IV Bag

New study examines treatment for diabetic ketoacidosis

IV Bag

Brain injuries that happen during episodes of diabetic ketoacidosis (DKA) – where the body converts fat instead of sugar into energy, and where the pancreas is unable to process insulin, such as in type 1 diabetes – are rare, and happen in less than 1 percent of DKA episodes, but these injuries can carry lasting consequences – including mild to severe neurological damage.

A new 13-center, randomized, controlled trial published on June 13, 2018, in the New England Journal of Medicine finds two variables – the speed of rehydration fluids administered to patients and the sodium concentrations in these intravenous fluids – don’t impact neurological function or brain damage.

“One medical center would never be able to study this independently because of the relatively small volume of children with DKA that present to any one site,” says Kathleen Brown, M.D., a study author, the medical director of the emergency medicine and trauma center at Children’s National Health System and a professor of pediatrics and emergency medicine at George Washington University School of Medicine. “The strength of this research lies in our ability to work with 13 medical centers to study almost 1,400 episodes of children with DKA over five years to see if these variables make a difference. The study design showcases the efficiency of the Pediatric Emergency Center Applied Research Network, or PECARN, a federally-funded initiative that powers collaboration and innovation.”

Researchers have speculated about the techniques of administering intravenous fluids, specifically speed and sodium concentrations, to patients experiencing a DKA episode, with many assuming a faster administration rate of fluids would produce brain swelling. Others argued, from previous data, that these variables may not matter – especially since higher levels of brain damage were noted among children with higher rates of dehydration before they were treated. Some thought DKA created a state of inflammation in the brain, which caused the damage, and that speed and sodium concentration wouldn’t reverse this initial event. The researchers set out to determine the answers to these questions.

The PECARN research team put the data to the test: They created a 2-by-2 factorial design to test the impact of providing 1,255 pediatric patients, ages zero to 18, with higher (.9 percent) and lower (.45 percent) concentrations of sodium chloride at rapid and slow-rate administration speeds during a DKA episode. They administered tests during the first DKA episode and again during a recurrent episode. After analyzing 1,389 episodes, they found that the four different combinations did not have a statistically significant impact on the rate of cognitive decline during the DKA episode or during the 2-month and 6-month recovery periods.

“One of the most important lessons from this study is that diabetic ketoacidosis should be avoided because it can cause harm,” says Dr. Brown. “But the best way to treat diabetic ketoacidosis is to prevent it. Parents can monitor this by checking blood sugar for insulin control and taking their children for treatment as soon as they show signs or symptoms that are concerning.”

According to the National Institute of Diabetes and Kidney Disease, symptoms of diabetic ketoacidosis include nausea and vomiting, stomach pain, fruity breath odor and rapid breathing. Untreated DKA can lead to coma and death.

An accompanying video and editorial are available online in the New England Journal of Medicine.

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the Health Resources and Services Administration. The PECARN DKA FLUID ClinicalTrials.gov number is NCT00629707.

Children’s National Health System’s Division of Pediatric Emergency Medicine has been a lead site for the PECARN network since its inception in 2001.

child measuring belly with tape measure

Children’s obesity research team presents compelling new findings

child measuring belly with tape measure

Faculty from Children’s National Health System’s Department of Psychology & Behavioral Health set out to learn if any demographic, psychiatric, or cognitive factors play a role in determining if an adolescent should be eligible for bariatric surgery, and what their weight loss outcomes might be. Presenting at the Society for Pediatric Psychology Annual Conference earlier this month, a group of researchers, fellows and clinicians, including surgeons from Children’s National showcased their findings. One of the posters developed by Meredith Rose, LGSW, ML, who works as an interventionist on a Children’s National clinical research team, received special recognition in the Obesity Special Interest Group category.

One presentation reported on a total of 222 pediatric patients with severe obesity, which is defined as 120 percent of the 95th percentile for Body Mass Index. Mean age of the participants was 16 years of age, 71 percent were female and 80 percent where Hispanic or non-White. As part of their preparation for surgery, all patients were required to complete a pre-bariatric surgery psychological evaluation, including a clinical interview and Schedule for Affective Disorders and Schizophrenia (KSADS-PL) screening. The studies by the Children’s teams were based on a medical record review of the pre-screening information. Adolescents being evaluated for surgery had high rates of mental health diagnoses, particularly anxiety and depression, but also included Attention Deficit Hyperactivity Disorder, eating disorders, and intellectual disability.

Another Children’s presentation at the conference looked at weight loss outcomes for adolescents based on IQ and intellectual disability. Overall, neither Full Scale IQ from the Wechsler Abbreviated Intelligence Scale – 2nd edition, nor the presence of an intellectual disability predicted weight loss following surgery.

“The sum of our research found that kids do really well with surgery,” said Eleanor Mackey, PhD, assistant professor of psychology and behavioral health. “Adolescents, regardless of the presence of intellectual disability areas are likely to lose a significant amount of weight following surgery,” added Dr. Mackey.

