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nurse checking boy's blood sugar levels

Improving glycemic control in diabetic children

nurse checking boy's blood sugar levels

A 10-week pilot study at Children’s National Health System integrated weekly caregiver coaching, personalized glucose monitoring and incentives into standard treatment for 25 pediatric patients with type 1 diabetes, lowering A1c by .5%

The life of a type 1 diabetes patient – taking daily insulin shots or wearing an insulin pump, monitoring blood sugar, prioritizing healthful food choices and fitting in daily exercise – can be challenging at age 5 or 15, especially as holidays, field trips and sleepovers can disrupt diabetes care routines, creating challenges with compliance. This is why endocrinologists from Children’s National Health System experimented with using health coaches over a 10-week period to help families navigate care for children with type 1 diabetes.

By assembling a team of diabetes educators, dietitians, social workers, psychologists and health care providers, Fran Cogen, M.D., C.D.E., director of diabetes care at Children’s National, helped pediatric patients with type 1 diabetes manage their glycemic status, or blood-sugar control.

On Saturday, June 8, 2019, Dr. Cogen will share results of the pilot program as poster 1260-P, entitled “A Clinical Care Improvement Pilot Program: Individualized Health Coaching and Use of Incentives for Youth with Type 1 Diabetes and their Caregivers,” at the American Diabetes Association’s 79th Scientific Sessions, which takes place June 7-11 at the Moscone Center in San Francisco.

Dr. Cogen’s study was offered at no cost to caregivers of 179 patients at Children’s National seeking treatment for type 1 diabetes. The pilot program included two components: 1) Weekly phone calls or emails from a health coach to a caregiver with personalized insulin adjustments, based on patient blood sugars submitted through continuous glucose monitoring apps; and 2) Incentives for patients to participate in the program and reach health targets.

Twenty-five participants, ages 4-18, with a mean age of 11.6 and A1c ranges between 8.6 – 10% joined the study. The average A1c was 9.4% at the beginning of the program and dropped by an average of .5% at the end of the trial. Twenty of the 25 participants, 80%, improved A1c levels by .5%. Seventeen participants, 68%, improved A1c levels by more than .5%, while seven participants, 28%, improved A1c levels by more than 1%.

“Chronic disease is like a marathon,” says Dr. Cogen. “You need to have constant reinforcement and coaching to get people to do their best. Sometimes what drives people is to have people on the other end say, ‘Keep it up, you’re doing a good job, keep sending us information so that we can make changes to improve your child’s blood sugar management,’ which gives these new apps and continuous glucose monitoring devices a human touch.”

Instead of waiting three months between appointments to talk about ways a family can make changes to support a child’s insulin control and function, caregivers received feedback from coaches each week. Health coaches benefitted, too: They reported feeling greater empathy for patients, while becoming more engaged in personalizing care plans.

Families who participated received a gift card to a local grocery store, supporting a child’s dietary goals. Children who participated were also entered into an iPad raffle. Improvements in A1c levels generated extra raffle tickets per child, which motivated participants, especially teens.

“These incentives are helpful in order to get kids engaged in their health and in an immediate way,” says Dr. Cogen. “Teenagers aren’t always interested in long-term health outcomes, but they are interested in what’s happening right now. Fluctuating blood sugars can cause depression and problems with learning, while increasing risk for future complications, including eye problems, kidney problems and circulation problems. As health care providers, we know the choices children make today can influence their future health outcomes, which is why we designed this study.”

Moving forward, Dr. Cogen and the endocrinologists at Children’s National would like to study the impact of using this model over several months, especially for high-risk patients, while  asynchronously targeting information to drive behavior change – accommodating the needs of families, while delivering dose-specific recommendations from health care providers.

Dr. Cogen adds, “We’re moving away from office-centric research models and creating interventions where they matter: at home and with families in real time.”

Read more about the study at Healio.com and dLife.

Additional study authors, all of whom work within the division of diabetes and endocrinology at Children’s National, include Lauren Clary, Ph.D., Sue-Ann Airborne, C.D.E., Andrew Dauber, M.D., Meredith Dillon, R.D., L.D.N., C.D.E., Beakel Eshete, B.S.N., R.N., C.D.E., Shaina Hatchell, B.S.N., R.N., Shari Jones, R.N., C.D.E., and Priya Vaidyanathan, M.D.

Robert J. Freishtat working in the lab

Detecting early signs of type 2 diabetes through microRNA

Robert J. Freishtat working in the lab

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Now researchers understand the pathogenesis better among teens with mid-level obesity, thanks to clues released from circulating adipocyte-derived exosomes.

Researchers know that exosomes, tiny nanoparticles released from fat cells, travel through the bloodstream and body, regulating a variety of processes, from growth and development to metabolism. The exosomes are important in lean, healthy individuals in maintaining homeostasis, but when fat gets ‘sick’ – the most common reason for this is too much weight gain – it can change its phenotype, becoming inflammatory, and disrupts how our organs function, from how our skeletal muscle and liver metabolize sugar to how our blood vessels process cholesterol.

Robert J. Freishtat, M.D., M.P.H., the chief of emergency medicine at Children’s National Health System and a professor of precision medicine and genomics at the George Washington University School of Medicine and Health Sciences, and Sheela N. Magge M.D., M.S.C.E., who is now the director of pediatric endocrinology and an associate professor of medicine at the Johns Hopkins School of Medicine, were curious about what this process looked like in teens who fell in the mid-range of obesity.

Obesity is a major risk factor for insulin resistance and type 2 diabetes, but Dr. Freishtat and Dr. Magge wanted to know: Why do some teens with obesity develop type 2 diabetes over others? Why are some teens in this mid-range of obesity metabolically healthy while others have metabolic syndrome? Can fat in obese people become sick and drive disease?

To test this, Dr. Freishtat and Dr. Magge worked with 55 obese adolescents, ages 12 to 17, as part of a study at Children’s National. The participants – 32 obese normoglycemic youth and 23 obese hyperglycemic youth – were similar in age, sex, race, pubertal stage, body mass index and overall fat mass. The distinguishing factor: The hyperglycemic study participants, the teens with elevated blood sugar, differed in where they stored fat. They had extra visceral fat (or adipose tissue) storage, the type of fat that surrounds the liver, pancreas and intestines, a known risk factor for type 2 diabetes.

Dr. Magge and Dr. Freishtat predicted that circulating exosomes from the teens with elevated blood sugar are enriched for microRNAs targeting carbohydrate metabolism.

They used three tests to examine study participants’ metabolism, body composition and circulating exosomes. The first test, an oral glucose tolerance test, measures how efficiently the body metabolizes sugar; the second test is the whole body DXA, or dual-energy x-ray absorptiometry, which analyzes body composition, including lean tissue, fat mass and bone mineral density; and the third test, the serum adipocyte-derived exosomal microRNA assays, is an analysis of circulating fat signals in the bloodstream.

They found that teens with elevated blood sugar and increased visceral fat had different circulating adipocyte-derived exosomes. These study participants’ exosomes were enriched for 14 microRNAs, targeting 1,304 mRNAs and corresponding to 179 canonical pathways – many of which are directly associated with carbohydrate metabolism and visceral fat.

Dr. Magge will present this research, entitled “Changes in Adipocyte-Derived Exosomal MicroRNAs May Play a Role in the Progression from Obese Normoglycemia to Hyperglycemia/Diabetes,” as an oral abstract at the American Diabetes Association’s 79th Scientific Sessions on Saturday, June 8.

Dr. Freishtat envisions having this information will be especially helpful for a patient in a mid-range of obesity. Exosomes primarily consist of small non-coding RNAs. In the current study, the altered RNAs affect P13K/AKT and STAT3 signaling, vital pathways for metabolic and immune function.

