware of the study participants’ status — to analyze two 10-minute video samples of the participants’ autism evaluations. The experts measured five behaviors, including responding, initiating, vocalizing, play, and response to name.

The article’s first author was Terisa Gabrielsen, PhD, NCSP, of Brigham Young University. Before moving to BYU, Dr. Gabrielsen completed an internship and postdoctoral training at Children’s Hospital, where she and Dr. Miller conducted research that informed the current study. That work, also published in Pediatrics, examined the feasibility of a formal autism screening process.

In the current study, the researchers found the experts missed referrals for 39 percent of the children in the autism group. Detecting autism risk based on the brief observations alone was challenging because the children who had autism showed more typical behavior (89 percent of the time) than atypical behavior (11 percent) during that short window.

“It’s not often the pediatrician’s fault that referrals are missed,” Dr. Gabrielsen said. “Even autism experts missed a high percentage of referrals within that short timeframe. Decisions for referral need to be based on more information, including autism screening and information from parents. We’re hoping that this information can really empower parents to talk with pediatric care providers about their concerns.”

In March of 2014, the Centers for Disease Control and Prevention announced that one in 68 children in the U.S. has an ASD — a 29 percent increase over the 2012 rate of 1 in 88. The seemingly growing prevalence of ASD demonstrates the need for accurate autism referral decisions. This decision-making process should include parent observations, developmental testing, a detailed history, and autism screening tools in addition to clinical judgment, the research team concluded.

“Certainly, some young children with autism are clearly impaired and easy to recognize,” noted Dr. Miller in a press release put out by BYU. “However, this study looked at the entire range of children who present to the pediatrician’s office, and we found that many children’s impairments are not immediately obvious. For these children, formalized screening instruments and more time with a specialist may be critical.”

For much more information about autism and autism research at The Children’s Hospital of Philadelphia, see the Center for Autism Research. A description of the diagnostic tests and other information on how parents can spot the developmental delays associated with ASD is available in the diagnosis section of Autism Roadmap. The Roadmap provides directories of service providers, community resources, government programs, ideas for various stages of childhood and beyond, and explanations of the latest research on ASD treatments and interventions.

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Researchers Developing Reliable Measures of Children’s Sleep Health


Healthy sleep is essential for children’s happiness, attentiveness, and energy, yet estimates suggest that up to 30 percent of children are affected by sleep problems. While parents usually have no difficulty describing their poor sleepers’ crankiness and fussiness, physicians have not had a standard, reliable way to measure these patient reports of children’s sleep.

Patient reported outcome measures are ways of obtaining information about your health or your well-being from your own perspective, without any translation from a clinician or an interviewer. The National Institutes of Health offers assessment tools called the Patient Reported Outcomes Measurement Information System (PROMIS) to help physicians precisely measure what patients are able to do and how they feel by asking a set of questions that have undergone rigorous scientific testing.

The PROMIS Pediatric Profile has core measures covering domains such as anxiety, depression, fatigue, pain, physical function, and social participation, but the missing piece of the portfolio is sleep health. Christopher B. Forrest, MD, PhD, a CHOP pediatrician and professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania, recently received a two-year grant from the Patient-Centered Outcomes Research Institute (PCORI) to develop PROMIS pediatric sleep health measures that will fill this gap and enable patients and their families to express exactly how health conditions and treatments affect their sleep.

“These questions address the dimensions of life that I like to call feelings, doings, and beings,” said Dr. Forrest, who has been involved with the PROMIS initiative since 2009. “It’s how you feel about yourself and your life, what you can do in life, and then your ‘beings’ is what you become — your personal growth and development. You cannot get that information unless you ask somebody, and what we’ve done through the National Institutes of Health PROMIS program is standardize the methodology.”

For example, “In the past seven days, I fell asleep during school,” is one of the PROMIS items being considered to measure wakefulness and sleep-related impairment. A section of questions on sleep practices includes, “In the past seven days, what time did you go to bed on school nights?”