“This is a particularly important fact to note because many programs and insurers restrict weight loss surgery to ‘perfect’ candidates, while these data points demonstrate that our institution does not offer or deny surgery on the basis of any cognitive characteristics,” says Evan P. Nadler, M.D., associate professor of surgery and pediatrics. “Without giving these kids a chance with surgery, we know they face a lifetime of obesity, as no other intervention has shown to work long-term in this patient population. Our research should empower psychologists and physicians to feel more confident recommending bariatric surgery for children who have exhausted all other weight loss options.”

The research team concluded that examining how individual factors, such as intellectual disability, psychiatric diagnoses, and demographic factors are associated with the surgery process is essential to ensuring adequate and empirically supported guidelines for referral for, and provision of bariatric surgery in adolescents. Next steps by the team will include looking into additional indicators of health improvement, like glucose tolerance, quality of life, or other lab values, to continue evaluating the benefits of surgery for this population.

Janelle Vaughns

Few prescribing options exist for obese kids

Janelle Vaughns

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author.

Despite years of study and numerous public health interventions, overweight and obesity continue to grow in the U.S. Currently, more than two-thirds of adults have these issues, according to data from the Centers for Disease Control and Prevention. Children and adolescents also are being affected at an increasing rate: About one in five is obese. Obesity and overweight have been linked with a bevy of health problems, including Type 2 diabetes, high blood pressure, coronary heart disease and stroke.

Additionally, because obesity increases the percentage of fat tissue in relation to lean tissue and enlarges kidney size, it can affect how readily the body takes up, metabolizes and excretes medicines.

This latter issue can be particularly problematic in children, a population for whom relatively few drug studies exist. Now, a study team that includes Children’s National Health System researchers suggests that, despite the U.S. Congress providing incentives to drug manufacturers to encourage the study of medications in children, few approved drugs include safe dosing information for obese kids.

The study, performed in conjunction with the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research, surveyed pediatric medical and clinical pharmacology reviews under the FDA Amendments Act of 2007 and the FDA Safety and Innovation Act of 2012. The researchers used search terms related to weight and size to determine the current incorporation of obesity as a covariate in pediatric drug development.

Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only four labels, according to the study “Obesity and Pediatric Drug Development,” published online Jan. 19, 2018, in The Journal of Clinical Pharmacology.

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author. “Moving forward, regulators, clinicians and the pharmaceutical industry should consider enrolling more obese patients in pediatric clinical trials to facilitate the safe and effective use of the next generation of medicines by obese children and adolescents.”

Study co-authors include Children’s Gastroenterologist Laurie Conklin, M.D., and Children’s Division Chief of Clinical Pharmacology Johannes N. van den Anker, M.D., Ph.D.; Ying Long, Pharm.D., University of Southern California; Panli Zheng, Pharm.D., University of North Carolina at Chapel Hill; Fahim Faruque, Pharm.D., University of Maryland; and Dionna Green, M.D., and Gilbert Burckart, Pharm.D., both of the FDA.

Research reported in this news release was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number 5T32HD087969.

Maureen Monaghan

Using text messages and telemedicine to improve diabetes self-management

Maureen Monaghan

Maureen Monaghan, Ph.D., C.D.E., clinical psychologist and certified diabetes educator in the Childhood and Adolescent Diabetes Program at Children’s National Health System, awarded nearly $1.6 million grant from American Diabetes Association.

Adolescents and young adults ages 17-22 with Type 1 diabetes are at high risk for negative health outcomes. If fact, some studies show that less than 20 percent of patients in this population meet targets for glycemic control, and visits to the Emergency Department for acute complications like diabetic ketoacidosis peak around the same age.

The American Diabetes Association (ADA) awarded Maureen Monaghan, Ph.D., C.D.E., clinical psychologist and certified diabetes educator in the Childhood and Adolescent Diabetes Program at Children’s National Health System, nearly $1.6 million to evaluate an innovative behavioral intervention to improve patient-provider communication, teach and help patients maintain self-care and self-advocacy skills and ultimately prepare young adults for transition into adult diabetes care, limiting the negative adverse outcomes that are commonly seen in adulthood.

Dr. Monaghan is the first psychologist funded through the ADA’s Pathway to Stop Diabetes program, which awards six annual research grants designed to spur breakthroughs in fundamental diabetes science, technology, diabetes care and potential cures. Dr. Monaghan received the Accelerator Award, given to diabetes researchers early in their careers, which will assist her in leading a behavioral science project titled, “Improving Health Communication During the Transition from Pediatric to Adult Diabetes Care.”

“Behavior is such a key component in diabetes care, and it’s wonderful that the American Diabetes Association is invested in promoting healthy behaviors,” says Dr. Monaghan. “I’m excited to address psychosocial complications of diabetes and take a closer look at how supporting positive health behavior during adolescence and young adulthood can lead to a reduction in medical complications down the road.”

During the five year study, Dr. Monaghan will recruit patients ages 17-22 and follow their care at Children’s National through their first visit with an adult endocrinologist. Her team will assess participants’ ability to communicate with providers, including their willingness to disclose diabetes-related concerns, share potentially risky behaviors like drinking alcohol and take proactive steps to monitor and regularly review glucose data.