“Instead of waiting until someone has the biochemical changes associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia and insulin resistance, we’re hoping physicians will use this information to work with patients earlier,” says Dr. Freishtat. “Through earlier detection, clinicians can intervene when fat shows sign of illness, as opposed to when the overt disease has occurred. This could be intervening with diet and lifestyle for an obese individual or intervening with medication earlier. The goal is to work with children and teens when their system is more plastic and responds better to intervention.”

As this research evolves, Dr. Freishtat continues to look at the intergenerational effects of circulating adipocyte-derived exosomes. Through ongoing NIH-funded research in India, he finds these exosomes, similar in size to lipoproteins, can travel across the placenta, affecting development of the fetus in utero.

“What we’re finding in our initial work is that these exosomes, or ‘sick’ fat, cross the placenta and affect fetal development,” Dr. Freishtat says. “Some of the things that we’re seeing are a change in body composition of the fetus to a more adipose phenotype. Some of our work in cell cultures shows changes in stem cell function and differentiation, but what’s even more interesting to us is that if the fetus is a female sex that means her ovaries are developing while she’s in utero, which means a mother’s adipocyte-derived exosomes could theoretically be affecting her grandchild’s phenotype – influencing the health of three generations.”

While this research is underway, Dr. Freishtat is working with JPOD @ Boston, co-located with the Cambridge Innovation Center in Cambridge, Massachusetts, to develop a test to provide analyses of adipocyte-derived exosomal microRNAs.

“It’s important for families to know that these studies are designed to help researchers and doctors better understand the development of disease in its earliest stages, but there’s no need for patients to wait for the completion of our studies,” says Dr. Freishtat. “Reaching and maintaining a healthy body weight and exercising are important things teens and families can do today to reduce their risk for obesity and diabetes.”

Matt Oetgen talks about an x-ray

Nicotine-like anti-inflammatories may protect limbs, testicles from inflammatory damage after injury

Matt Oetgen talks about an x-ray

Dr. Matt Oetgen is teaming up with pediatric urologist Dan Casella for a POSNA-funded pre-clinical study of the anti-inflammatories varenicline and cytisine.

A new pre-clinical study will explore the use of anti-inflammatory medications to prevent the body’s inflammatory response from further damaging limbs after an injury restricts blood flow. Varenicline and cytisine, anti-inflammatories with similarities to nicotine, have shown early promise in similar pre-clinical laboratory studies of the testicles and will now be tested in arms and legs.

Matthew Oetgen, M.D., MBA, chief of Orthopaedic Surgery and Sports Medicine at Children’s National and Children’s pediatric urologist Daniel Casella, M.D., will jointly lead the new study entitled, “Modulation of the Injury Associated with Acute Compartment Syndrome,” which builds on Dr. Casella’s previous work with the two anti-inflammatory agents. Drs. Oetgen and Casella recently were awarded the Angela S.M. Kuo Memorial Award Research Grant to fund this research during the Pediatric Orthopaedic Society of North America’s (POSNA) Annual Meeting.

“We are honored that this important research was selected by POSNA for support,” says Dr. Oetgen. “An arm or leg injury can trigger the body’s natural inflammatory response, causing severe swelling that restricts blood flow. Even after blood flow is restored, the inflammatory response can lead to permanent muscle or nerve damage or even loss of limb. This grant will give us the opportunity to truly explore the application of anti-inflammatories after injury and see if this approach can modulate the immune response to protect the limbs.”

If successful in the laboratory, the team hopes to expand this work to human clinical trials.

The Angela S.M. Kuo Memorial Award Research Grant is given each year to an outstanding investigator aged 45 or younger based on criteria including the study’s potential significance, impact, originality/innovation, the investigator’s track record and study feasibility. The award totals $30,000.

While at POSNA’s 2019 Annual Meeting, Dr. Oetgen and Children’s pediatric orthopaedic surgery colleagues also participated in podium presentations and poster sessions, including:

  • “Achieving Consensus on the Treatment of Pediatric Femoral Shaft Fractures,” Matthew Oetgen, M.D., MBA
  • “A Prospective, Multi-centered Comparative Study of Non-operative and Operative Containment Treatments in Children Presenting with Late-stage Legg-Calve-Perthes Disease,” Benjamin Martin, M.D.

The Pediatric Orthopaedic Society of North America is an organization of 1,400 surgeons, physicians, and allied health members dedicated to advancing musculoskeletal care for children and adolescents. The annual meeting presents the latest research and expert clinical opinion in pediatric orthopaedics through presentations, posters, and symposia. It was held May 15-18, 2019, in Charlotte, North Carolina.

Pediatric Neurology Update Attendees

Pediatric neurologists get a primer on the state of ASD research and care

Pediatric Neurology Update Attendees

Neurologists who attended the 2019 Pediatric Neurology Update received a broad look at autism spectrum disorders, ranging from biology to clinical care and advocacy.

Autism spectrum disorders (ASD) took center stage for the afternoon sessions of the annual Pediatric Neurology Update in April. The meeting, hosted by the Center for Neuroscience and Behavioral Medicine at Children’s National Health System, brings together 150-plus pediatric neurologists each year to discuss critical research and clinical care of pediatric neurological conditions.

Led by the Center for Autism Spectrum Disorders Director Lauren Kenworthy, Ph.D., the afternoon’s slate of presentations sought to give broad perspective of the current state of ASD research and treatment best practices.

“We know that the brain is different in autism, but many times we continue to define autism by behavioral traits,” Dr. Kenworthy told the crowd in her introduction. “Sitting between the brain and behavior often is cognition – how do you understand your world and interpret it?”

The afternoon’s presentations were organized to provide the audience with a clear picture of many facets of ASD research and treatment. Highlights included:

  • Joshua Corbin, Ph.D., director of the Center for Neuroscience Research, offered “New Insights into the Neurobiologic Underpinnings of Autism,” which mapped out some of the biological mechanisms of autism.
  • Adelaide Robb, M.D., and Dr. Kenworthy presented current clinical care outlines, with Dr. Robb focusing on pharmacological therapies and Dr. Kenworthy sharing successful strategies to improve executive functioning and day to day task management for school-aged children.

Attendees also received a taste of two current “hot topics” in autism research and care:

  • Kevin Pelphrey, Ph.D., presented recent findings on “Gender Differences in Autism Spectrum Disorders: Girls with Autism” calling attention to the fact that the current diagnostic standards may not capture some female-associated phenotypes of ASD.
  • Julia Bascom of the Autistic Self Advocacy Network brought the autistic person’s point of view to the table via her presentation: “Autism: Society and Government Challenges and Solutions,” which focused on her organization’s efforts to improve inclusivity in advocacy and research, which she sums up as, “Nothing about us without us.”

The session concluded with a real-world focused “Autism-Friendly Hospital Roundtable,” of six panelists from the clinical, advocacy, community and technology fields, who are all involved in hands-on practices to improve medical experiences for autistic children and adults.

  • CASD’s Yetta Myrick talked about her work to engage families of autistic children in discussions of research and clinical care programs, including the start of CASD’s first-ever Stakeholder Advisory Board.
  • Julia Bascom talked about some of the less-often discussed challenges for many autistic people who seek medical services.
  • Kathleen Atmore, Psy.D., and Eileen Walters, MSN, RN, CPN, provided an overview of Beyond the Spectrum, the clinical service at Children’s National that coaches providers and families in techniques to reduce the stress of routine medical visits for patients with autism and other developmental disabilities.
  • Amy Kratchman, director of the LEND Family Collaboration at Children’s Hospital of Philadelphia, talked about some of the autism-friendly strategies underway at her institution.
  • Michael O’Neil, JD, MBA, founder and CEO of the GetWell Network, Inc., previewed how GetWell and Children’s National are partnering on a new tool that harnesses app technology to bring better information to autistic children and their families after a new autism diagnosis.
  • Vijay Ravindran, CEO and co-founder at Floreo, demonstrated how it might be possible to reduce stress and create a calm peaceful autism-friendly environment even in the busiest of waiting rooms, by allowing the patient to escape via virtual reality.

