Diabetes & Endocrinology

Nikki Gillum Posnack

Do plastic chemicals contribute to the sudden death of patients on dialysis?

Nikki Gillum Posnack

Nikki Posnack, Ph.D., assistant professor with the Children’s National Heart Institute, continues to explore how repeat chemical exposure from medical devices influences cardiovascular function.

In a review published in HeartRhythm, Nikki Posnack, Ph.D., an assistant professor at the Children’s National Heart Institute, and Larisa Tereshchenko, M.D., Ph.D., FHRS, a researcher with the Knight Cardiovascular Institute at Oregon Health and Science University, establish a strong foundation for a running hypothesis: Replacing BPA- and DEHP- leaching plastics for alternative materials used to create medical devices may help patients on dialysis, and others with impaired immune function, live longer.

While Drs. Tereshchenko and Posnack note clinical studies and randomized controlled trials are needed to test this theory, they gather a compelling argument by examining the impact exposure to chemicals from plastics used in dialysis have on a patient’s short- and long-term health outcomes, including sudden cardiac death (SCD).

“As our society modifies our exposure to plastics to mitigate health risks, we should think about overexposure to plastics in a medical setting,” says Posnack. “The purpose of the review in HeartRhythm is to gather data about the impact chemical compounds, leached from plastic devices, have on cardiovascular outcomes for patients spending prolonged periods of time in the hospital.”

In this review, the authors explore chemical risk exposures in a medical setting, starting with factors that influence sudden cardiac death (SCD) among dialysis patients.

Why study dialysis patients?

SCD in dialysis patients accounts for one-third of deaths in this population. This prompts a need to develop prevention strategies, especially among patients with end-stage renal disease (ESRD).

The highest mortality rate observed among dialysis patients is during the first year of hemodialysis, a dialysis process that requires a machine to take the place of the kidneys and remove waste from the bloodstream and replenish it with minerals, such as potassium, sodium and calcium. During this year, mortality during hemodialysis is observed more frequently during the first three months of treatment, especially among older patients.

Possible reasons for an increased risk of an earlier death include chemical exposure, which is casually associated with altered cardiac function, as well as genetic risks for irregular heart rhythms and heart failure. In the HeartRhythm review, Drs. Tereshchenko and Posnack analyze factors that influence mortality:

Hemodialysis treatment, dialysis, is associated with plastic chemical exposure

Drs. Tereshchenko and Posnack note that dialysis tubing and catheters are commonly manufactured using polyvinyl chloride (PVC) polymers. The phthalate plastics used to soften PVC can easily leech if exposed to lipid-like substances, like blood. Research shows phthalate chemical concentrations increase during a four-hour dialysis.

Di(2-ethylhexyl) phthalate (DEHP) is a common plastic used to manufacture dialysis tubes, thanks to its structure and economy.

Bisphenol-A (BPA) is another common material used in medical device manufacturing. From the membranes of medical tools to resins, or external coatings and adhesives, BPA leaves behind a chemical residue on PVC medical devices.

In reviewing the research, the authors find dialysis patients are often exposed to high levels of DEHP and BPA. The amount of exposure to these chemicals varies in regards to room temperature, time of contact, other circuit coatings and the flow rate of dialysis. A faster flow rate correlates with reductions in chemical leaching and lower mortality rates.

Plastic chemical exposure is casually associated with altered cardiac function

Drs. Tereshchenko and Posnack note a causal relationship already exists between chemicals absorbed from plastics and cardiovascular outcomes.

Dr. Posnack’s previous research found BPA concentrations impaired electrical conduction in neonatal cardiomyocytes – young, developing heart cells – potentially altering the heart’s normal rhythm and function.

To the best of their knowledge, no clinical research has been conducted on DEHP exposure and SCD. However, proof-of-concept models find in vivo phthalate exposure alters autonomic regulation, which can slow down natural heart-rate rhythm and create a lag in recovery time to stressful stimuli. For humans, this type of stressful stimulation would be equivalent to recovering from a bike ride, car accident, or in this case, ongoing dialysis treatment with impaired immune function.

In other models, BPA exposure has been shown to cause bradycardia, or a delayed heart rate. In excised whole heart models, BPA has also been shown to alter cardiac electrical activity.

Abnormal electrophysiological substrate in end-stage renal disease

Since the heart and kidneys work in tandem to transport blood throughout the body, and manage vital functions, such as our heart rate, blood flow and breathing, the authors cite additional factors that lead to ongoing heart and kidney problems, with a look at end-stage renal disease (ESRD).