Once the set of PROMIS pediatric sleep health measures are developed, the idea is for the questionnaires to be offered on tablets, computer kiosks, or paper forms in physicians’ waiting rooms. Two versions will be available for child self-report (ages 8 and up) and parent-proxy (children ages 5 and up).

At CHOP, efforts are underway to eventually incorporate answers to the sleep bank items and other patient-reported outcomes measures as part of the electronic health record. In addition to giving clinicians a standardized way to assess sleep quality and address pediatric sleep concerns as they change over time, the sleep health measures could be used as clinical trial endpoints.

“A medical treatment ought to make kids feel better, but they are not fully recovered until they are able to do things better, like go to school, interact with friends, have sleepovers,” Dr. Forrest said. “Those tend to be the kinds of concerns that families have, but often they don’t get brought up at conventional medical encounters.”

An innovative facet of how the pediatric sleep health item banks are being created is the project’s engagement model. Twenty individuals from five stakeholder groups (parents, youth, advocates, clinicians, and researchers) are helping design and oversee the research. One leader from each group plus the project staff make operational decisions.

The team already has accomplished a substantial part of the groundwork. They have interviewed sleep experts, parents, and children, as well as conducted a literature search to identify pediatric sleep measures that were developed previously. Based on the information that they gathered, they generated a preliminary list of 180 pediatric sleep measures. Their next step is to test and validate the questions by surveying about 4,000 children and parents from across the country. They will be recruiting children from CHOP’s Sleep Center, and another group of children with autism being treated at CHOP have agreed to participate in the research.

Dr. Forrest expects the PROMIS pediatric sleep measures will be narrowed down to about 100 items that will be ready for the engagement team to disseminate within the next two years. The final set of measures will be posted on the PROMIS website for free access.

“In addition to publishing papers, we will want to make known across the country through advocacy groups, through scientific communities, and clinical societies that these measures are available,” Dr. Forrest said. “Our hope is that they get used by thousands of researchers and tens of thousands of clinicians and patients.”

Dr. Forrest also serves as the principal investigator of PEDSnet, which is part of the PCORnet national patient-centered research network established by PCORI to reduce the time and effort needed to launch new studies and focus research on questions and outcomes especially useful to patients and those who care for them.

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Project Explores Enzymes’ Role in Cancer


The Children’s Hospital of Philadelphia Matthew D. Weitzman, PhD, recently received an award from the National Cancer Institute to study the role a family of proteins play in disrupting genome integrity and generating mutations that could cause cancer. The proteins in question, the ponderously named APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) family of deaminases, play a key role in defending against viruses, but are also being investigated as a possible cause of cellular DNA damage that can lead to cancer.

Dr. Weitzman has been working closely with Abby Green, MD, currently an instructor in Pediatric Oncology. Dr. Green first came to CHOP in 2007 as a resident physician, and from 2010-2014 served as a fellow physician in Pediatric Infectious Diseases and Hematology/Oncology. In July of 2014 Dr. Green received a grant of her own to study APOBECs — a two-year Young Investigator Award from Alex’s Lemonade Stand Foundation (ALSF).

Drs. Weitzman and Green’s work seeks to understand better how these enzymes disrupt the genome and cause mutations, and how APOBECs (pronounced AE-POE-BECK) are regulated. Their broad, long-term goal is to discover and develop new treatment methods based on a deeper understanding of the relationship between A3 enzymes and cancer cells. For her part, Dr. Green’s ALSF grant specifically funds an investigation into whether the DNA mutations caused by APOBECs make cancer cells more receptive to drugs that inhibit DNA repair.

The work builds on recent investigations into the enzymes’ relation to cancer by Dr. Weitzman and others. In 2011 he published a paper in EMBO Reports with colleagues from the Salk Institute showing that some APOBECs could cause genomic instability. “Uncontrolled deamination of the cellular genome is potentially harmful and could lead to genomic instability and cancer initiation,” Dr. Weitzman and colleagues noted in their EMBO Reports study.