The roundtable showcased how Children’s National and other health care institutions are using evidence-based strategies to improve medical care experiences for autistic people and their families. Ideally any provider, including pediatric neurologists, who cares for people from the autism community, can incorporate any or all of these strategies as a way to meet the unique needs of this patient population.

The content was so timely and relevant to the audience that many attendees stayed past the official end of the meeting to continue discussing best practices with the panelists and each other.

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference

CME spotlight: Treating adult congenital heart disease

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference, which takes place Oct. 4-5, 2019.

A two-day continuing medical education (CME) conference for physicians and clinicians treating patients with adult congenital heart disease (ACHD) takes place Oct. 4-5, 2019, at the Bethesda Marriott in Bethesda, Maryland.

The eighth-annual conference, “Adult Congenital Heart Disease in the 21st Century,” hosted by Children’s National Health System and MedStar Washington Hospital Center provides a comprehensive review of the evaluation, diagnosis and management of ACHD, including guidelines to help ACHD patients manage a healthy pregnancy and clinical guidance about the progression of congenital heart disease (CHD) treatment from adolescence through adulthood.

Two tracks accommodate these themes, with the first focusing on a multidisciplinary approach clinicians can use to help ACHD patients assess risks for pregnancy complications, while planning and managing a healthy pregnancy, with input from cardiologists, anesthesiologists and maternal fetal medicine specialists. The second focuses on cardiac defects, starting with anatomical cardiac lessons with 3D heart models, then moves to imaging review, examining echocardiograms and MRI’s, and ends with clinical management review.

“This conference brings the best science and the most innovative approaches to treatment with questions doctors receive in the exam room,” says Anitha John, M.D., Ph.D., the conference organizer and director of the Washington Adult Congenital Heart program at Children’s National. “We’re inviting patients to join the afternoon of the second day of the CME conference again this year to support shared knowledge of these concepts, which supports lifelong treatment and education.”

Dr. John planned this year’s conference with the November 6 ACHD board exams in mind, integrating topics that will appear on the third ACHD certification exam issued by the American Board of Internal Medicine.

At this year’s CME conference, more than a dozen faculty members, including several physicians and nurses from Children’s National, will guide lectures to help attendees meet 13 objectives, from understanding the prevalence of congenital heart disease and its complications to learning about when surgical interventions and referrals to specialists are necessary.

Attendees will review new and innovative PAH therapies, mechanical support therapies, catheter-based interventional procedures and appraise the use of pacemaker and defibrillator therapy among adults with CHD.

Patients and families attending the patient sessions, held from 12:30 to 3:45 p.m. on Saturday, October 5, have a chance to participate in three sessions that support the medical and social needs of ACHD patients. Topics range from workshops that address the neurodevelopment and psychosocial factors of living with a congenital heart defect to sessions that focus on reproductive options for patients and personalized lifestyle recommendations, including fitness and exercise guidelines.

“To support cardiovascular health throughout the lifespan, it helps to educate patients about their heart’s structure and unique needs,” notes Dr. John. “We want to spark a dialogue now and have future conversations with patients, especially while they are young.”

The American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines updated ACHD treatment recommendations in August 2018, the first time in 10 years, and many of these guidelines manifest as panel discussions and interactive lectures presented at the 2019 Adult Congenital Heart Disease in the 21st Century conference.

Attendees can receive up to 12.5 credits from the Accreditation Council for Continuing Medical Education, the Accreditation Council for Pharmacy Education, the American Nurses Credentialing Center and the American Academy of PAs.

Those interested in starting their own ACHD program can attend an evening symposium, entitled “ACHD Program Building 101,” hosted by representatives from the Mid-Atlantic ACHD Regional Group. Topics in the six-session panel range from managing ACHD patients in a pediatric hospital setting to the role of clinical nurse coordinators in ACHD care.

To learn more about or to register for the conference, visit CE.MedStarHealth.org/ACHD.

Kaushalendra Amatya

Measuring quality of life after pediatric kidney transplant

Kaushalendra Amatya

“Overall, children who receive kidney transplants had minimal concerns about quality of life after their operation. While it’s comforting that most pediatric patients had no significant problems, the range of quality of life scores indicate that some patients had remarkable difficulties,” says Kaushalendra Amatya, Ph.D., a pediatric psychologist in Nephrology and Cardiology at Children’s National and the study’s lead author.

After receiving a kidney transplant, children may experience quality-of-life difficulties that underscore the importance of screening transplant recipients for psychosocial function, according to Children’s research presented May 4, 2019, during the 10th Congress of the International Pediatric Transplant Association.

About 2,000 children and adolescents younger than 18 are on the national waiting list for an organ transplant, according to the Department of Health and Human Services, with most infants and school-aged children waiting for a heart, liver or kidney and most children older than 11 waiting for a kidney or liver. In 2018, 1,895 U.S. children received transplants.

The research team at Children’s National wanted to hear directly from kids about their quality of life after kidney transplant in order to tailor timely interventions to children. Generally, recipients of kidney transplants have reported impaired quality of life compared with healthy peers, with higher mental health difficulties, disrupted sleep patterns and lingering pain.

The Children’s team measured general health-related quality of life using a 23-item PedsQL Generic Core module and measured transplant-related quality of life using the PedsQL- Transplant Module. The forms, which can be used for patients as young as 2, take about five to 10 minutes to complete and were provided to the child, the parent or the primary care giver – as appropriate – during a follow-up visit after the transplant.

Thirty-three patient-parent dyads completed the measures, with an additional 25 reports obtained from either the patient or the parent. The patients’ mean age was 14.2; 41.4% were female.

“Overall, children who receive kidney transplants had minimal concerns about quality of life after their operation. While it’s comforting that most pediatric patients had no significant problems, the range of quality of life scores indicate that some patients had remarkable difficulties,” says Kaushalendra Amatya, Ph.D., a pediatric psychologist in Nephrology and Cardiology at Children’s National and the study’s lead author.

When the study team reviewed reports given by parents, they found their descriptions sometimes differed in striking ways from the children’s answers.

“Parents report lower values on emotional functioning, social functioning and total core quality of life, indicating that parents perceive their children as having more difficulties across these specific domains than the patients’ own self reports do,” Amatya adds.

10th Congress of the International Pediatric Transplant Association presentation

  • “An exploration of health-related quality of life in pediatric renal transplant recipients.”

Kaushalendra Amatya, Ph.D., pediatric psychologist and lead author; Christy Petyak, CPNP-PC, nurse practitioner and co-author; and Asha Moudgil, M.D., medical director, transplant and senior author.

3d illustration of a constricted and narrowed artery

dnDSA and African American ethnicity linked with thickening of blood vessels after kidney transplant

3d illustration of a constricted and narrowed artery

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

Children who developed anti-human leukocyte antibodies against their donor kidney, known as de novo donor-specific antibodies (dnDSA), after kidney transplant were more likely to experience carotid intima-media thickening (CIMT) than those without these antibodies, according to preliminary research presented May 7, 2019, during the 10th Congress of the International Pediatric Transplant Association.

dnDSA play a key role in the survival of a transplanted organ. While human leukocyte antibodies protect the body from infection, dnDSA are a major cause of allograft loss. CIMT measures the thickness of the intima and media layers of the carotid artery and can serve as an early marker of cardiac disease.

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

To investigate the issue, Children’s researchers enrolled 38 children who had received kidney transplants and matched them by race with 20 healthy children. They measured their CIMT, blood pressure and lipids 18 months and 30 months after their kidney transplants. They monitored dnDSA at 18 months and 30 months after kidney transplant. The transplant recipients’ median age was 11.3 years, 50 percent were African American, and 21% developed dnDSA.

“In this prospective controlled cohort study, we compared outcomes among patients who developed dnDSA with transplant recipients who did not develop dnDSA and with race-matched healthy kids,” says Kristen Sgambat, Ph.D., a pediatric renal dietitian at Children’s National who was the study’s lead author.  “Children with dnDSA after transplant had 5.5% thicker CIMT than those who did not have dnDSA. Being African American was also independently associated with a 9.2% increase in CIMT among transplant recipients.”