General heart-function kidney risks include abnormal electrophysiological (EP) substrate, the underlying electrical activity of the cardiac tissue, and genetic risk factors, including the TBX3 gene, a gene associated with a unique positioning of the heart and SCD.

“We don’t want to cite alarm about having a medical procedure or about relying on external help, such as dialysis, for proper kidney function,” says Posnack. “Especially since dialysis is a life-saving medical intervention for patients with inadequate kidney function.”

Pre-existing abnormal EP substrate interacts with plastic chemical exposure in incident dialysis, which increases risk of SCD in genetically predisposed ESRD patients

To summarize their findings, Drs. Tereshchenko and Posnack list a handful of support areas, starting with observations about reductions in cardiovascular mortality and SCD following kidney transplants. They note hemodialysis catheters are associated with larger DEHP exposure and a higher risk of SCD, compared to arteriovenous fistulas, highways surgically created to connect blood from the artery to the vein.

Drs. Posnack and Tereshchenko also note a correlative observation about higher SCD rates observed six hours after hemodialysis, when peak levels of DEHP and BPA are circulating in the bloodstream.

To compare and control for these factors among dialysis patients, the researchers cite different mortality patterns with hemodialysis and peritoneal dialysis. Patients on hemodialysis experience higher mortality during the first year of treatment, compared to peritoneal dialysis, who have higher mortality rates after the second year of treatment. Hemodialysis relies on a machine to take the place of kidney function, while peritoneal dialysis relies on a catheter, a small tube surgically inserted into the stomach.

“Our goal is to build on our previous research findings by analyzing variables that have yet to be studied before, and to update the field of medicine in the process,” says Dr. Posnack. “This includes investigating the cardiovascular risks of using BPA- and DEHP-materials to construct medical devices. Ultimately, we hope to determine whether plastic materials contribute to cardiovascular risks, and investigate whether patients might benefit from the use of alternative materials for medical devices.

Drs. Tereshchenko and Posnack note that despite the associations between chemical exposure from medical devices and increased cardiovascular risks, there are no restrictions in the United States on the use of phthalates and BPA chemicals used to manufacture medical devices.

Their future research will explore how replacing BPA- and DEHP-leaching plastics influence mortality and morbidity rates of ESRD patients on dialysis, as well as other patients exposed to repeat chemical exposure, such as patients having cardiac surgery.

“We want to make sure we identify and then work to minimize any potential risks of plastic exposure in a medical setting,” adds Dr. Posnack. “Our goal is to put the health and safety of patients first.”

Dr. Posnack’s research is funded by two grants (R01HL139472, R00ES023477) from the National Institutes of Health.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

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.

Electronic medical record on tablet

Children’s National submissions make hackathon finals

Electronic medical record on tablet

This April, the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and The George Washington University (GW) will hold their 2nd Annual Medical and Health App Development Workshop. Of the 10 application (app) ideas selected for further development at the hackathon workshop, five were submitted by clinicians and researchers from Children’s National.

The purpose of the half-day hackathon is to develop the requirements and prototype user interface for 10 medical software applications that were selected from ideas submitted late in 2017. While idea submissions were not restricted, the sponsors suggested that they lead to useful medical software applications.

The following five app ideas from Children’s National were selected for the workshop:

  • A patient/parent decision tool that could use a series of questions to determine if the patient should go to the Emergency Department or to their primary care provider; submitted by Sephora Morrison, M.D., and Ankoor Shah, M.D., M.P.H.
  • The Online Treatment Recovery Assistance for Concussion in Kids (OnTRACK) smartphone application could guide children/adolescents and their families in the treatment of their concussion in concert with their health care provider; submitted by Gerard Gioia, Ph.D.
  • A genetic counseling app that would provide a reputable, easily accessible bank of counseling videos for a variety of topics, from genetic testing to rare disorders; submitted by Debra Regier, M.D.
  • An app that would allow the Children’s National Childhood and Adolescent Diabetes Program team to communicate securely and efficiently with diabetes patients; submitted by Cynthia Medford, R.N., and Kannan Kasturi, M.D.
  • An app that would provide specific evidence-based guidance for medical providers considering PrEP (pre-exposure prophylaxis) for HIV prevention; submitted by Kyzwana Caves, M.D.

Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sean Cleary, Ph.D., M.P.H., associate professor in epidemiology and biostatistics at GW, created the hackathon to provide an interactive learning experience for people interested in developing medical and health software applications.

The workshop, which will be held on April 13, 2018, will start with short talks from experts on human factors engineering and the regulatory environment for medical and health apps. Attendees will then divide into small groups to brainstorm requirements and user interfaces for the 10 app ideas. After each group presents their concepts to all the participants, the judges will pick the winning app/group. The idea originator will receive up to $10,000 of voucher funding for their prototype development.