“Our results raise the possibility that deregulated activity of APOBEC proteins might contribute to genomic instability and suggest their potential contribution to malignant transformation should be carefully investigated,” the authors write.

Dr. Weitzman’s new, five-year R01 grant seeks to build on the EMBO Reports work. “The grant is asking basically can we show that these enzymes actually cause those [mutational] signatures and fulfill what is predicted retrospectively,” he said. “The next questions address what regulates activity, what makes sure it doesn’t happen normally, what are the modifications, what are the interactive proteins, where’s it expressed and localized in the cell, and other fundamental questions about these potentially harmful enzymes.”

Potentially Paradoxical Proteins

Though APOBECs have been the focus of increased attention in recent years, they remain poorly understood. How, some have wondered, could enzymes that perform an immune function also induce cancer-causing mutations? A 2013 review of these enzymes offered a possible answer: age.

Published in the book Intrinsic Immunity, Current Topics in Microbiology, the University of Minnesota’s Reuben S. Harris, PhD, and Eric W. Refsland, PhD, address the question of how, and why, enzymes whose primary role is to fight viruses could be a cause of human cancer.

“Obviously, the potential benefits to encoding APOBEC3B must outweigh potential costs of carcinogenesis,” they write. “An attractive explanation for this apparent conundrum may be that its innate function is important early in life and for the health of the species, for instance, in germ cells or early development, whereas the toll of cancer is not imposed in most instances until after the reproductive years. In any event, much more work is now justified on APOBEC3B and its role in breast and, potentially, other human cancers.”

However, this explanation of APOBECs’ possible role in cancers brings up the question of how these enzymes might be involved in pediatric cancers. “Maybe there’s a subset of children who are more susceptible to APOBEC-induced editing or mutation, and a viral infection actually would in those kids trigger mutagenesis,” Dr. Green opined.

Hence the importance of studies like Drs. Weitzman and Green’s. Dr. Weitzman pointed out that while cancer genome sequencing studies have revealed a great deal of information about how cancer arises, and discovered genes associated with certain cancers, they don’t necessarily provide the mechanism by which things happen.

“We want to bridge that gap,” said Dr. Green.

And though their study is mechanistic, greater knowledge of APOBECs’ role in causing cancer, and how this family of enzymes is regulated, could lead to diagnostic and therapeutic approaches in the future. “If we find that these APOBECs are involved in pediatric cancers, there may be a diagnostic role, or a therapeutic opportunity. We have lots of translational ideas, but we just have to get this first work done,” Dr. Green added.

Indeed, it is CHOP’s unique ability to pair laboratory researchers with clinicians like Dr. Green that allows investigators to think more translationally, Dr. Weitzman noted. He said that his work has really benefitted from the input and expertise of Dr. Green, who is the first clinician to work in his lab.

“CHOP has this ability to pair basic researchers with clinicians, and both sides stimulate each other to think together about translational ideas,” Dr. Weitzman said.

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NIH Grant Will Fund TMJ Biology, Maintenance Study


Of all the joints in the body, perhaps the most unique, complex, and understudied is the temporomandibular joint (TMJ). The TMJ, which is located close to the ears, is a bilateral movable articulation, connecting the lower jaw (mandible) to the bone at the side of the skull (temporal bone). Its structure include a distinctive feature called an articular disc that acts as a shock absorber and reduces friction so that the bony parts of the joint can glide smoothly, allowing us to chew, talk, yawn, and open our mouths wide to say “Ahhh.”

Researchers at The Children’s Hospital of Philadelphia, Eiki Koyama, DDS, PhD, a faculty member in the Division of Orthopedics, and Hyun-Duck Nah, DMD, PhD, an orthodontist in the Division of Plastic and Reconstructive Surgery who works with patients who have craniofacial deformities, recently received a grant from the National Institute of Dental & Craniofacial Research to study the development of the TMJ, the mechanisms that maintain it, and how these processes may be altered in disease. They aim to use this knowledge to inform future therapeutic strategies in pediatric and adult medicine.