Additional studies will need to be conducted in larger numbers of pediatric kidney transplant recipients to verify this preliminary association, Sgambat adds.

10th Congress of the International Pediatric Transplant Association presentation:

  • “Circulating de novo donor-specific antibodies and carotid intima-media thickness in pediatric kidney transplant recipients.”

Kristen Sgambat, Ph.D., pediatric renal dietitian and study lead author; Sarah Clauss, M.D., cardiologist and study co-author; and Asha Moudgil, M.D., Medical Director, Transplant and senior study author, all of Children’s National.

M and her daughter

Tracing the history of aggrecan gene mutations

M and her daughter

M takes a photo with her daughter in Washington, where they learned they have an ACAN gene mutation that causes short stature.

On Sunday, April 28, 2019 a team of researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for their abstract, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data,” and presented this at the PES Presidential Poster Session.

Eirene Alexadrou, M.D., a fellow at Cincinnati Children’s Hospital Medical Center, accepted the award and honorarium, while ongoing research is underway. This study started in 2017, with the objective of characterizing the phenotypic spectrum and response to a standardized regimen of growth hormone in a small cohort of 10 patients and their families.

In 2017, Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System, led an international consortium of researchers in publishing a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with aggrecan gene (ACAN) mutations.

Dr. Dauber and his colleagues have established that short stature and accelerated bone age is common among people with ACAN mutations. In a review of retrospective data, including patients treated with a variety of growth-promoting therapies at varying doses, the research team found that over the first one, two and three years of treatment, the standard deviation scores (SDS) for height increased by .4, .7 and 1, respectively. The current abstract now describes seven children enrolled in a prospective standardized trial of growth hormone therapy. After six months of treatment, the children have increased their height SDS by an average of 0.46.

Additionally, the researchers are performing an in-depth look at the joint effects, including special MRIs of the knees. They found that two of the children had a problem with their knee cartilage called osteochondritis dissecans. They had not yet presented with clinical symptoms. The researchers hope that early intervention with physical therapy can help prevent significant joint disease in the future.

M and her mother and daughter in Cincinnati

M, her daughter, and M’s mother take a photo in Cincinatti, where they are pariticipating in a clinical trial for aggrecan deficiency.

“Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” notes Dr. Dauber. “Previously, the assumption was that this was just short stature. We’ll continue to diagnose ACAN mutations in a clinical setting and work with families to reduce the risk of complications, such as joint problems or early-onset arthritis, which may co-occur with this gene mutation.”

As an example, Dr. Dauber met an 8-year-old patient several months ago who presented with symptoms of short stature. The patient is healthy, confident and still growing so her mother wasn’t worried about her but she made the appointment to see if there was an underlying cause to her daughter’s short stature. Her family history revealed clues to an ACAN mutation, which was later confirmed through genetic tests. Her mom, M, stands 4’8; her grandmother is 4’9. Her great grandmother was short and her great, great grandfather was 5’1. Short stature and joint problems run in the family. Once M mentioned she had osteochondritis dissecans and a hip replacement, she provided a textbook case study for carrying the ACAN mutation.

After the appointment, M shared the news with her mother about the possibility of having aggrecan deficiency. After taking genetic tests, M, her mother and M’s daughter learned they all have the ACAN mutation, and enrolled in the study that Dr. Dauber is guiding. Suddenly, it all made sense. After examining family photos, they traced the ACAN mutation back through four generations.

They could tell what relatives had an altered copy of the ACAN gene. M had it, while her two sisters did not. M’s mother was an only child, so she didn’t have aunts or uncles to compare her mother’s height to, but M’s grandmother was short, while her grandmother’s brother was average height. Although her mother’s family was from Germany, she learned that there is no specific ancestry associated with this mutation. It happens by chance and is passed down from a single parent to, on average, half of their children, a form of genetic inheritance called autosomal dominant transmission.

Ms great grandmother and grandfather

M’s great grandfather was noticeably shorter than her great grandmother, who was 5’4.

Through further research, M learned that the ACAN gene provides instructions for producing aggrecan protein, which is essential for bone growth, as well as for the stability of cartilage that lines bones and joints, explaining her recurring joint problems.

She also looked into the future, examining potential risk factors for her daughter: joint pain and bone conditions, which could contribute to arthritis, hip dysplasia and back problems.

The diagnosis now makes it easier for M and her daughter to favor bone-building activities that are easy on the joints, like swimming or water aerobics, instead of gymnastics and weight lifting. After having a hip replacement, M was careful to supplement with calcium and vitamin D. Now, she’ll take the same steps to ensure optimal bone health for her daughter. She’ll work with orthopedic specialists as her daughter grows into her pre-teen and adolescent years, carefully monitoring joint pain – altering activities that are tough on the joints, as necessary.

M let her daughter make a decision about growth hormone therapy, which she decided to try. The benefits of the treatment, increased height, carry inconveniences, such as taking daily shots, but they are sticking with it.

“We’re at the tip of the iceberg with research that explores this gene mutation,” says Dr. Dauber. “We’ll continue to study these families, and more, over time to assess growth patterns and  gene expression, which may reveal other mutations associated with short stature or joint problems, and guide future treatment options. It was a coincidence that this family had the ACAN mutation and scheduled an appointment, while we’re conducting this study. Otherwise, they may not have had an answer since this is fairly new research.”

M and her daughter are happy to be part of this study, which they will participate in for the next few years. M’s mother is also glad to participate. She made a different choice, decades ago, to reject hormone treatment when it was offered to her for undiagnosed short stature, but she’s sharing genetic clues, which may influence treatment options for her granddaughter and for her family’s next generation.

The original study, “Clinical Characterization of Patients with Autosomal Dominant Short Stature due to Aggrecan Muations,” appeared in the Feb. 2017 issue of the Journal of Clinical Endocrinology and Metabolism, and published as an online advance on Nov. 21, 2016.

Thirty-six researchers collaborated on this original paper, which was funded by 16 international health institutes and foundations, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, the Swedish Research Council, the Swedish Governmental Agency for Innovation Systems, the Marianne and Marcus Wallenberg Foundation, the Stockholm County Council, the Swedish Society of Medicine, Byggmastare Olle Engkvist’s Foundation, the Sao Paulo Research Foundation, the Spanish Ministry of Education and Science, the Czech Health Research Council and the Ministry of Health, Czech Republic.

preterm brain scans

Early lipids in micropreemies’ diets can boost brain growth

preterm brain scans

Segmentation of a preterm brain T2-weighted MRI image at 30 gestational weeks [green=cortical grey matter; blue=white matter; grey=deep grey matter; cyan=lateral ventricle; purple=cerebellum; orange=brainstem; red=hippocampus; yellow=cerebrospinal fluid].

Dietary lipids, already an important source of energy for tiny preemies, also provide a much-needed brain boost by significantly increasing global brain volume as well as increasing volume in regions involved in motor activities and memory, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

“Compared with macronutrients like carbohydrates and proteins, lipid intake during the first month of life is associated with increased overall and regional brain volume for micro-preemies,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and senior author. “Using non-invasive magnetic resonance imaging, we see increased volume in the cerebellum by 2 weeks of age. And at four weeks of life, lipids increase total brain volume and boost regional brain volume in the cerebellum, amygdala-hippocampus and brainstem.”

The cerebellum is involved in virtually all physical movement and enables coordination and balance. The amygdala processes and stores short-term memories. The hippocampus manages emotion and mood. And the brainstem acts like a router, passing messages from the brain to the rest of the body, as well as enabling essential functions like breathing, a steady heart rate and swallowing.

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. babies is born preterm, or before 37 weeks gestation. Regions of the brain that play vital roles in complex cognitive and motor activities experience exponential growth late in pregnancy, making the developing brains of preterm infants particularly vulnerable to injury and impaired growth.

