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Young girl sleeping

Is actigraphy helpful for assessing sleep-wake disorders?

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Young girl sleeping

The second most-read article in 2018 in the Journal of Clinical Sleep Medicine, published by the American Academy of Sleep Medicine (AASM), was about using actigraphy to evaluate sleep disorders and circadian rhythm sleep-wake disorders.

FDA-approved actigraphy devices are typically kept on the wrist or ankle and track movement activity, which researchers can use as part of a larger toolset to analyze how much activity occurs right before and during sleep.

The AASM guidelines, entitled “Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline,” included the AASM’s stance on clinical recommendations for children and adults, rated as strong or conditional.

The conditions for evaluating pediatric health conditions are as follows:

  1. The AASM suggests that clinicians use actigraphy in the assessment of pediatric patients with insomnia disorder. (Conditional)
  2. The AASM suggests that clinicians use actigraphy in the assessment of pediatric patients with circadian rhythm sleep-wake disorder. (Conditional)
  3. The AASM suggests that clinicians use actigraphy to monitor total sleep time prior to testing with the Multiple Sleep Latency Test in adult and pediatric patients with suspected central disorders of hypersomnolence. (Conditional)
  4. The AASM recommends that clinicians not use actigraphy in place of electromyography for the diagnosis of periodic limb movement disorder in adult and pediatric patients. (Strong)

In an interview with Neurology Today, Daniel Lewin, Ph.D., a sleep medicine specialist, pediatric psychologist and associate director of the sleep medicine program at Children’s National Health System, offered advice, alongside other sleep medicine experts, about the new guidelines:

“It’s a very powerful tool, but it does require some knowledge of basic sleep mechanisms and of how the tool can be used and what variables can be extracted from the tool,” Dr. Lewin said in the interview with Susan Kreimer.

Anne Goldstein, M.D., M.S., assistant professor of neurology at the University of Michigan Sleep Disorders Center, tells Kreimer that “Actigraphy records only movement and that non-moving is often misinterpreted as sleep.”

Dr. Lewin has used actigraphy in sleep research studies but notes the use of these devices come with extensive training. Other researchers expressed similar sentiments with Neurology Today, noting the value of the sleep assessment tool to capture preliminary sleep behavior assessments, similar to a self-reported sleep log, while noting their limitations, such as capturing sleep patterns over extended periods of time, instead of in 14-day increments.

“When you’re living a typical active human life, sleep can wax and wane, depending on travel patterns, work responsibilities and stress levels,” Nathaniel F. Watson, M.D., professor of neurology at the University of Washington School of Medicine in Seattle and director of the UW Medicine Sleep Clinic, tells Kreimer. “This variability in sleep highlights the need for additional technologies capable of assessing sleep over longer periods of time.”

Read about other researcher’s perspectives captured by Susan Kreimer for Neurology Today.

Test tube that says IGF-1 test

PAPPA2: A genetic mystery

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Test tube that says IGF-1 test

What would happen if you suddenly stopped growing at age 12 or 13?

Solving genetic growth mysteries and scheduling regular appointments with pediatric endocrinologists is atypical for most parents and pediatricians.

However, for children with growth disorders – a classification that typically describes children below the third or above the 97th percentile of growth charts for their age – receiving a diagnosis is half the battle to reaching average height. Understanding and creating treatment for a growth disorder, which could stem from an underlying medical illness, a genetic mutation or a problem with endocrine function, such as the production or action of growth hormone, is often the next step.

For Andrew Dauber, M.D., MMSc., the chief of endocrinology at Children’s National Health System, a third step is to use these clues to create larger datasets and blueprints to identify risk factors for rare growth disorders. By understanding genetic markers of growth disorders, endocrinologists can identify solutions and create plans for multidisciplinary care to help children reach developmental milestones and receive coordinated care throughout their lifespan.

A case study that Dauber and his research team continue to explore is how to correct for mutations in the PAPPA2 gene, which regulates human growth by releasing a key growth factor called insulin-like growth factor 1 (IGF-1). Dauber and his colleagues recently described a mutation in PAPPA2, observed in two families with multiple children affected with significant short stature. He found that this mutation decreased the bioavailability of IGF-1, stunting the growth and development of the children who carry this mutation.

While the PAPPA2 mutation is rare, endocrinologists, like Dauber, who understand its function and dysregulation can create solutions to support IGF-1 bioavailability, thereby supporting healthy growth and development in children.

Understanding barriers to IGF-1 function can also help researchers gain insight into the relationship between PAPPA2, levels of circulating insulin in the body, which could cause insulin resistance, and other growth hormones. For now, Dauber and his research team are exploring how to use PAPPA2 to increase IGF-1 in circulation among people with height disorders in the hopes of improving their growth.

“The population of children who have PAPPA2 mutations is small and we’re finding out that two children could respond to the same treatment in different ways,” says Dauber. “One medication could work modestly in one child and support short growth spurts, such as growing by 5 or 6 cm a year. It could also create undesirable side effects, such as headaches and migraines in another, and render it ineffective. However, the clues we walk away with enable us to test new solutions, and confirm or dissolve our hunches, about what may be preventing the bioactive release of essential growth hormones.”