The TMJ begins to form within the first few months after conception, experiences active growth during childhood and adolescence, and then undergoes adaptive remodeling throughout life. The exact prevalence of TMJ disorders in the general pediatric population is uncertain, but guidelines from the American Academy of Pediatric Dentistry cite that upwards of 25 percent of children ages 5 to 17 have some symptoms of TMJ disease, and 1 percent to 2 percent are in need of treatment.

Pediatric TMJ disorders can be congenital or acquired, such as craniofacial abnormalities, juvenile rheumatoid arthritis, and injuries or infection that damage the joint. Symptoms and signs of TMJ disorders vary depending on etiology and severity, but commonly include difficulty opening the mouth, locking of the joint, difficulty with mastication and nutrition, and facial and jaw muscle pain. Furthermore, defective TMJ function often results in under-development of the mandible and abnormal facial growth.

In previous research, Dr. Koyama’s group demonstrated that mice with deletion of a specific gene, Indian hedgehog (Ihh), failed to form a normal TMJ. The joint lacked integral components including its distinctive articular disc, joint cavities, and the specialized cell layers that produce lubricin. Lubricin is a lubricant that protects the TMJ from frictional loads and thus is essential for long-term maintenance of joint integrity.

In the current study, the team plans to further define the roles of Ihh and additionally to delineate the role of two genetic pathways, TGF-β1 and PTHrP, that they suggest Ihh uses to orchestrate TMJ formation, function, and lubricin production. They predict that deterioration of joint lubrication with age or by other insults may underlie disc adhesion and degenerative TMJ disorders, which are prevalent in the adult population.

While this research is still at the basic science stage, Dr. Nah, who is also a research associate professor of surgery at the Perelman School of Medicine at the University of Pennsylvania, said that the ultimate goals of the study include translation of findings to recreate a functional TMJ for those patients with missing or defective TMJs.

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Pediatric Trauma Nurses Know Trauma-Informed Care


A recent study from The Children’s Hospital of Philadelphia (CHOP) and Penn State Hershey Children’s Hospital published in the Journal of Pediatric Nursing reveals pediatric trauma nurses are knowledgeable about practicing trauma-informed care, but points to the need for additional nurse training to help families cope after a child’s injury.

When an injury occurs, both the child and other family members may experience traumatic stress reactions interfering with a full recovery. Pediatric nurses play a key role in preventing injury-related post-traumatic stress by providing trauma-informed care, which includes recognizing pre-existing trauma, addressing acute traumatic stress reactions associated with the traumatic event, minimizing potentially traumatic aspects of treatment, and identifying children who need additional monitoring or referrals for more help.

Researchers surveyed 232 nurses across five level I and level II pediatric trauma centers about their knowledge, opinions, and current practices in addressing psychological recovery in their injured patients. More than 90 percent of the nurses surveyed recognize the importance of attending to psychosocial needs as part of trauma nursing care, and 75 to 80 percent report that they encourage parents to turn to family and friends for support and help parents manage a child’s pain and anxiety during procedures. However, far fewer nurses surveyed reported directly assessing a child or parent’s distress or providing specific instruction in how to cope with difficult or painful experiences.

“When a child is hospitalized for an injury, nurses play a key role not only in medical care, but also in helping families cope and fully recover emotionally,” said Nancy Kassam-Adams, PhD, a psychologist, director of CHOP’s Center for Pediatric Traumatic Stress, and a lead author on the study. “Taken together with other recent studies that found only one in five trauma centers routinely screen child and youth for traumatic stress responses, these results help to identify gaps in current practice and point to possible policy and training needs.”

According to one parent’s experience after her son suffered severe injuries, the care he received at the hospital from the nursing staff made all the difference in his healthy recovery, both medically and emotionally.

