Four years ago, spurred by the desire to give premature babies a better chance for a healthy life, a team of multidisciplinary researchers at CHOP began to develop a fluid-filled system that would imitate life for a fetus in the womb. Containing the necessary nutrients that a fetus requires to develop and thrive, the environment would support and stabilize babies born too soon, particularly between 23 and 26 weeks. Because extremely premature infants often have underdeveloped lungs that cannot adapt to gas ventilation, the system would give them a valuable few weeks to mature these and other vital organs — just as if they were still being carried in their mother’s uterus.

The research team led by Alan Flake, MD, fetal surgeon at CHOP, reported on their most recent prototype in Nature Communications. The study captivated both the scientific community and the mainstream media as it described how the current preclinical model supported eight fetal lambs for as long as 28 days, keeping them healthy as indicated by vital signs, blood flow, fetal blood gases, and other parameters monitored 24 hours a day.

“This system is potentially far superior to what hospitals can currently do for a 23-week-old baby born at the cusp of viability,” said Dr. Flake who is also a professor of Surgery at the University of Pennsylvania’s Perelman School of Medicine. “This could establish a new standard of care for this subset of extremely premature infants.”

After four rounds of prototypes, the current system is a sealed, sterile, fluid-filled container custom-made to fit each fetus and insulated from fluctuations in temperature, pressure, light, and hazardous infections. It provides nutrients and growth factors to each fetal lamb through a continuous amniotic fluid exchange system developed by Marcus Davey, PhD, a fetal physiologist at CHOP and associate professor of Surgery at Penn. Meanwhile, the lamb’s heart pumps blood via its umbilical cord into a low-resistance external oxygenator that substitutes for the mother’s placenta. Mimicking the normal physiology of a fetus, this flow of blood is driven entirely by the fetal lamb itself.

While the system has only been tested in animals, Dr. Flake believes that if more research shows that the system can translate into clinical care, it could help reduce mortality and disability for extremely premature babies by bridging their time from the womb to the world.

Snapping a photo could soon be a simple way to help clinicians recognize rare, genetic diseases such as 22q11.2 deletion syndrome (22q11.2 DS). Children who inherit 22q11.2 DS often have multiple birth defects — from congenital heart disease, to endocrine problems, to developmental differences such as autism, and more. In collaboration with the National Institutes of Health (NIH), researchers at CHOP contributed to the development of a unique facial recognition software, which is similar to systems used by airports and Facebook, to facilitate earlier diagnosis of 22q11.2 DS. Further-refined models of the technology may allow providers to take a cell phone photo of their patient to be analyzed and accurately diagnosed when confirmatory laboratory studies are unavailable.

The team published a report of the current software in the American Journal of Medical Genetics with Elaine Zackai, MD, director of clinical genetics at CHOP and professor of Pediatrics in Genetics at Penn, and Donna McDonald-McGinn, MS, LCGC, associate director of Clinical Genetics and director of the 22q and You Center at CHOP, as well as T. Blaine Crowley, data manager, and Daniel E. McGinn, Davidson College undergraduate student, as co-authors. The study compared photos of 156 children and adults with 22q11.2 DS to 156 photos of individuals in a control group matched for age and gender.

Altogether, the participants represented 11 different countries. Based on 126 distinct facial features, the researchers made correct diagnoses 96 percent of the time for participants from all ethnic groups using the facial analysis software. The diversity of this cohort — and the software’s sensitivity to ethnicity — is significant: Dr. McDonald-McGinn noted that in a previous study, she and her colleagues observed that diverse populations may be underdiagnosed for 22q11.2 DS. The research is also part of the NIH Atlas of Human Malformations in Diverse Populations, which will contain pictures and written descriptions of individuals from diverse ancestries.

“Healthcare providers here in the United States as well as those in other countries with fewer resources will be able to use the atlas and the facial recognition software for early diagnoses,” said senior author Maximilian Muenke, MD, a former trainee and attending geneticist at CHOP and currently chief of the National Human Genome Research Institute’s Medical Genetics Branch. “Early diagnosis means early treatment along with the potential for reducing pain and suffering experienced by these children and their families.”

Families often wonder how long a child who has experienced a concussion should rest and which activities to avoid. When it comes to putting an exact number to recovery, however, the optimal timeframe varies for each individual. A CHOP research team harnessed the power of “real-time” updates found in today’s mobile apps, in order to gain ground in personalizing pediatric post-concussion care.

The team led by Christina Master, MD, sports medicine pediatrician at CHOP and professor of Clinical Pediatrics at Penn, in collaboration with Douglas Wiebe, PhD, at Penn’s Center for Clinical Epidemiology and Biostatistics, developed an app and monitoring system using Ecologic Momentary Assessment (EMA) that tracked the activity and concussion symptoms of 34 children ages 11 to 19 who had just sustained a concussion. The app prompted the patients to report their symptoms in real time at random intervals during the day, as well as report how much time they spent performing cognitive activities such as reading, gaming, or using the computer. In addition to carrying an Ipod Touch® for the app, the patients also wore accelerometers (step counters) to track their physical activity.

In results published in JAMA Pediatrics, Dr. Master and her team found that generally, symptoms decreased as the two-week follow-up period progressed. Regardless of their activity levels, more than 68 percent of study participants had acute symptoms resolve by the end of the follow-up. Additionally, the team discovered that cognitive activities often increased symptoms, while physical exercise lowered them.

As a research strategy, EMA could be used in future studies to further explore the relationship between activity and symptoms over the course of concussion recovery. In clinical care, EMA could help physicians adjust their care plans according to updates from their patients in real time. This new method of communication and care management could eliminate the wait for follow-up visits, and it also could prevent physicians from having to rely on what patients or parents remember about concussion symptoms.