“The period of transition from pediatric to adult diabetes care represents a particularly risky time. Patients are going through major life changes, such as starting new jobs, attending college, moving out of their parents’ homes and ultimately managing care more independently,” says Dr. Monaghan. “Behavioral intervention can be effective at any age, but we are hopeful that we can substantially help youth during this time of transition when they are losing many of their safety nets.”

Study leaders will help participants download glucose device management tools onto their smartphones and explain how to upload information from patients’ diabetes devices into the system. Participants will then learn how to review the data and quickly spot issues for intervention or follow-up with their health care provider.

Patients also will participate in behavioral telemedicine visits from the convenience of their own homes, and receive text messages giving them reminders about self-care and educational information, such as “Going out with your friends tonight? Make sure you check your glucose level before you drive.”

At the study’s conclusion, Dr. Monaghan anticipates seeing improvements in psychosocial indicators, mood and transition readiness, as well as improved diabetes self-management and engagement in adult medicine.

Veronica-Gomez-Lobo

Multidisciplinary care for children with urogenital differences

Veronica-Gomez-Lobo

Veronica Gomez-Lobo, M.D., brought together a multidisciplinary team to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic.

When a child is born with urogenital differences, the chromosomes, internal organs or external genitalia are considered to be atypical. While these differences were once thought to be rare, they are more common than people realize, with about 1 in 100 newborns affected.

The complexities of caring for children with urogenital differences, also known as differences of sex development (DSD), were not fully understood for many years. In the past, if a child was born with DSD, the family would see an endocrinologist for hormone therapy and a urologist for surgical options. Counseling was not part of the standard of care, so there was little support available to help families understand the tremendous psychosocial impacts of DSD.

In the last decade, fundamental changes have occurred in the way physicians care for children affected by DSD, with psychosocial health becoming a prominent focus. Veronica Gomez-Lobo, M.D., a Children’s National pediatric and adolescent gynecologist, was one of the physicians who embraced this focus and sought out a new care paradigm for her patients.

Creating the PROUD Clinic

Dr. Gomez-Lobo brought together a multidisciplinary team – including medical geneticist Eyby Leon Janampa, M.D., geneticist Eric Vilain, M.D., Ph.D., urologist Daniel Casella, M.D., endocrinologist Kim Shimy, M.D., psychiatrist David Call, M.D., and psychologist Elaine Goldberg, Ph.D. – to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic. It can be very challenging to bring together diverse specialists in a complex area like DSD, but her team possesses a similar philosophy – to care for the whole family by managing both the psychosocial and medical aspects of care in one location.

The team meets before each clinic to discuss the patients they will see that day. Patients vary significantly by the type of DSD and also by age – some patients are still in utero, while others may be newborns, children, adolescents or even occasionally adults.

Families see the entire team during their appointment, which can often last two to three hours to ensure that families receive the full support resources offered by the team.

“Even in difficult cases without a clear answer, we present the facts we know to the families, discussing all possibilities about psychosocial issues, gender identity, sexuality, function and fertility,” says Dr. Gomez-Lobo.

Long after the initial appointment, the PROUD Clinic continues to work closely with families and individual providers, following up as needed for medical diagnosis and care and providing continued psychosocial support with the entire team. Due to the efforts of the PROUD Clinic, patients and their families are now receiving compassionate care that looks at all facets of DSD, from childhood through adulthood.

Increasing DSD knowledge in the medical community

In order to give her patients the most thorough understanding of DSD and to expand the medical community’s knowledge, Dr. Gomez-Lobo’s program also participates in the Disorders of Sex Development Translational Research Network (DSD-TRN), which is led by Dr. Vilain. Supported by the National Institutes of Health (NIH), the DSD-TRN provides physicians across the country with the ability to perform research to advance knowledge regarding these conditions, as well as learn how to improve the care of these individuals and families. The DSD-TRN also provides a forum to seek advice about complex cases and to communicate how to transition patients from pediatric to adult medicine.

The relationship with the DSD-TRN helps the PROUD Clinic team further their goal of creating care for their patients that is current, individualized and compassionate.

 

Eric Vilain

Exploring differences of sex development

Eric Vilain, M.D., Ph.D.

Eric Vilain, M.D., Ph.D., analyzes the genetic mechanisms of sex development to give families more answers that will help them make better treatment (or non treatment) decisions for a child diagnosed with DSD.

Eric Vilain, M.D., Ph.D., is well versed in the “world of uncertainty” that surrounds differences of sex development. Since joining Children’s National as the director of the Center for Genetic Medicine Research in 2017, he’s shared with our research and clinical faculty and staff his expertise about the ways that genetic analysis might help address some of the complex social, cultural and medical implications of these differences.

Over the summer, he gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week, an annual celebration of research, education, innovation and scholarship at Children’s National and around the world. In January 2018, he shared a more clinically oriented version of the talk at a special Children’s National Grand Rounds session.