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.

Children’s National Diabetes Program Honored at SAMHSA’s National Children’s Mental Health Awareness Day

Maureen Monaghan and Fran Cogen at SAMHSA

The Substance Abuse and Mental Health Services Administration (SAMHSA) spotlighted the Children’s National diabetes program as an exemplar of integrated care for children and adolescents. Maureen Monaghan, Ph.D., CDE, (left) and Fran Cogen, M.D., CDE, interim co-chief of the Division of Endocrinology and Diabetes and director of the Childhood and Adolescent Diabetes Program, were in attendance.

On May 4, Maureen Monaghan, Ph.D., CDE, clinical and pediatric psychologist and certified diabetes educator in the Childhood and Adolescent Diabetes Program at Children’s National, participated in a panel emphasizing the importance of integrating physical and mental health in the care of young patients as part of the Substance Abuse and Mental Health Services Administration’s (SAMHSA) National Children’s Mental Health Awareness Day. SAMHSA also spotlighted the Children’s National diabetes program as an exemplar of integrated care for children and adolescents.

“Many of our families start out knowing nothing about the disease, and they now have a child whose care requires day-to-day management for the rest of their lives,” says Dr. Monaghan. “It’s not a disease you ever get a break from – which can take both a physical and emotional toll on children and their families.”

Maureen Monaghan at SAMHSA National Children’s Mental Health Awareness Day

Dr. Monaghan participated in a panel emphasizing the importance of integrating physical and mental health in the care of young patients with diabetes.

To combat this issue and reduce barriers and stigma related to seeking mental health care, the program brings a dedicated, multidisciplinary care team together in one convenient location.

From the initial diagnosis, patients have access to care from a comprehensive team, including six physicians, three nurse practitioners, eight nurse educators, three psychologists, a physical therapist, dietitian and social worker. Each expert counsels the patient and the family, helping them navigate all aspects of living with the disease – from overcoming stress and anxiety to offering healthy meal-planning guides and exercise routines.

“We aren’t just concerned about how they are doing medically or what emotions they are experiencing,” says Dr. Monaghan. “Instead, our team’s integration allows us to focus on the whole child and his or her total quality of life, which is so important for patients and families with chronic disease.”

To learn more, watch this short video, featuring employees and patients of the Children’s National Childhood and Adolescent Diabetes Program, which was presented during the events surrounding the SAMHSA National Children’s Mental Health Awareness Day.

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.”

test tubes

2016: A banner year for innovation

test tubes

In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.

“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.

The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:

  • Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
  • The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
  • Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
  • Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
  • There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
  • Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Cas9-mediated correction of metabolic liver disease

AAV.CRISPR-SaCas9

In vivo gene correction of the OTC locus in the mouse liver by AAV.CRISPR-SaCas9. Source: Nature Publishing Group copyright 2016.

PDF Version

What’s known

A deficiency of the enzyme ornithine transcarbamylase (OTC) in humans causes life-threatening hyperammonemic crises.  The OTC gene enables the body to make an enzyme that is a critical player in the urea cycle, a process that ensures excess nitrogen is excreted by the kidneys. Left unchecked, accumulating nitrogen becomes a toxic form of ammonia. Infants with OTC deficiency can suffer their first metabolic crisis as newborns. Up to 50 percent die or sustain severe brain injury, and survivors typically need a liver transplant by age 1. Gene therapy could cure OTC deficiency, but currently used viruses, such as adeno-associated virus (AAV), are not optimal in the neonatal setting.

What’s new

A research team led by Children’s National Health System and the University of Pennsylvania reasoned that the newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR-Cas9 gene editing. They intravenously infused two AAVs into two-day-old mice with partial OTC deficiency. One AAV expressed Cas9 and the other expressed a guide RNA and a donor OTC DNA. This resulted in correction of the mutation in 10 percent of liver cells and increased survival in mice challenged with a high-protein diet, which normally exacerbates disease. After consuming a high-protein diet for one week, the treated newborns had a 40 percent reduction in ammonia compared with the untreated group. The correction appears to last long term. The study “provides evidence for efficacy of gene editing in neonatal onset OTC deficiency,” says Mark L. Batshaw, M.D., Physician-In-Chief and Chief Academic Officer at Children’s National, and a study co-author. “This study provides convincing evidence for efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease,” the research team concludes.

Questions for future research

Q: More than 400 mutations can cause OTC deficiency, and each would require a separate gene-editing approach. Is it possible instead to insert the OTC genome using CRISPR-Cas9 to correct the disorder irrespective of the mutation?
Q: Will such gene editing also work in adult animal models of the OTC disorder?
Q: Do these encouraging results in animals translate to efficacy in infants?