Children’s research faculty examined the impact of lipid intake in the first month of life on brain volumes for very low birth weight infants, who weighed 1,500 grams or less at birth. These micro-preemies are especially vulnerable to growth failure and neurocognitive impairment after birth.

The team enrolled 68 micro-preemies who were 32 weeks gestational age and younger when they were admitted to Children’s neonatal intensive care unit during their first week of life. They measured cumulative macronutrients – carbohydrates, proteins, lipids and calories – consumed by these newborns at 2 and 4 weeks of life. Over years, Limperopoulos’ lab has amassed a large database of babies who were born full-term; this data provides unprecedented insights into normal brain development and will help to advance understanding of brain development in high-risk preterm infants.

“Even after controlling for average weight gain and other health conditions, lipid intake was positively associated with cerebellar and brainstem volumes in very low birthweight preterm infants,” adds Katherine M. Ottolini, the study’s lead author.

According to Limperopoulos, Children’s future research will examine the optimal timing and volume of lipids to boost neurodevelopment for micro-preemies.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Early lipid intake improves brain growth in premature infants.”
    • Saturday, April 27, 2019, 1:15-2:30 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

newborn in incubator

In HIE lower heart rate variability signals stressed newborns

newborn in incubator

In newborns with hypoxic-ischemic encephalopathy (HIE), lower heart rate variability correlates with autonomic manifestations of stress shortly after birth, underscoring the value of this biomarker, according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Tethered to an array of machines that keep their bodies nourished, warm and alive, newborns with health issues can’t speak. But Children’s research teams are tapping into what the machinery itself says, looking for insights into which vulnerable infants are most in need of earlier intervention.

Heart rate variability – or the variation between heartbeats – is a sign of health. Our autonomic nervous system constantly sends signals to adjust our heart rate under normal conditions. We can measure heart rate variability non-invasively, providing a way to detect potential problems with the autonomic nervous system as a sensitive marker of health in critically ill newborns,” says An N. Massaro, M.D., co-Director of Research for the Division of Neonatology at Children’s National, and the study’s senior author. “We’re looking for validated markers of brain injury in babies with HIE, and our study helps to support heart rate variability as one such valuable physiological biomarker.”

In most newborns, the autonomic nervous system reliably and automatically receives information about the body and the outside world and, in response, controls essential functions like blood pressure, body temperature, how quickly the baby breathes and how rapidly the newborn’s heart beats. The sympathetic part stimulates body processes, while the parasympathetic part inhibits body processes. When the nervous system’s internal auto-pilot falters, babies can suffer.

The Children’s team enrolled infants with HIE in the prospective, observational study. (HIE is brain damage that occurs with full-term babies who experience insufficient blood and oxygen flow to the brain around the time they are born.) Fifteen percent had severe encephalopathy. Mean age of babies in the observational study was 38.9 weeks gestation. Their median Apgar score at five minutes was 3; the 0-9 Apgar range indicates how ready newborns are for the rigors of life outside the womb.

The team analyzed heart rate variability metrics for three time periods:

  • The first 24 to 27 hours of life
  • The first three hours after babies undergoing therapeutic cooling were rewarmed and
  • The first three hours after babies’ body temperature had returned to normal.

They correlated the relationship between heart rate variability for 68 infants during at least one of these time periods with the stress z-score from the NICU Network Neurobehavioral Scale. The scale is a standardized assessment of newborn’s neurobehavioral integrity. The stress summary score indicates a newborn’s overall stress response, and six test items specifically relate to autonomic function.

“Alpha exponent and root mean square in short timescales, root mean square in long timescales, as well as low and high frequency powers positively correlated with stress scores and, even after adjusting for covariates, remained independently associated at 24 hours,” says Allie Townsend, the study’s lead author.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Heart rate variability (HRV) measures of autonomic nervous system (ANS) function relates to neonatal neurobehavioral manifestations of stress in newborn with hypoxic-ischemic encephalopathy (HIE).”
    • Monday, April 29, 2019, 5:45 p.m. (EST)

Allie Townsend, lead author; Rathinaswamy B. Govindan, Ph.D., staff scientist, Advanced Physiological Signals Processing Lab and co-author; Penny Glass, Ph.D., director, Child Development Program and co-author; Judy Brown, co-author; Tareq Al-Shargabi, M.S., co-author; Taeun Chang, M.D., director, Neonatal Neurology and Neonatal Neurocritical Care Program and co-author; Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine and co-author; An N. Massaro, M.D., co-Director of Research for the Division of Neonatology and senior author, all of Children’s National.

Claire Marie Vacher

Placental function linked to brain injuries associated with autism

Claire Marie Vacher

“We saw long-term cerebellar white matter alterations in male experimental models, and behavioral testing revealed social impairments and increased repetitive behaviors, two hallmark features of ASD,” says Claire-Marie Vacher, Ph.D., lead study author.

Allopregnanolone (ALLO), a hormone made by the placenta late in pregnancy, is such a potent neurosteroid that disrupting its steady supply to the developing fetus can leave it vulnerable to brain injuries associated with autism spectrum disorder (ASD), according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

In order to more effectively treat vulnerable babies, the Children’s research team first had to tease out what goes wrong in the careful choreography that is pregnancy. According to the Centers for Disease Control and Prevention, about 1 in 10 babies is born preterm, before 37 weeks of gestation. Premature birth is a major risk factor for ASD.

The placenta is an essential and understudied organ that is shared by the developing fetus and the pregnant mother, delivering oxygen, glucose and nutrients and ferrying out waste products. The placenta also delivers ALLO, a progesterone derivative, needed to ready the developing fetal brain for life outside the womb.

ALLO ramps up late in gestation. When babies are born prematurely, their supply of ALLO stops abruptly. That occurs at the same time the cerebellum – a brain region essential for motor coordination, posture, balance and social cognition– typically undergoes a dramatic growth spurt.

“Our experimental model demonstrates that losing placental ALLO alters cerebellar development, including white matter development,” says Anna Penn, M.D., Ph.D., a neonatologist in the divisions of Neonatology and Fetal Medicine, and a developmental neuroscientist at Children’s National. “Cerebellar white matter development occurs primarily after babies are born, so connecting a change in placental function during pregnancy with lingering impacts on later brain development is a particularly striking result.”

The research team created a novel experimental model in which the gene encoding the enzyme responsible for producing ALLO is deleted in the placenta. They compared these preclinical models with a control group and performed whole brain imaging and RNAseq gene expression analyses for both groups.

“We saw long-term cerebellar white matter alterations in male experimental models, and behavioral testing revealed social impairments and increased repetitive behaviors, two hallmark features of ASD,” says Claire-Marie Vacher, Ph.D., lead study author. “These male-specific outcomes parallel the increased risk of brain injury and ASD we see in human babies born prematurely.”

ALLO binds to specific GABA receptors, which control most inhibitory signaling in the nervous system.

“Our findings provide a new way to frame poor placental function: Subtle but significant changes in utero may set in motion neurodevelopmental disorders that children experience later in life,” adds Dr. Penn, the study’s senior author. “Future directions for our research could include identifying new targets in the placenta or brain that could be amenable to hormone supplementation, opening the potential for earlier treatment for high-risk fetuses.”

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Placental allopregnanolone loss alters postnatal cerebellar development and function.”
    • Sunday, April 28, 2019, 5:15 p.m. to 5:30 p.m. (EST)

Claire-Marie Vacher, Ph.D., lead author; Jackie Salzbank, co-author; Helene Lacaille, co-author; Dana Bakalar, co-author; Jiaqi O’Reilly, co-author; and Anna Penn, M.D., Ph.D., a neonatologist in the divisions of Neonatology and Fetal Medicine, developmental neuroscientist and senior study author.

DNA Molecule

Using genomics to solve a 20-year case study

DNA Molecule

“The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought all together,” says Andrew Dauber, M.D., MMSc.