The educational objective of these talks is to inform researchers and providers about the mechanisms of differences of sex development (DSD), which are defined as congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.

The primary goal, though, is to really shine light on the complexity of this hot topic, and share how powerful genetic tools can be used to provide vital, concrete information for care providers, patients and families to assist with difficult treatment (and non-treatment) decisions.

“A minority of DSD cases are able to receive a genetic diagnosis today,” he points out. “But geneticists know how important it is to come to a diagnosis and so we seek to increase the number of patients who receive a concrete genetic diagnosis. It impacts genetic counseling and reproductive options, and provides a better ability to predict long term outcomes.”

“These differences impact physiology and medicine. We want to better understand the biology of reproduction, with an emphasis on finding ways to preserve fertility at all costs, and how these variations may lead to additional complications, including cancer risk.”

At conception, he explains, both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.

Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.

Dr. Vilain notes that a variation of enzymes or transcription factors can occur at any single step of sex development and alter all the subsequent steps. Depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia, for example.

He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues, including differences in gene expression within the brain. One study in the lab of investigator Matt Bramble, Ph.D., investigates if gonadal hormones impact sex differences in the brain by modifying the genome.

This work is a prime example of research informing the care provided to patients and families. Dr. Vilain is also a member of the multidisciplinary clinical team of the PROUD Clinic at Children’s National, a program completely devoted to caring for patients with a wide array of genetic and endocrine issues, including urogenital disorders and variations of sex development.

iLet-Bionic-Pancreas

Children’s National to test bionic pancreas

iLet-Bionic-Pancreas

The iLet bionic pancreas helps patients manage their diabetes by both monitoring blood glucose levels and administering insulin and glucagon.

Children’s National Health System has been selected to participate in a multi-center clinical trial to test the efficacy of the iLet bionic pancreas — a device that automatically regulates blood sugar levels in patients with Type 1 diabetes.

Patients generally manage diabetes by constantly monitoring their blood sugar levels and administering insulin when necessary. Unfortunately, too much insulin can cause hypoglycemia, or low blood sugar, which can result in hypoglycemic seizures, coma or rarely, death. Thus, it is extremely important for people with diabetes to regulate their insulin dosages and maintain their blood sugar levels within a range decided by the family and diabetes team.

“The burden of caring for diabetes on a daily basis is grueling,” says Seema Meighan, FNP, a nurse practitioner involved in the upcoming clinical trial. “It is by far one of the most challenging chronic diseases to manage, and requires vigilant participation 100 percent of the time to stay well controlled.”

The iLet bionic pancreas helps patients manage their diabetes by both monitoring blood glucose levels and administering insulin and glucagon — a pancreatic hormone that raises blood sugar levels.

“In a traditional infusion pump, patients only have access to insulin to control glucose levels,” explains Meighan. “This can become problematic when it comes to hypoglycemia. The hope with a bi-hormonal system is that glucagon can be delivered during times that the glucose is low in order to stabilize levels without user interaction.”

Developed at Boston University by Edward Damiano, Ph.D., and Firas El-Khatib, Ph.D., the iLet is a hand-held device about the size of an iPhone but twice as thick, and can easily fit into a pocket. The unit consists of a dual chamber infusion pump that can be configured to deliver only insulin, only glucagon or both hormones. The device uses a wireless glucose sensor on the patient’s body to test blood sugar levels every five minutes. It then determines which hormone is needed and administers it via catheters connected to the patient.

In short-term studies, the iLet was able to maintain blood glucose levels close to normal in both adults and children in carefully controlled environments.

In 2016, the Children’s National Health System Division of Endocrinology and Diabetes, led by diabetologist Fran Cogen, M.D., C.D.E., was one of several pediatric sites that were selected to participate in pivotal clinical trials to further test the efficacy of the bionic pancreas. Later this year, the team at Children’s National will begin enrolling five to 10 children to test iLet devices that only deliver insulin. Once these initial studies are completed, the team will perform an additional trial to test iLet devices configured to deliver both insulin and glucagon.

“This trial is important as it represents the first dual chamber pump to manage glucose levels,” says Meighan. “It could potentially change the way we treat diabetes entirely. It represents a hope to our patients and families that one day this disease will have far less of a daily burden than it currently does.”

Adolescent brain scan from obesity study

Imaging captures obesity’s impact on the adolescent brain

Adolescent brain scan from obesity study

For the first time, a team of researchers led by Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University, has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery.

Obesity affects the whole body, from more obvious physical impacts on bones and joints to more subtle, internal impacts on organs like the brain.

For the first time, a team of researchers has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery. The goal is to better understand the neural changes that occur when an adolescent is obese, and determine the effectiveness of interventions, such as vertical sleeve gastrectomy, at improving brain function as weight is lost.

The study, published as the November Editors’ Choice in the journal Obesity, found that executive and reward-related brain functions of study participants with obesity improved following the surgical procedure and initial weight loss.

How bariatric surgery changes the teenage brain from Research Square on Vimeo.