Many serious pediatric diseases are so rare that no individual institution can accumulate enough samples or data to gain significant insights into what drives the conditions at a molecular level. In the last few years, however, CHOP investigators have teamed up to build networks across the nation that break down these research silos and encourage the collaborative use of shared patient data.

For example, Adam Resnick, PhD, co-director of the Center for Data-Driven Discovery in Biomedicine (D3b), is currently the scientific chair of the Children’s Brain Tumor Tissue Consortium (CBTTC), headquartered at CHOP, and the Pacific Pediatric Neuro-Oncology Consortium (PNOC). Meanwhile, D3b, which is co-led by Phillip ‘Jay’ Storm, MD, chief of the division of Neurosurgery and associate professor of Neurosurgery at Penn, drives forward a data-based ecosystem on behalf of CHOP’s diverse patient population. D3b leads the Kids First Data Resource Center, a new NIH program supported by a nearly $15,000,000 grant, representing one of the largest initiatives of its kind focused on “big data genomics” in pediatric cancers and birth defects. 

In October 2016, CBTTC and PNOC announced the release of CAVATICA, an open-access, cloud-based biomedical data analysis platform created in partnership with Seven Bridges, to give clinicians and scientists across CHOP and the world rapid access to large amounts of genomics data and other types of information about pediatric diseases. The data collectively represents more than 20 pediatric hospitals and covers a range of illnesses including cancer, congenital disorders, epilepsy, and autism. It is the first time that the information will exist in one single and accessible environment in the cloud, giving researchers the ability to move beyond the study of one disease and instead, analyze data from a number of rare diseases, in order to learn about their potential shared mechanisms. Under the Kids First Data Resource Program, CAVATICA and its associated portals will expand to include more than 25,000 patients and family members.

“CAVATICA gives us an unprecedented opportunity to research a number of childhood diseases, ranging from pediatric brain tumors that are the leading cause of disease-related death in children to rare pediatric disorders that get limited attention and resources,” stated Dr. Resnick in a press release.

Mitochondria, the power plants of a cell, generate the energy we need for nearly every organ or system in the body to function properly. Shana McCormack, MD, an attending physician in the division of Endocrinology and Diabetes at CHOP and assistant professor of Pediatrics at Penn, along with colleagues at the University of Pennsylvania’s Center for Magnetic Resonance and Optical Imaging, developed a noninvasive way to track mitochondria and gain insights into their bioenergetics.

The new approach is a unique magnetic resource imaging tool, called creatine chemical exchange saturation transfer (CrCEST) MRI, that could help researchers study the impact of metabolic disease longitudinally in children. CrCEST detects changes in muscle creatine content before and after exercise. These changes allow researchers to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity, which is an important indicator of how the body generates energy.

In their study published in JCI Insight, Dr. McCormack and her colleagues demonstrated that CrCEST was a viable technique for measuring OXPHOS capacity after exercise in individuals with genetic mitochondrial disease, a group of conditions that can produce symptoms in many different organs, including fatigue, cardiac problems, diabetes, hearing and vision impairment, and more — depending on which cells within the body have disrupted mitochondria.

CrCEST has several benefits beyond the current techniques used to measure mitochondrial function, which often require a muscle biopsy. Along with being noninvasive, CrCEST gives researchers a high-resolution picture of mitochondrial function in different muscle groups simultaneously. With further development, the new tool may give physicians an objective biomarker to determine whether a particular intervention is truly helping a patient’s mitochondria to function better.

Investigators also could take the tool in new directions. For example, CrCEST could be used to address one of Dr. McCormack’s research questions: How does muscle mitochondria dysfunction contribute to precipitating diabetes?

“In order for me to study diabetes risk in these individuals, it’s helpful to have a measure of muscle mitochondrial dysfunction,” Dr. McCormack said. “Then, the next question is: ‘Does muscle uptake of glucose depend on the degree of OXPHOS capacity?’ And if it does, this might be an area to intervene to prevent the development of diabetes, in individuals with mitochondrial diseases as well as individuals with ‘common’ type 2 diabetes.”

When surgeons repair a type of heart condition known as a conotruncal defect, residual holes can appear between a patient’s two heart chambers — a rare but life-threatening complication known as intramural ventricular septal defects (VSDs). Researchers from the Cardiac Center at CHOP investigated a novel approach to detecting VSDs that would give surgeons the powerful ability to repair the complication during the same operation.

Transesophageal echocardiography (TEE) is a type of echocardiography that takes pictures of the heart by inserting a small transducer into a patient’s esophagus. Though the imaging tool is typically used in exams, TEE had not yet been studied as a way to detect VSDs during surgery. The CHOP research team is the first to do so, publishing their findings in the Journal of Thoracic and Cardiovascular Surgery. Meryl Cohen, MD, a pediatric cardiologist at CHOP and professor of Pediatrics at the Perelman School of Medicine, led the research.

In a retrospective analysis of 337 children, mostly infants, who underwent surgery for conotruncal defects between 2006 and 2013, Dr. Cohen and her fellow researchers compared the use of TEE during surgery with that of another echocardiography tool, transthoracic echocardiography (TTE) after surgery. Unlike TEE, TTE is noninvasive. In their results, the team found that both TTE and TEE identified 19 VSDs out of 34 surgical patients who had the intramural defect, while only TTE identified an additional 15. Overall, the data showed that TEE had modest sensitivity (56 percent) but high specificity (100 percent) for identifying intramural VSDs.

The findings build on a previous study from the Cardiac Center and led by Dr. Cohen that recognized intramural VSDs as distinct from other types of residual holes. In that study, published in Circulation in 2015, the research team concluded that intramural VSDs were uniquely associated with an increased risk of complications and mortality in children with heart disease, making it important to address and identify the defects as quickly as possible.