After 20 years, a patient’s family received an answer to a decades-long genetic mystery. Their daughter had two rare disorders, Angelman syndrome and P450scc deficiency, which was detected after researchers found out she had uniparental disomy, two copies of chromosome 15 from one parent and none from another.

The research paper, entitled “Adrenal Insufficiency, Sex Reversal and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1,” was published on March 22, 2018, and recognized as the best novel insight paper published by Hormone Research in Paediatrics in 2018, announced at the Pediatric Endocrine Society’s Annual Meeting in Baltimore on Saturday, April 27, 2019.

By using a variety of genetic tools, including whole-exome sequencing, microarray analyses and in-vitro modeling for gene splicing, the researchers were able to confirm this patient had uniparental disomy, a recessive genetic condition. They learned that after she received two impaired copies of chromosome 15 from her father, this woman developed a hormonal problem that led to adrenal insufficiency and sex reversal. This explained why she physically presented as a female, despite having testes and a Y-chromosome. It also explained other symptoms, including developmental delays and seizures.

“It’s a unique conglomeration of symptoms, manifested by the combination of these two very rare disorders,” says Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System and a guiding research author of this study. “The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought together, commencing a 20-year diagnostic odyssey.”

For example, each of the conditions this patient has is known and rare: Angelman syndrome affects about one in 10 to 20,000 people in the U.S. Typical symptoms include those observed in this patient: delayed development, intellectual disability, speech impairment and seizures. Side-chain cleavage disorder, which leads to adrenal disorders and sex reversal, is also very rare. In 2005 the chances of survival with a P450scc defect were slim, but since then more than 28 infants have been diagnosed with this gene deficiency, which is required to convert cholesterol to pregnenolone, a hormone in the adrenal gland.

Dr. Dauber notes the chances of this occurring again are highly unlikely. The odds here are one in a gazillion. In this case, one disorder unmasked another, leaving researchers with new insights into the methodology for unraveling ultra-rare genetic disorders or for more common rare conditions.

“Knowing about the gene that caused the adrenal insufficiency and understanding this etiology won’t change medical care for this patient, but it will change the way researchers think about genetic detective work and about combining different technologies,” says Dr. Dauber. “We know that genetic disorders can be complex presentations of different disorders combined. This patient didn’t have one disorder, but three.”

When asked about the significance of the award, Dr. Dauber notes that, “It’s not that other people haven’t recognized this concept before, but this case is a striking example of it. Different technologies will unveil different types of genetic changes, which is why you have to use the right technology or the right technologies in the right combination to piece together the whole picture.”

Ahlee Kim, M.D., the lead study author and a clinical research fellow at Cincinnati Children’s Hospital Medical Center, will receive the award and the honorarium.

Additional study authors include Masanobu Fujimoto, Ph.D., Vivian Hwa, Ph.D., and Philippe Backeljauw, M.D., from Cincinnati Children’s Hospital.

The research was supported by grant K23HD07335, awarded to Dr. Dauber, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Additional funding included grant 1UL1TR001425 from the NIH’s National Center for Advancing Translational Sciences.

Katie Donnelly

Firearm injuries disproportionately affect African American kids in DC Wards 7 and 8

Katie Donnelly

“Because the majority of patients in our analyses were injured through accidental shootings, this particular risk factor can help to inform policy makers about possible interventions to prevent future firearm injury, disability and death,” says Katie Donnelly, M.D.

Firearm injuries disproportionately impact African American young men living in Washington’s Wards 7 and 8 compared with other city wards, with nearly one-quarter of injuries suffered in the injured child’s home or at a friend’s home, according to a hot spot analysis presented during the Pediatric Academic Societies 2019 Annual Meeting.

“We analyzed the addresses where youths were injured by firearms over a nearly 12-year period and found that about 60 percent of these shootings occurred in Ward 7 or Ward 8, lower socioeconomic neighborhoods when compared with Washington’s six other Wards,” says Monika K. Goyal, M.D., MSCE, assistant chief of Children’s Division of Emergency Medicine and Trauma Services and the study’s senior author. “This granular detail will help to target resources and interventions to more effectively reduce firearm-related injury and death.”

In the retrospective, cross-sectional study, the Children’s research team looked at all children aged 18 and younger who were treated at Children’s National for firearm-related injuries from Jan. 1, 2006, to May 31, 2017. During that time, 122 children injured by firearms in Washington were treated at Children’s National, the only Level 1 pediatric trauma center in the nation’s Capitol:

  • Nearly 64 percent of these firearm-related injuries were accidental
  • The patients’ mean age was 12.9 years old
  • More than 94 percent of patients were African American and
  • Nearly 74 percent were male.

Of all injuries suffered by children, injuries due to firearms carry the highest mortality rates, the study authors write. About 3 percent of patients in Children’s study died from their firearm-related injuries. Among surviving youth:

  • Patients had a mean Injury Severity Score of 5.8. (The score for a “major trauma” is greater than 15.)
  • 54 percent required hospitalization, with a mean hospitalization of three days
  • Nearly 28 percent required surgery, with 14.8 percent transferred directly from the emergency department to the operating room and
  • Nearly 16 percent were admitted to the intensive care unit.

“Regrettably, firearm injuries remain a major public health hazard for our nation’s children and young adults,” adds Katie Donnelly, M.D., emergency medicine specialist and the study’s lead author. “Because the majority of patients in our analyses were injured through accidental shootings, this particular risk factor can help to inform policy makers about possible interventions to prevent future firearm injury, disability and death.”

Pediatric Academic Societies 2019 Annual Meeting poster presentatio

  • “Pediatric firearm-related injuries and outcomes in the District of Columbia.”
    • Monday, April 29, 2019, 5:45 p.m. to 7:30 p.m. (EST)

Katie Donnelly, M.D., emergency medicine specialist and lead author; Shilpa J. Patel, M.D., MPH, emergency medicine specialist and co-author; Gia M. Badolato, co-author; James Jackson, co-author; and Monika K. Goyal, M.D., MSCE, assistant chief of Children’s Division of Emergency Medicine and Trauma Services and senior author.

Other Children’s research related to firearms presented during PAS 2019 includes:

April 27, 8 a.m.: “Protect kids, not guns: What pediatric providers can do to improve firearm safety.” Gabriella Azzarone, Asad Bandealy, M.D.; Priti Bhansali, M.D.; Eric Fleegler; Monika K. Goyal, M.D., MSCE;  Alex Hogan; Sabah Iqbal; Kavita Parikh, M.D.; Shilpa J. Patel, M.D., MPH; Noe Romo; and Alyssa Silver.

April 29, 5:45 p.m.: “Emergency department visits for pediatric firearm-related injury: By intent of injury.” Shilpa J. Patel, M.D., MPH; Gia M. Badolato; Kavita Parikh, M.D.; Sabah Iqbal; and Monika K. Goyal, M.D., MSCE.

April 29, 5:45 p.m.: “Assessing the intentionality of pediatric firearm injuries using ICD codes.” Katie Donnelly, M.D.; Gia M. Badolato; James Chamberlain, M.D.; and Monika K. Goyal, M.D., MSCE.

April 30, 9:45 a.m.: “Defining a research agenda for the field of pediatric firearm injury prevention.” Libby Alpern; Patrick Carter; Rebecca Cunningham, Monika K. Goyal, M.D., MSCE; Fred Rivara; and Eric Sigel.

Catherine Limperopoulos

Breastfeeding boosts metabolites important for brain growth

Catherine Limperopoulos

“Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites that may play a critical role for growth and explain what makes breastfeeding beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D.

Micro-preemies who primarily consume breast milk have significantly higher levels of metabolites important for brain growth and development, according to sophisticated imaging conducted by an interdisciplinary research team at Children’s National.

“Our previous research established that vulnerable preterm infants who are fed breast milk early in life have improved brain growth and neurodevelopmental outcomes. It was unclear what makes breastfeeding so beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National. “Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites essential for growth and answer that lingering question.”