“For a long time after my son Stephen’s accident, I was committed to remaining strong for him and my family and just powering us all through the crisis,” said Kathy Conaboy, a member of the Center’s Family Advisory Committee. “What I realized over time with the help of his nurses was that our entire family was traumatized, and we needed help that I didn’t even know that I needed to ask for. We gradually learned from his nurses how to talk about what happened and to seek positive coping skills and supports to be able to move forward.”

The results of this survey suggest that efforts to improve trauma-informed pediatric nursing care should highlight specific skills related to helping patients and their parents manage emotional responses to difficult medical experiences. As one nurse surveyed for the study noted: “I would like to have information about what to teach parents to say and how to talk about the event without re-traumatizing the patient.”

To help nurses build on the skills they already possess and to promote full recovery in the pediatric patients they treat, the Center for Pediatric Traumatic Stress is now offering free continuing education courses in trauma-informed care at HealthCareToolbox. The training is based on the “DEF Protocol” created by the Medical Trauma Working Group of the National Child Traumatic Stress Network, which helps healthcare providers address distress, emotional support, and family needs in a systematic manner. Downloadable patient education materials in English and Spanish are also available on the website.

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Findings Lay Groundwork for Novel Huntington’s Disease Therapy


New findings by researchers in the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia suggest that an intricate pathway crucial to the development of Huntington’s disease (HD) rests on a “biological teeter-totter” that when carefully balanced could help to control this devastating neurodegenerative disorder.

HD affects about 30,000 Americans and is an incurable, inherited disease entailing progressive loss of brain cells and motor function, usually beginning in midlife. A defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances. A key signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD.

In their experiments, study leader Beverly L. Davidson, PhD, director of the CCMT, and co-investigators adjusted levels of mTORC1 in mice bred to model features of HD. They injected bioengineered viruses as a gene therapy tool to carry DNA that directed the production of regulatory proteins called Rheb and Rhes that act along the mTORC1 pathway. After the researchers restored mTORC1 activity to more normal levels, brain areas that had begun to atrophy recovered volume and permitted better motor function.

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Dr. Davidson, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. “This shows that brain cells are capable of responding even after disease onset and hints at the potential for reversing Huntington’s disease.”

She added that restoring proper balance to these delicate biological processes may offer even broader benefits in treating other neurological diseases, such as amyotrophic lateral sclerosis (ALS), fragile X mental retardation, and autism. Fragile X mental retardation and autism both feature overactive mTORC1 activity, while mTORC1 is reduced in ALS and HD.

“This pathway is poised on a biological teeter-totter, and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease,” Dr. Davidson said.

In the future, the research team will focus on increasing their understanding of how they can carefully manipulate the dysregulated pathway to treat HD, with the goal of finding a potential drug therapy. Much work remains, as researchers must identify drug candidates that appropriately activate the mTORC1 pathway. Although gene therapy vectors were used for this research, Dr. Davidson envisions developing a small molecule that can appropriately modulate this pathway. Such a treatment might be combined with a gene therapy approach, also being pursued by her team and other groups, delivered directly to the brain to curtail mHTT expression.

The study team published its results online Dec. 31 in the journal Neuron. They performed a substantial part of this research in Dr. Davidson’s laboratory at the University of Iowa, before she and many of her colleagues moved to CHOP in 2014. John H. Lee, the paper’s first author, remains at the University of Iowa, where he is completing his MD/PhD training. For more information about their research, a press release is available.

The National Institutes of Health and the Roy J. Carver Trust supported this study.

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CPCE Supports New Pilot Projects on Clinical Decision-Making


The Center for Pediatric Clinical Effectiveness (CPCE) at The Children’s Hospital of Philadelphia supports outstanding pilot research studies designed to produce evidence for what works best for treating, diagnosing, and preventing disease. Winners chosen for the fall round of the CPCE’s Pilot Grant Program will focus on two projects that aim to have an impact on clinical decision-making.