“We’ve known for some time that severe obesity has negative consequences on some neurocognitive function areas for adults,” says Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University and a senior author of the study. “But for the first time, we’ve captured fMRI evidence in young patients, and also shown that surgical intervention and the resulting weight loss can reverse some of those deficits.”

“For me, this early evidence makes a strong case that when kids are struggling with severe obesity, we need to consider surgical intervention as an option sooner in the process,” notes Evan Nadler, M.D., director of the Bariatric Surgery Program at Children’s National Health System, who also contributed to the study. “The question that remains is whether the neurocognitive function improves more if surgery, and thus weight loss, happens earlier – and is there a time factor that should help us determine when to perform a procedure that will maximize improvements?”

The preliminary study included 36 participants and was conducted using patients recruited from the Children’s National Bariatric Surgery program, one of the first children’s hospitals to achieve national accreditation by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program.

“We asked these questions because we know that in the kids we see, their behavioral, brain, and physical health are all very closely related to one another and have an impact on each other,” adds Eleanor Mackey, Ph.D., study senior author and co-principal investigator on the National Institute of Diabetes and Digestive and Kidney Diseases grant that funded the project. “We expected that as physical health improves, we might see corresponding improvements in brain and behavior such as cognitive and school performance.”

The study also pointed out some technical and practical challenges to studying this particular young population. Anyone with a BMI greater than 50 was not able to fit within the MR bore used in the study, preventing fMRI participation by those patients.

“In addition to future studies with a larger sample size, we’d like to see if there are neuroimaging markers of plasticity differences in a population with BMI greater than 50,” says Dr. Vaidya. “Does the severity of the obesity change how quickly the brain can adapt following surgery and weight loss?”

The abstract was selected by the journal’s editors as one that provides insights into preventing and treating obesity. It was featured at the Obesity Journal Symposium during Obesity Week 2017 in Washington, D.C., as part of the Obesity Week recognition, and a digital video abstract was also released about the findings.

child measuring belly with tape measure

Defining cardiovascular disease and diabetes risks in kids

child measuring belly with tape measure

In the Clinical Report, a study team describes the current state of play and offers evidence-based recommendations to guide clinicians on how to approach metabolic syndrome in children and adolescents.

For more than a decade and a half, researchers and clinicians have used the term “metabolic syndrome” (MetS) to describe a set of symptoms that can raise the risk of cardiovascular disease. Although this constellation of factors has proven to be a good predictor of cardiometabolic risk in adults, it has not been as useful for children. That’s why the American Academy of Pediatrics (AAP) now recommends that pediatricians instead focus on clusters of cardiometabolic risk factors that are associated with obesity, a condition that currently affects one in six U.S. children and adolescents.

In a new collaborative report, a study team from Children’s National Health System’s Division of Endocrinology and Diabetes, Harvard Medical School and Duke Children’s Hospital and Health Center describes the current state of play and offers evidence-based recommendations to guide clinicians on how to approach MetS in children and adolescents.

Adults with MetS have at least three of the following five individual risk factors:

  • High blood sugar (hyperglycemia)
  • Increased waist circumference (central adiposity)
  • Elevated triglycerides
  • Decreased high-density lipoprotein cholesterol (HDL-C), so-called “good” cholesterol and
  • Elevated blood pressure (hypertension).

This toxic combination ups adults’ odds of developing diabetes or heart disease. The process is set in motion by insulin resistance. Think Mousetrap, with each new development facilitating the next worrisome step. As fat expands, the cells become enlarged and become more resistant to insulin – a hormone that normally helps cells absorb glucose, an energy source. However, insulin retains the ability to stimulate fatty acids, which promotes even more fat cell expansion. Ectopic fat ends up stored in unexpected places, such as the liver. To top it off, the increased fat deposits end up causing increased inflammation in the system.

At least five health entities, including the World Health Organization, introduced clinical criteria to define MetS among adults, the study authors write. Although more than 40 varying definitions have been used for kids, there is no clear consensus whether to use a MetS definition for children at all, especially as adolescents mature into adulthood. Depending on the study, at least 50 percent of kids no longer meet the diagnostic criteria weeks or years after diagnosis.

“Given the absence of a consensus on the definition of MetS, the unstable nature of MetS and the lack of clarity about the predictive value of MetS for future health in pediatric populations, pediatricians are rightly confused about MetS,” the study authors write.

As a first step to lowering their patients’ cardiometabolic risks, pediatricians should prevent and treat obesity among children and adolescents, the study authors write. Each year, clinicians should perform annual obesity screening using body mass index (BMI) as a measure, and also should screen children once a year for elevated blood pressure. Nonfasting non-HDL-C or fasting lipid screening should be done for children aged 9 to 11 to identify kids whose cholesterol levels are out of line. The team also recommends screening for abnormal glucose tolerance and Type 2 diabetes in youth with BMI greater than or equal to the 85th percentile, 10 years or older (or pubertal), with two additional risk factors, such as family history, high-risk race/ethnicity, hypertension or a mother with gestational diabetes.

Pediatricians do not need to use cut points based on MetS definitions since, for many risk factors, the growing child’s risk lies along a continuum.