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. infants is born preterm. The Children’s research team presented their findings during the Pediatric Academic Societies 2019 Annual Meeting.

The research-clinicians enrolled babies who were very low birthweight (less than 1,500 grams) and 32 weeks gestational age or younger at birth when they were admitted to Children’s neonatal intensive care unit in the first week of life. The team gathered data from the right frontal white matter and the cerebellum – a brain region that enables people to maintain balance and proper muscle coordination and that supports high-order cognitive functions.

Each chemical has its own a unique spectral fingerprint. The team generated light signatures for key metabolites and calculated the quantity of each metabolite. Of note:

  • Cerebral white matter spectra showed significantly greater levels of inositol (a molecule similar to glucose) for babies fed breast milk, compared with babies fed formula.
  • Cerebellar spectra had significantly greater creatine levels for breastfed babies compared with infants fed formula.
  • And the percentage of days infants were fed breast milk was associated with significantly greater levels of both creatine and choline, a water soluble nutrient.

“Key metabolite levels ramp up during the times babies’ brains experience exponential growth,” says Katherine M. Ottolini, the study’s lead author. “Creatine facilitates recycling of ATP, the cell’s energy currency. Seeing greater quantities of this metabolite denotes more rapid changes and higher cellular maturation. Choline is a marker of cell membrane turnover; when new cells are generated, we see choline levels rise.”

Already, Children’s National leverages an array of imaging options that describe normal brain growth, which makes it easier to spot when fetal or neonatal brain development goes awry, enabling earlier intervention and more effective treatment. “Proton magnetic resonance spectroscopy may serve as an important additional tool to advance our understanding of how breastfeeding boosts neurodevelopment for preterm infants,” Limperopoulos adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Improved cerebral and cerebellar metabolism in breast milk-fed VLBW infants.”
    • Monday, April 29, 2019, 3:30–3:45 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; Sudeepta Basu, M.D., neonatologist and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

An-Massaro

Looking for ‘help’ signals in the blood of newborns with HIE

An Massaro

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” says An N. Massaro, M.D.

Measuring a number of biomarkers over time that are produced as the body responds to inflammation and injury may help to pinpoint newborns who are more vulnerable to suffering lasting brain injury due to disrupted oxygen delivery and blood flow, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Hypoxic-ischemic encephalopathy (HIE) happens when blood and oxygen flow are disrupted around the time of birth and is a serious birth complication for full-term infants. To lessen the chance of these newborns suffering permanent brain injury, affected infants undergo therapeutic cooling, which temporarily lowers their body temperatures.

“Several candidate blood biomarkers have been investigated in HIE but we still don’t have one in clinical use.  We need to understand how these markers change over time before we can use them to direct care in patients,” says An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program at Children’s National and the study’s senior author. “The newborns’ bodies sent out different ‘help’ signals that we detected in their bloodstream, and the markers had strikingly different time courses. A panel of plasma biomarkers has the potential to help us identify infants most in need of additional interventions, and to help us understand the most optimal timing for those interventions.”

Past research has keyed in on inflammatory cytokines and Tau protein as potential biomarkers of brain injury for infants with HIE who are undergoing therapeutic cooling. The research team led by Children’s faculty wanted to gauge which time periods to measure such biomarkers circulating in newborns’ bloodstreams. They enrolled 85 infants with moderate or severe HIE and tapped unused blood specimens that had been collected as cooling began, as well as 12, 24, 72 and 96 hours later. The infants’ mean gestational age was 38.7 weeks, their mean birth weight was about 7 pounds (3.2 kilograms), and 19% had severe brain disease (encephalopathy).

Cytokines – chemicals like Interleukin (IL) 6, 8 and 10 that regulate how the body responds to infection, inflammation and trauma – peaked in the first 24 hours of cooling for most of the newborns. However, the highest measure of Tau protein for the majority of newborns was during or after the baby’s temperature was restored to normal.

“After adjusting for clinical severity of encephalopathy and five-minute Apgar scores, IL-6, IL-8 and IL-10 predicted adverse outcomes, like severe brain injury or death, as therapeutic hypothermia began. By contrast, Tau protein measurements predicted adverse outcomes during and after the infants were rewarmed,” Dr. Massaro says.

IL-6 and IL-8 proteins are pro-inflammatory cytokines while IL-10 is considered anti-inflammatory.  These chemicals are released as a part of the immune response to brain injury. Tau proteins are abundant in nerve cells and stabilize microtubules.

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” she adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Serial plasma biomarkers of brain injury in infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH).”
    • Saturday, April 27, 2019, 6 p.m. (EST)

Meaghan McGowan, lead author; Alexandra C. O’Kane, co-author; Gilbert Vezina, M.D.,  director, Neuroradiology Program and co-author; Tae Chang, M.D., director, Neonatal Neurology Program and co-author; and An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program and senior author; all of Children’s National; and co-author Allen Everett, of Johns Hopkins School of Medicine.

Ololade Okito

Parents of older, healthier newborns with less social support less resilient

Ololade Okito

“We know that having a child hospitalized in the NICU can be a high-stress time for families,” says Ololade Okito, M.D., lead author of the cross-sectional study. “The good news is that as parental resiliency scores rise, we see a correlation with fewer symptoms of depression and anxiety.

Parents of older, healthier newborns who had less social support were less resilient during their child’s hospitalization in the neonatal intensive care unit (NICU), a finding that correlates with more symptoms of depression and anxiety, according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Resiliency is the natural born, yet adaptable ability of people to bounce back in the face of significant adversity. Published research indicates that higher resilience is associated with reduced psychological distress, but the phenomenon had not been studied extensively in parents of children hospitalized in a NICU.

“We know that having a child hospitalized in the NICU can be a high-stress time for families,” says Ololade Okito, M.D., lead author of the cross-sectional study. “The good news is that as parental resiliency scores rise, we see a correlation with fewer symptoms of depression and anxiety. Parents who feel they have good family support also have higher resilience scores.”

The project is an offshoot of a larger study examining the impact of peer mentoring by other NICU parents who have experienced the same emotional rollercoaster ride as their tiny infants sometimes thrived and other times struggled.

The research team enrolled 35 parents whose newborns were 34 weeks gestation and younger and administered a battery of validated surveys, including:

Forty percent of these parents had high resilience scores; parents whose infants were a mean of 27.3 gestational weeks and who had more severe health challenges reported higher resilience. Another 40% of these parents had elevated depressive symptoms, while 31% screened positive for anxiety. Parental distress impairs the quality of parent-child interactions and long-term child development, the research team writes.

“Higher NICU-related stress correlates with greater symptoms of depression and anxiety in parents,” says Lamia Soghier, M.D., MEd, medical director of Children’s neonatal intensive care unit and the study’s senior author. “Specifically targeting interventions to these parents may help to improve their resilience, decrease the stress of parenting a child in the NICU and give these kids a healthier start to life.”

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Parental resilience and psychological distress in the neonatal intensive care unit (PARENT) study”
    • Tuesday, April 30, 2019, 7:30 a.m. (EST)

Ololade Okito, M.D., lead author; Yvonne Yui, M.D., co-author; Nicole Herrera, MPH, co-author; Randi Streisand, Ph.D., chief, Division of Psychology and Behavioral Health, and co-author; Carrie Tully, Ph.D., clinical psychologist and co-author; Karen Fratantoni, M.D., MPH, medical director, Complex Care Program, and co-author; and Lamia Soghier, M.D., MEd, medical unit director, neonatal intensive care unit, and senior author; all of Children’s National.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents:
Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students:
Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty:
Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students:
Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents:
Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students:
Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty:
Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff:
Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents:
Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students:
Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty:
Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff:
Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents:
Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students:
Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Johannes Van den Anker

Dr. Johannes van den Anker awarded 2019 Sumner J. Yaffe Lifetime Achievement Award

Johannes Van den Anker

Johannes van den Anker, M.D., Ph.D., division chief of Clinical Pharmacology and vice chair of Pediatrics for Experimental Therapeutics at Children’s National Health System, has been selected to receive the 2019 Sumner J. Yaffe Lifetime Achievement Award in Pediatric Pharmacology and Therapeutics by the Pediatric Pharmacy Advocacy Group (PPAG). Given annually, the Yaffe Award was established in 2002 by the PPAG Board of Directors and recognizes individuals with significant and sustained contributions toward the improvement of children’s health through the field of pediatric pharmacology and therapeutics.