Maya Dewan, MD, MPH, a fellow in CHOP’s Department of Anesthesiology and Critical Care Medicine, will evaluate a low-cost intervention with the goal of reducing the rates of unnecessary alarm signals. It has been well-established that alarm fatigue is a growing threat to patient safety, but little research has been done that focuses on approaches to solve the problem of excessive alarms in the pediatric setting.

“Often when you’re in the pediatric intensive care unit (PICU), you’re overwhelmed by the amount of noise,” Dr. Dewan said. “You’ll go into a sick patient’s room, and sometimes it’s even hard for you to communicate or hear someone speaking because everything is beeping in the room.”

The barrage of alarms also can be stressful for families, Dr. Dewan added. She recalled sitting at 2 a.m. beside a concerned mother who was fixated on her child’s monitors and would jump at every blip.

Physiologic alarms display heart rate, respiratory rate, blood pressure, and oxygen saturation and are important tools to alert clinicians to signs of instability and prevent cardiac and respiratory arrest. In CHOP’s PICU, patients average 100 to 110 crisis and warning alarms per day, yet the majority are false, which can interrupt patient care and reduce nurses’ trust in the alarms.

“We decided to devise an intervention that could safely decrease alarms that are unnecessary,” Dr. Dewan said. “But our goal isn’t just to get rid of the false alarms. We want to ensure that the alarms you hear are true and people respond to them faster. If you filter out the false alarms, maybe we’ll pay more attention and identify kids who are getter sicker sooner.”

Preliminary data show that 25 percent to 30 percent of the crisis and warning alarms in CHOP’s PICU are caused by just 4 percent to 8 percent of patients who are mainly low acuity and require less complicated care. On a daily basis, Dr. Dewan and her study team will identify one or two low-acuity patients in the PICU who have high physiologic monitor alarm rates. During safety huddles — brief, structured conversations with physicians, nurses, and other staff to mitigate safety risks — they will review the alarm data and determine if the patients could benefit from adjustment of the alarm parameters.

Patients recognized during the safety huddles as eligible for intervention will be discussed further during rounds, when their physicians will decide if safe tailoring of alarm limits is warranted.

“We wanted to individualize the approach for every patient,” Dr. Dewan said. “And we didn’t want to take away any of the autonomy of the providers at the bedside who know the patient best.”

Dr. Dewan was excited to receive funding from the CPCE, which will pay for research assistance to help launch the project by early spring. She expects the pilot study to include about 200 intervention patients over a six-month period and anticipates that their alarm rates will decrease by at least 10 percent when compared to control patients.

If the huddle intervention is shown to be safe and effective in the PICU, the next step would be to integrate the data-driven approach into the workflow throughout the hospital. The data they collect eventually could be used to support application for funding from the National Institutes of Health to evaluate the intervention’s effectiveness in a multicenter study of PICUs across the U.S.

Pilot Study to Help Assess Metabolic Bone Health More Closely During Hemodialysis

Nephrology fellow Aadil Kakajiwala, MBBS, is equally as thrilled to have been chosen by the CPCE to conduct a research project that will focus on the variability in measures of mineral metabolism in pediatric end-stage kidney disease. Chronic kidney disease (CKD) is associated with nearly universal disturbances in metabolism of calcium, phosphate, parathyroid hormone, and vitamin D that present multiple obstacles to children’s bone and cardiovascular health, nutrition, and growth.

As part of his training at CHOP, Dr. Kakajiwala spent six months getting to know the young patients who visited the pediatric hemodialysis center, usually three times a week. As part of the standard of care, the patients were monitored monthly for calcium, phosphate, parathyroid hormone. These measurements aided clinicians in making adjustments to the patients’ medications and growth hormone therapy. Dr. Kakajiwala and his mentors, including Michelle Denburg, MD, MSCE, an attending physician in the Division of Nephrology, suspect that flux in these parameters may occur often in children on dialysis, so they planned a pilot study to investigate if more frequent assessment of mineral homeostasis could help clinicians to assess bone health more closely.