Treatments can include lifestyle modifications – such as adopting a negative energy balance diet, drinking water instead of sugar-sweetened beverages, participating in a moderate- to high-intensity weight-loss program, increasing physical activity and behavioral counseling.

“Identifying children with multiple cardiometabolic risk factors will enable pediatricians to target the most intensive interventions to patients who have the greatest need for risk reduction and who have the greatest potential to experience benefits from such personalized medicine,” the study authors conclude.

Fat Cells

Cellular signals may increase atherosclerosis risk

Fat Cells

Fat cells from obese patients have the ability to send signals that can accelerate biological processes leading to atherosclerosis.

Obesity has been linked to a variety of adverse health conditions, including Type 2 diabetes, cancer, heart attack and stroke – conditions that may begin as early as childhood in patients whose obesity also begins early. While this much is known, it has been unclear how extra fat mass might lead to these chronic health conditions.

New research from Children’s National Health System scientists might help answer this question. In findings presented at the 2017 annual meeting of the Pediatric Academic Societies, the research team shows that exosomes – nanosized chemical messages that cells send to each other to regulate protein production – isolated from very obese teenage patients behave very differently from those derived from lean patients and could be key players in heightening the risk of developing atherosclerosis. This hardening of the arteries can, in turn, increase the risk of heart disease and stroke in adulthood.

A research team led by Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National, is exploring possible links between extra belly fat and obesity-related diseases, such as atherosclerosis, a buildup of plaque in arteries that can harden and restrict blood flow. More precise knowledge of the mechanisms by which obesity ratchets up heart risks holds the promise of helping the next generation of kids avoid experiencing chronic disease.

The working theory is that exosomes derived from belly fat from obese patients have the distinct ability to accelerate biological processes leading to atherosclerosis.

The research team isolated exosomes from five obese teenagers and compared them to five sex-matched lean adolescents. It turns out that exosomes derived from fat pick up their marching orders from microRNA content likely to target cholesterol efflux genes, which help reduce cholesterol buildup in cells.

The research team looked at differences in cholesterol efflux gene expression in THP-1 macrophages. Uptake of low-density lipoprotein cholesterol, “bad” cholesterol, was 92 percent higher than in those exposed to exosomes from obese patients compared with their lean counterparts. Exposure to obese exosomes also reduced cholesterol efflux.

“Atherogenic properties of fat-cell derived exosomes from obese patients differ markedly from the non-atherogenic profile of exosomes from lean patients. It is especially concerning that we see biological clues of heightened risk in teenagers, and the finding underscores how the seeds for atherosclerosis can be planted very early in life,” Dr. Freishtat says.

The presentation is the latest finding from a research team that, over years of work, is unraveling the mechanisms of cellular signaling by fat cells.  By closely examining very obese children – who have the most severe cardiometabolic disease – the team identified strong molecular signals of disease risk that they can search for in leaner patients who may be at risk for disease years from now.

“We know that morbidly obese patients have cardiovascular issues,” explains Dr. Freishtat. “An unanswered question is for patients with no clinical symptoms who are a little overweight. Can we look at them and say whether they are at risk for developing atherosclerosis, insulin resistance or Type 2 diabetes five or 10 years down the line? That’s the whole rationale for doing this work.”

The critical issue is what exosomes are up to. Dr. Freishtat says in lean people, they’re active and are very important in maintaining stable metabolism and homeostatic processes.

“When a person becomes obese, however, exosomes evolve,” he says. “They no longer support insulin signaling, which is helpful, and drive processes in the reverse direction, repressing insulin signaling – which can be harmful,” he adds.

Ultimately, the research team aims to revolutionize how chronic diseases like Type 2 diabetes are diagnosed. For far too long, clinicians have relied on symptoms like high glucose levels and excess urination to diagnose diabetes.

“By the time you have symptoms, it’s too late,” says Dr. Freishtat. “In many cases, damage has been done by relentless exposure to high sugar levels. The biological processes that underlie the Type 2 diabetes process began five, 10, 15 years earlier. If we can detect it earlier, before symptoms arise, intervention is going to have a more significant impact on improving and extending patients’ lives.”

Teen Girl drawing a heart on an iPad

Illuminating cardiometabolic risk in Down syndrome

Teen Girl drawing a heart on an iPad

A leading researcher at Children’s National says researchers should look closely at the increased risks of obesity and thyroid disease common in patients with Down Syndrome, and determine how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

Over the last several decades, physicians’ improved ability to treat the common comorbidities of Down syndrome, such as congenital heart disease, has dramatically prolonged survival. Today, more than 400,000 people across the country are living with Down syndrome, and life expectancy has increased to 60 years.

New strategies to manage care for patients with Down syndrome must include preventive, evidence-based approaches to address the unique needs of these patients, according to Sheela N. Magge, M.D., M.S.C.E., Director of Research in the Division of Endocrinology and Diabetes at Children’s. She says that these efforts should include looking more closely at the increased risks of obesity and thyroid disease common in this population, and determining how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

An NIH-funded study from Children’s National and the Children’s Hospital of Philadelphia (CHOP), led by Dr. Magge and her colleague from CHOP, Dr. Andrea Kelly, seeks to better understand how the body composition of patients with Down syndrome impacts their likelihood for developing diabetes and obesity-related cardiovascular risks long term.