To generate controls for healthy patterns of growth and development, Dauber and his research team are analyzing the relationship between PAPPA2, STC2 and IGFBP-3 concentrations among 838 relatively healthy pediatric participants, ages 3-18, with traditional growth patterns.

They are studying PAPPA2, STC2 and intact IGFBP-3 concentrations throughout childhood and the researchers are already surprised to find PAPPA2, a positive modulator of growth and IGF- bioavailability, decreased with age, while STC2, a negative modulator and traditional growth inhibitor, increased with age.

“As pediatric endocrinology researchers and clinicians, we’re looking at the pathology of traditional growth patterns and growth disorders with an open mind,” says Dr. Dauber. “These data sets are invaluable as they confirm or challenge our theories, which enable us to create and test new forms of personalized treatments. We’ll continue to share this knowledge, which informs other researchers and accelerates the field of pediatric endocrinology.”

This research was presented at the annual meeting of the European Society of Pediatric Endocrinology in Athens on Sept. 28, 2018.

Dauber and his research team will present their findings at endocrinology conferences and grand rounds throughout 2018 and 2019.

To view Dr. Dauber’s most recent research and pediatric endocrinology reviews, visit PubMed.

Eugene Hwang

Unexpected heterogeneity in CNS-PNET patients treated as a single entity

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Eugene Hwang

“We found that some patients diagnosed with standard tools underwent much more treatment than necessary or intended,” said Eugene Hwang, M.D.

Eugene I. Hwang, M.D., a neuro-oncologist in the Center for Cancer and Blood Disorders, and other researchers at Children’s National Health System, Seattle Children’s Hospital and Research Institute, the Fred Hutchinson Cancer Research Center and the Hopp-Children’s Cancer Center at the NCT Heidelberg recently published the results of a clinical trial focusing on children with histologically diagnosed supratentorial primitive neuroectodermal tumors (CNS-PNET) and pineblastomas (PBLs).

The clinical trial, published online October 17, 2018 in the Journal of Clinical Oncology, included children and adolescents aged 3-22 with these brain cancers who were randomly assigned to receive carboplatin during radiation and/or isotretinoin after the standard intensive therapy (high-dose craniospinal radiation and months of inpatient chemotherapy).  Importantly, because each patient was treated prospectively according to the clinical trial design, the conclusions related to tumor biology were felt to be less affected by varied treatment plans.

“This trial really highlighted the importance of new molecular testing methods in accurately diagnosing some of the brain cancers included in the trial. We found that some patients diagnosed with standard tools underwent much more treatment than necessary or intended.” says Dr. Hwang. “Kids who aren’t receiving the right form of cancer treatment may not get better despite months and months of intensive treatment.”

During this clinical trial, 85 participants with institutionally-diagnosed CNS-PNETs/PBLs were enrolled. Out of the 60 patients with sufficient tissue, 31 were non-pineal in location, 22 of which represented tumors that did not fit in the diagnoses intended for trial inclusion.

The researchers discovered that patient outcomes across each molecularly-diagnosed tumor type were strikingly different. Patients with molecularly-confirmed supratentorial embryonal tumors/PBLs exhibited a five-year event free survival (EFS) and an overall survival rate of 62 percent and 78.5 percent, respectively. However, patients with molecularly-classified high-grade gliomas (HGGs) had a five-year EFS of 5.6 percent and OS of 12 percent, showing no benefit even with the chemotherapy and craniospinal radiation.

Researchers determined that for patients with CNS-PNETs/PBLs, prognosis is considerably better than previously assumed when molecularly-confirmed HGG are removed. Dr. Hwang and co-authors concluded that molecular diagnosis can greatly aid standard pathological diagnostic tools, preventing unnecessary intensive therapy for some patients while enabling more rational treatment for others.

“The findings from our clinical trial have highlighted the immense challenges of histology-based diagnosis for some types of pediatric brain tumors, and the enormous importance this has for children with brain cancer,” Dr. Hwang says. “We hope that ultimately our study will pave the way for molecular profiling to become a standard component of initial diagnosis.”

Shayna Coburn

Shayna Coburn, Ph.D., receives APA Achievement Award for Early Career Psychologists

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Shayna Coburn

Shayna Coburn, Ph.D assistant professor and psychologist at Children’s National Health System.

Shayna Coburn, Ph.D., assistant professor and psychologist at Children’s National Health System, has been awarded an American Psychological Association (APA) Achievement Award for Early Career Psychologists.

APA’s Committee on Early Career Psychologists announced the award for early career members who work in all areas of psychology (education, practice, public interest and science) to attend the APA Annual Convention August 2018 in San Francisco.

“At this early stage in my career, the recognition of my achievements thus far is highly valuable as I expand my body of work and strive to advance my career,” Coburn says.