“Our concern is that patients on dialysis have vitamin D and parathyroid hormone levels that are variable, and they need a lot of fine-tuning and management,” Dr. Kakajiwala said. “What we want to show from this study is whether we need to check these levels more than just every month, with the intention that we can intervene quicker and not lead to any bone or cardiovascular issues.”

As a major goal of the study is to see how decision-making would differ based on serial measures, the study will not alter usual care in any way except that an extra 3 mL of blood will be drawn pre-dialysis twice weekly from about 10 study participants over a 12-week period during the winter season. The study team will collect, store, and then analyze the blood samples, also taking note of any medication changes that were made based on the usual monthly laboratory results.

The investigators will determine how many times an intervention would have been made based on the weekly results. Dr. Kakajiwala noted that a similar study of adults showed that almost 25 percent to 40 percent of the time, the physician would have made changes to the patient’s care plan.

Dr. Kakajiwala is especially thankful for the guidance from Dr. Denburg, an assistant professor of pediatrics for the Perelman School of Medicine at the University of Pennsylvania, during his application for the CPCE grant.

“With Dr. Denburg’s expertise in chronic kidney disease and metabolic bone health, and my passion for the dialysis patients, I think this is going to be a fantastic study,” Dr. Kakajiwala said.

The CPCE accepts proposals for its pilot grant program twice a year, and promising projects undergo at least two rounds of reviews to determine that they fully meet the selection criteria. Read more about the program’s winners chosen on the blog in spring 2014.

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CHOP Expert Elected to Scoliosis Society Presidency


The Children’s Hospital of Philadelphia’s John P. Dormans, MD, FACS, was recently elected to the presidency of the Scoliosis Research Society’s board of directors. The former chief of Children’s Hospital’s Division of Orthopedics, Dr. Dormans is an internationally recognized orthopedic surgeon and spine disorder researcher.

A condition in which the spine is curved sideways, scoliosis is most often seen in late childhood and adolescence, and is more common in girls than boys. There are several different types of scoliosis, including congenital, neuromuscular (when it is associated with cerebral palsy or another condition), and idiopathic scoliosis, or that of largely unknown origin. Idiopathic scoliosis affects approximately 2 to 3 percent of the U.S. population, about 9 million Americans.

The Scoliosis Research Society (SRS) is a premier organization of roughly 1200 leading spine surgeons and researchers from more than 50 countries. Since it was founded in 1966, according to the Society’s website the SRS “has maintained a commitment to research and education in the field of spinal deformities.” Dr. Dormans’ fellow board members hail from the University of Minnesota, Johns Hopkins, and Louisville, Ky.’s Norton Leatherman Spine Center.

In late 2014, Dr. Dormans published a series of papers on scoliosis and orthopedics, including one in the Journal of Children’s Orthopaedics on surgical management of fibrous dysplasia (a condition in which fibro-osseous tissue proliferates in bone) of the proximal femur, and a Journal of Pediatric Orthopaedics (JPO) study of scoliosis in children who have Aicardi syndrome (ACS). A rare disorder occurring mainly in females, ACS is characterized by brain and eye abnormalities, distinctive facial features, and recurrent seizures that can be difficult to treat.

In the JPO paper, Dr. Dormans — along with CHOP’s Emmouil Grigoriou, MD, who held a 2013-2014 Orthopedic Surgery Research Fellowship — described for the first time scoliosis in patients with ACS. By performing a review of records of ACS patients treated for scoliosis at Children’s Hospital, they found scoliosis represents “a clinically significant problem that is underdiagnosed and overshadowed by the other severe medical complications associated with the syndrome.”

“It certainly is an honor to serve as President of the Scoliosis Research Society,” Dr. Dormans said. “I look forward to working with my fellow members to advance scoliosis research and care.”

To learn more about scoliosis and other spine treatments at CHOP, see The Children’s Hospital of Philadelphia’s Spine Program.

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