“We know that individuals with Down syndrome are at increased risk for obesity, but what hasn’t been clear is whether or not they also have the same cardiometabolic risk associated with obesity that we know holds true for other populations,” says Dr. Magge. “In this previously under-studied population, the common assumption based on very limited studies from the 1970’s was that individuals with Down syndrome were protected from the diabetes and cardiovascular risks that can develop in other overweight people. However, more recent epidemiologic studies contradict those early findings.”

The study has enrolled 150 Down syndrome patients and almost 100 controls to date, and the team is currently beginning to analyze the data. Dr. Magge believes that the findings from this study will help to provide new, research-driven evidence to inform the long term clinical management of obesity and cardiometabolic risk in adolescents with Down syndrome.

She concludes, “The goal is for our research to provide the foundation that will advance prevention and treatment strategies for this understudied group, so that individuals with Down syndrome not only have a longer life expectancy, but also a healthier and better quality of life.”

Eric Vilain, M.D., Ph.D.

Eric Vilain to lead genetic medicine research

Eric Vilain

Eric Vilain, M.D., Ph.D., emphasizes the idea of health and disease as a compound process that will transform children’s health and impact a patient throughout life.

Eric Vilain, M.D., Ph.D., an internationally renowned geneticist well known for groundbreaking studies of gender based biology, will soon lead the Center for Genetic Medicine Research at Children’s National Health System.

Dr. Vilain joins Children’s National from the University of California, Los Angeles (UCLA) where he serves as Professor of Human Genetics, Pediatrics and Urology, Chief of Medical Genetics, and attending physician in the Department of Pediatrics.

As the Director of the Center for Genetic Medicine Research, Dr. Vilain will emphasize the idea of health and disease as a compound process, which he believes “can transform children’s health and help the treatment and prevention of illness, not only in childhood, but throughout a patient’s life.”

The Center for Genetic Medicine Research currently houses a highly interdisciplinary faculty of over 50 scientists and physician investigators and brings together a variety of clinical and scientific disciplines to coordinate scientific and clinical investigations simultaneously from multiple angles. The Center also provides access to the leading edge innovative technologies in genomics, microscopy, proteomics, bioinformatics, pre-clinical drug trials, and multi-site clinical trial networks for faculty within the Children’s Research Institute, the academic arm of Children’s National.

Dr. Vilain’s current laboratory focuses on the genetics of sexual development and sex differences – specifically the molecular mechanisms of gonad development and the genetic variants of brain sexual differentiation. His research also explores the biological bases of sex variations in predisposition to disease. His work crosses several disciplines (genetics, neuroscience, psychology) leading to findings with major societal implications. In addition to scientific investigation, Dr. Vilain created a clinic devoted to caring for patients with a wide array of genetic and endocrine issues, particularly those with variations of sexual development.

He brings nearly 30 years of expertise with him to Children’s National. He has authored seminal articles regarding the field of sexual development, and his research program has continuously been funded by the National Institutes of Health (NIH). Dr. Vilain is a Fellow of the American College of Medical Genetics and a member of numerous professional committees. The recipient of numerous awards, he has been recognized by organizations ranging from the NIH to the Doris Duke Charitable Foundation, March of Dimes, and the Society for Pediatric Research. He has served as an advisor to the International Olympic Committee Medical Commission since 2011 and has been a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development since 2015.

Mark Batshaw, M.D., Executive Vice President, Physician-in-Chief, and Chief Academic Officer at Children’s National says, “Dr. Vilain’s vision and expertise in the study and use of precision medicine approaches, and the development of novel treatments for diseases of childhood, will lead to drastically different and improved outcomes for some of the most devastating diseases, such as cancer.”

“I am honored to join the world-renowned team at Children’s National, and look forward to continuing to find new, innovative ways to research, diagnose and treat rare and common disorders,” Dr. Vilain adds.

Diabetes telemedicine program launches study survey and retrospective chart review

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Telemedicine isn’t new. And diabetes telemedicine isn’t new either. But the Diabetes Program at Children’s National Health System is doing more than just providing education and support groups via telemedicine. The largest pediatric diabetes program in the Mid-Atlantic region is evaluating just how successful its telemedicine program is with a six-month survey and retrospective chart review. “This is our opportunity to prove [the success] not anecdotally but with evidence,” says Colleen Meehan, M.D., M.P.H., a third-year resident at Children’s and one of the co-investigators for the project.

According to published literature, the Children’s National cohort is one of the largest of any other diabetes telemedicine program and extends the time period of care.

History of the program

Around the world, there isn’t enough endocrinology care, says Fran Cogen, M.D., C.D.E. Dr. Cogen and others at Children’s National have recognized the need right in their region—and worldwide—to deliver specialty care to patients who live too far from Washington, DC.