Source: Yang, Y., L. Wang, P. Bell, D. McMenamin, Z. He, J. White, H. Yu, C. Xu, H. Morizono, K. Musunuru, M.L. Batshaw and J.M. Wilson. “A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice.” Published Feb. 1, 2016 by Nature Biotechnology.

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.”

Scientist with centrifuge

Giving fat cell messages a positive spin

Woman on a scale

Study findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that detrimental effects of carrying too much weight can recede. (Image source: Centers for Disease Control and Prevention)

Losing weight appears to reset the chemical messages that fat cells send to other parts of the body that otherwise would encourage the development of Type 2 diabetes, substantially reducing the risk of that disease, a team led by Children’s National Health System researchers report in a new study. The findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that many of the detrimental effects of carrying too much weight can recede, even on the molecular level, once they lose weight.

In 2015, Robert J. Freishtat, M.D., M.P.H., Chief of Emergency Medicine at Children’s National and Associate Professor of Pediatrics, Emergency Medicine and Integrative Systems Biology at The George Washington University School of Medicine & Health Sciences, and colleagues showed that fat cells (also known as adipocytes) from people who are obese send messages to other cells that worsen metabolic function. These messages are in the form of exosomes, nanosized blobs whose contents regulate which proteins are produced by genes. Exosomes are like “biological tweets,” Dr. Freishtat explains — short signals designed to travel long distances throughout the body.

Dr. Freishtat’s earlier research showed that the messages contained in exosomes from patients who are obese alter how the body processes insulin, setting the stage for Type 2 diabetes. However, says Dr. Freishtat, it has remained unclear since that publication whether these aberrant messages from adipocytes improve after weight loss.

“We’ve known for a long time that too much adipose tissue is bad for you, but it’s all moot if you lose the weight and it’s still bad for you,” he explains. “We wanted to know whether these negative changes are reversible. If you reduce fat, does the disease risk that goes along with excess fat also go away?”

Details of the study

To investigate this question, Dr. Freishtat and colleagues worked with six African American adults scheduled to receive gastric bypass surgery — a nearly surefire way to quickly lose a large amount of weight. The volunteers, whose average age was 38 years, started out with an average body mass index (BMI) of 51.2 kg/m2. (The Centers for Disease Control and Prevention considers a healthy BMI to range between 18.5 to 24.9.)

Two weeks before these volunteers underwent surgery, researchers collected blood samples and took a variety of measurements. The researchers then performed a repeat blood draw and measurements one year after the surgery took place, when the volunteers’ average BMI had dropped to 32.6.

Dr. Freishtat and colleagues drew out the adipocyte-derived exosomes from both sets of blood samples and analyzed their contents. The team reports in the January 2017 issue of Obesity that at least 168 microRNAs — the molecules responsible for sending specific messages — had changed before and after surgery. Further analyses showed that many of these microRNAs were involved in insulin signaling, the pathways that the body uses to regulate blood sugar. By changing these outgoing microRNAs for the better, Dr. Freishtat says, adipocytes actively were encouraging higher insulin sensitivity in other cells, warding off Type 2 diabetes.

Sure enough, each volunteer had better insulin sensitivity and other improved markers of metabolic health post-surgery, including lower branched chain amino acids and a two-fold reduction in their glutamate to glutamine ratio.

“These volunteers were essentially cured of their diabetes after surgery. The changes we saw in their surgery-responsive microRNAS correlated with the changes we saw in their metabolic health,” Dr. Freishtat says.

A glimpse into the future

Dr. Freishtat and colleagues plan to study this phenomenon in other types of weight loss, including the slower and steadier paths that most individuals take, such as improving diet and doing more exercise. The team expects to see similar changes in exosomes of patients who lose weight in non-surgical ways.

By further examining the aberrant messages in microRNAs being sent out from adipocytes, he says, researchers eventually might be able to develop treatments to reverse metabolic problems in overweight and obese patients before they lose the weight, improving their health even before the often challenging process of weight loss begins.

“Then, if you can disrupt this harmful signaling in combination with weight-loss strategies,” Dr. Freishtat says, “you’re really getting the best of both worlds.”

Eventually, he adds, tests might be available so that doctors can warn patients that their fat cells are sending out harmful messages before disease symptoms start. By giving patients an early heads up, Dr. Freishtat says, patients might be more likely to heed advice from physicians and make changes before it’s too late.

“If doctors could warn patients that their fat is telling their blood vessels to fill up with plaque and trigger a heart attack in 10 to 20 years,” he says, “patients might be more compliant with treatment regimens.”

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.”