Dr. van den Anker was selected as this year’s recipient for his contributions to the field of pediatric pharmacology and therapeutics, which have expanded and enhanced medical knowledge about the use of drugs in children and about the treatment of disease. He has also played an integral role in training the next generation of clinical pharmacists and pharmacologists.

“This award means a lot to me as it recognizes the importance of the field I am so passionate about and to which I have dedicated my career,” says Dr. van den Anker.

Dr. van den Anker joined Children’s National in 2002 and has become a leader in the discipline of pediatric pharmacology and therapeutics with significant contributions to research in this field. Some of his work includes changes in the dosing guidelines for frequently used antibacterial agents in newborns, the optimization of the dosing of pain medications in newborns and young infants and studies addressing the pharmacology of drugs in obese pediatric and adolescent patients.

“I am excited about being the 2019 recipient of this award” Dr. van den Anker says, “I am enthusiastic about future developments in the field of pediatric pharmacology and therapeutics with multiple ongoing studies with my colleagues, ranging from antibiotic dosing to the management of muscular dystrophy with novel drugs.”

The award will be presented at the 28th PPAG Annual Meeting on Friday, April 12 in Oklahoma City, OK., where he will also present the 2019 Yaffe Award Lecture to the attendees. The title of his lecture is “The Evolution of Neonatal Pharmacology and Therapeutics:  A Story of Resistance, Resilience and Revelation”.

Congratulations to Dr. Johannes van den Anker for this highly deserved honor!

The Rare Disease Institute staff on Rare Disease Day

Genetics 101: Rare diseases aren’t rare

The Rare Disease Institute staff on Rare Disease Day

Children’s National Health System is home to the Rare Disease Institute, the National Organization for Rare Disease’s first Center of Excellence, the largest clinical genetics program in the United States.

With the advent of DNA databanks, informatics, new technology, pediatric consortiums and global partnerships, clinical researchers have never been in a better position to diagnose and treat rare diseases. A rare disease is categorically defined as a condition that affects less than 200,000 people. However, 25 to 30 million Americans, about one in 10, have a rare disease.

Accelerations in genetic research and diagnostic criteria remain one of the most significant accomplishments in medicine, but these breakthroughs invite new challenges: How will researchers provide ongoing care and treatment for patients navigating a rare disease? How can doctors and researchers multiply themselves to ensure everyone has the latest information and resources they need? How can researchers use existing trials to augment other fields? How can we diagnose, catalogue and treat hundreds of new rare diseases each year, while accelerating the research and care of 7,000 existing rare conditions?

If these questions intrigue you, excite you and make you want to collaborate with scientific peers, welcome to the field of genetics. A common theme researchers and families talk about is that rare diseases affect a small proportion of the population, but have a huge impact.

On April 10, 1,200 international researchers, lawmakers, scientists and drug developers from 50 countries will meet in Oxon Hill, Md., 10 miles south of Washington, for a three-day summit, the World Orphan Drug Congress USA, to discuss how to unify efforts to enhance and maximize care for rare disease patients.

Here are eight themes to keep in mind:

  1. Rare diseases are chronic diseases. The human genome project has enabled the molecular mapping of 8,000 diseases with genetic underpinnings. Of these diseases, 600 diseases have therapies. A child born with a urea cycle disorder had a 5% chance of surviving the disease 40 years ago. Now the survival rate is 95%. Helping children survive is essential, but we need to think about the best treatments and standards for long-term care.
  2. Rare diseases are expensive. In Western Australia, according to the 2010 Western Australia Population Cohort, rare diseases account for less than 5% of hospital visits but for 10% of hospital costs. Similar data from Cleveland finds one-third of pediatric hospital visits have a genetic link but account for half of hospital costs.
  3. Rare diseases share common links. We’ve diagnosed 7,000 rare diseases but there are more to unravel. For example, breast cancer has over 30 molecular subtypes – some of which turn into rare diseases. By better understanding these molecular pathways, we may be able to inform common fields of medicine.
  4. Marshall Summar's Rare Disease 101 presentation

    Dr. Marshall Summar, a medical geneticist, speaks about the future of rare disease research and treatment at a Rare Disease 101 lecture hosted by the Rare Disease Congressional Caucus on Capitol Hill on Feb. 27. To sustain discoveries, Dr. Summar mentions a digital-first, flexible mindset is essential. Standard language and scalable, universal reference structures are required.

  5. Global partnerships create research repositories. Gold-standard research models – double blind, controlled studies with numerous participants – aren’t possible if five people in the world share the same disease. To increase the number of study participants, global partnerships and longitudinal registries are essential.
  6. Standard language helps. To avoid replicating existing research and to help teams quickly reference findings, we need to adopt standardized language to quantify measurements. Researchers from Berlin and Brazil may help inform the etiology of and future treatments for PKU, but they need to manage, store, access and share their collective findings, while remaining flexible.
  7. The science is here. The FDA is approving more drugs for rare diseases than ever before including gene therapy and micro organs, or Rare Diseases-on-chip models. The challenge with treating so many rare diseases isn’t developing new research, but creating therapies and studies to accommodate this patient volume. About 250 rare disease discoveries happen each year. At the current rate, it will take 2,000 years to treat them all.
  8. Progress is here. The Orphan Drug Act fast-tracked approval for rare disease treatments and therapies, and nearly half of all drugs coming in for FDA approval are for rare diseases. However, only 5% of rare diseases have FDA-approved drugs.
  9. We need to replicate geneticists. To provide optimal care, doctors need to standardize education models and use new forms of technology, such as artificial intelligence and deep learning, to share resources faster via patient education portals, resources for families, CME courses and virtual connections with pediatricians or families.

If you would like to learn more or get involved, watch this international summit, the Rare Disease Day Policy Event, which took place at the United Nations Headquarters in New York on Feb. 21. (Some of these issues are covered in video 4.)

If you are a patient, download this patient toolkit from the National Center for Advanced Translational Sciences.

If you live in Washington, D.C., follow the genetics team and consider working with us as we move into a new home, the Children’s National Research and Innovation Campus, in 2020.

Jeffrey Lukish

Pediatric Surgeon receives ACS/APSA Health Policy Scholarship

Jeffrey Lukish

Jeffrey Lukish, M.D., a pediatric surgeon at Children’s National Health System, has been named a 2019 American College of Surgeons (ACS) and American Pediatric Surgical Association (APSA) Health Policy Scholar for 2019.

The scholarship supports Dr. Lukish’s attendance at the Executive Leadership Program in Health Policy and Management at Brandeis University, which teaches knowledge and skills essential for participating in health care policy and equips health leaders with tools to create innovative and sustainable ways to improve health care service delivery. As a 2019 scholar, he will also provide health policy-related assistance to the ACS and the APSA as requested, and will have opportunities to build relationships with local, state and federal lawmakers.

Dr. Lukish is a nationally recognized expert in advanced minimally invasive surgery in infants and children, as well as pediatric surgical innovation. He has been voted a Baltimore Top Doctor by his peers for five of the last eight years. He holds academic appointments as a professor of surgery from the Uniformed Services University and associate professor of surgery at the George Washington University.

Dr. Lukish is a fellow of the American College of Surgeons and the American Academy of Pediatrics, and member of several prominent professional societies, including the American Pediatric Surgical Society, the Pediatric Cancer Oncology Group and the International Pediatric Endosurgery Group.  He has authored over 100 publications.