Many of the patients Dr. Cogen sees at Children’s National live on Maryland’s Eastern Shore, including the island of Tangiers, and in Delaware. That’s a two-and-a-half-hour drive over the Chesapeake Bay Bridge and an obstacle to scheduling follow-up appointments. To solve this issue, Children’s National partnered with Peninsula Regional Medical Center, in Salisbury, Md., three years ago to improve patients’ quality of life while getting them the care they needed.

How the program works

A nurse practitioner at Peninsula Regional sees patients for blood glucose checks and more frequently. Once a month, or depending on the severity of the diabetes, Dr. Cogen will observe—on a large TV screen from Children’s National—physical examinations, and then review insulin regimens and dosing, download the glucose meters in real time, discuss concerns, and develop treatment plans. There’s diabetes-specific software that patients can see at Peninsula Regional.

What the study can reveal

A 2014 pilot survey showed caregivers had great satisfaction with the program. Now, the team wants to formally study caregiver satisfaction and patient quality of life, as measured by a validated diabetes-specific Pediatric Quality of Life survey. With the largest cohort in diabetes telemedicine (75, type 1), it will also look at frequency of blood glucose monitoring, HbA1c, incidence of ER visits and hospitalizations for DKA or hypoglycemia, and percentage of missed clinic appointments. The team believes that this will show the diabetes telemedicine program is as effective as traditional face-to-face visits.

Other specialties at Children’s National are planning to provide telemedicine services, and some already do. The Diabetes Telemedicine Program is looking to expand coverage in Delaware, Maryland, and Virginia, to other rural areas that lack pediatric endocrinology or diabetes specialists.

“We can deliver quality care and develop a personal relationship without actually being physically present in the exam room,” Dr. Cogen says.

Robert J. Freishtat

A game changer for detecting complications from obesity

Robert J. Freishtat

The work that Children’s National Health System physician-scientist Robert J. Freishtat, M.D., M.P.H., and colleagues are doing could soon be a game changer when it comes to early intervention and prevention of obesity-related illnesses.

They already knew there’s a direct relationship between the amount of visceral adipose, or belly fat, a person has and development of some of the most common and life-threatening complications of obesity, including cardiovascular disease and the insulin resistance that leads to diabetes. What remained unclear, until recently, were the precise mechanisms for how the increase in belly fat triggers the onset of additional disease.

Dr. Freishtat, senior author of “Adipocyte-Derived Exosomal miRNAs: A Novel Mechanism for Obesity-Related Disease,” published by Pediatric Research, studies the adipocytes, or fat cells, of visceral adipose in both lean and obese patients to understand exactly how these fat cells can and do wreak havoc — not just locally but throughout the body. Cells leverage exosomes to communicate among themselves, but in overweight patients those cellular communications can go awry.

“As the body’s visceral fat grows, somewhere on the path to obesity the fat cells change and begin to release different exosomes than lean adipose cells do. These new messages disrupt some important processes that eventually prevent the body from effectively dealing with sugar and cholesterol,” says Dr. Freishtat, chief of Emergency Medicine at Children’s National, and associate professor of Pediatrics, Emergency Medicine, and Integrative Systems Biology at the George Washington University.

Dr. Freishtat describes exosomes as “biological tweets”— short messages shed by all cells that allow for intercellular communication and alter gene expression. In the case of the adipocytes that exist in large quantities of visceral fat, these “tweets” actually cause the downregulation of proteins impacting two key signaling pathways — TGF-β and Wnt/β-catenin — associated with controlling chronic inflammation and fibrotic disease throughout the body. These signaling changes make morbidly obese patients more vulnerable to systemwide issues, such as cholesterol accumulation and changes to how the liver processes fat.

Details of the study

The study authors surgically collected fat tissue from lean and obese female patients aged 11 to 19 and used modified bead-based flow cytometry to separate, identify, and compare the exosomal RNA shed by the fat cells in both lean and obese samples. To confirm the unique impact of the obese adipose exosomes on gene expression, the research team then exposed lung cells in vivo to the exosomes shed by both lean and obese adipose. They measured the impact of exposure and uptake on a single receptor type — activin receptor type-2B — known to have a major influence on the TGF-β pathway. The exosomes from obese adipose caused the receptor to slow down, leading to significant changes in the function of the TGF-β pathway.

The team continues to explore how the exosomes shed from excess amounts of visceral adipose spread throughout the body and how the function of organs such as the liver, the heart, and the brain are impacted by the migrating fat cells.

A Look into the future

Successfully identifying and isolating these exosomes also has opened the door to developing a test to detect them, an idea that may permit even earlier intervention to delay or prevent the onset of obesity-related illnesses.

“It is entirely plausible, and is on its way to happening very soon, that someone could walk into their physician’s office for a routine physical and, via a urine test, find out that they are on the road to some dangerous additional side effects of significant weight gain,” says Dr. Freishtat. “That type of early detection could really be a game changer for the millions of Americans who are on track to developing heart, liver, and other diseases resulting from morbid obesity.”