The awards program was designed to reduce barriers to early career members’ attending APA conventions and to support their ability to make meaningful connections and engage in professional development. As a recipient of the award, Coburn received reimbursement up to $400 for convention-related expenses that could cover travel, lodging, meals and/or convention registration fees.

Throughout her career, Coburn has been passionate about clinical and research excellence as well as advocacy. In her current position in the celiac disease program, she has been involved with establishing a new psychosocial health program that combines multidisciplinary clinical service, research and community outreach.

During a previous APA convention, Coburn was able to attend as an exhibitor to promote a free continuing education program. This year was the first time she was featured as a presenter, speaking about celiac disease and psychosocial challenges associated with the disease.

Coburn presented data from Children’s National celiac disease multidisciplinary clinic to report the incidence rates of symptoms that patients experience such as anxiety, depression and stress from a gluten-free diet.

“The most important aspect of the award was having the largest organization of psychologists recognize that during the early stages of my career, I have been involved in work that is meaningful to the community,” Coburn says. “It’s always helpful to have extra support to attend a conference that is across the country from my home in Maryland,” she adds.

The leader and collaborator in a range of scientific, clinical and community-based activities thanks the award for being invaluable in facilitating her attending the conference and being able to participate in career-building and networking opportunities that will help enable her to build professional relationships nationwide.

Stephen Teach does an asthma exam

Stephen J. Teach, M.D., MPH, inaugural holder of new endowed chair

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Stephen Teach does an asthma exam

Stephen J. Teach, M.D., M.P.H., has been named the inaugural Wendy Goldberg Professor in Translational Research in Child Health and Community Partnerships. This professorship comes with an endowed chair at Children’s National Health System.

The prestigious honor is given for the duration of Dr. Teach’s (and future chair holders’) employment at Children’s National. The award’s namesake, Wendy Goldberg, and her husband, Fred T. Goldberg Jr., are among the brightest stars in the constellation of Children’s National supporters, says Dr. Teach, Associate Dean for Pediatric Academic Affairs and Chair of the Department of Pediatrics at The George Washington University School of Medicine & Health Sciences.

In addition to serving on many Children’s boards, in the mid-2000s the Goldbergs made a $250,000 gift that benefited Improving Pediatric Asthma Care in the District of Columbia (IMPACT DC), Dr. Teach’s award-winning program to improve clinical care, empower patients and families, and conduct new research to improve patients’ outcomes.

“In recognition of the anchor aims of Children’s new strategic plan, the Goldbergs wanted this new gift to focus on the intersection of community health and research,” Dr. Teach says. “Thanks to their generosity, my team will work with community partners to use data to drive improvements in population health.”

With the dedicated funding Dr. Teach was able to hire a new staffer, Caitlin Munoz, to help mine electronic health records to create disease-specific registries that include 15,000 children and adolescents – the lion’s share of kids younger than 17 who live in Washington and have asthma.

“For the first time, we will be able to describe in granular detail the near-universe of local children who have this chronic respiratory disease,” he says. “We will be able to describe many of the most clinically meaningful aspects of nearly every child with asthma who lives in D.C., including mean age, gender, ethnicity and mean number visits to the emergency department.”

Such a richly textured database will help identify children who should be prescribed daily controller medications to help them avoid missing school days due to asthma exacerbations, he says. The next pediatric chronic disease they will track via registry will be pediatric obesity via elevated body mass index.

“That, in and of itself, is insightful data. But the enduring impact of this applied research is it will inform our continuous quality-improvement efforts,” he adds.

By querying the registries the team will be able to tell, for example, how Children’s primary care centers rank comparatively by asking such questions as which percentage of kids with asthma actually take the medicines they had been prescribed the year prior.

“Increasingly, clinical research falls into one of two buckets. You can either do better things: That’s discovering new drugs or processes, like our ongoing clinical trial to desensitize kids to asthma allergens. Or, you can do things better. We often know what to do already. We know that guideline-based asthma care works well. We don’t need to prove that again. We just need to do things better by getting this care to the kids who need it. That’s where this line of research/quality improvement comes in: It’s getting people to do things better.”

Andrew Dauber

Andrew Dauber, M.D., joins Children’s National as Chief of Endocrinology

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Andrew Dauber

“Researchers, clinicians and medical trainees are pressed for time,” says Andrew Dauber, M.D. “Merging these three arenas into a joint infrastructure powers institutional collaboration and fuels transformative, cutting-edge care.”

Imagine an endocrinology division staffed with endowed researchers, clinicians and specialists, that serves as an engine of innovation, making it easy for pediatricians to make the right referrals, based on the best research, to endocrinologists who can provide families with cutting-edge care.

Andrew Dauber, M.D., MMSc, the new chief of endocrinology at Children’s National, is turning this dream into a reality. Over the next few years, Dr. Dauber will work with a nationally-ranked endocrinology and diabetes center to build a clinical endocrinology research program, housing specialty clinics for Turner’s syndrome, thyroid care and growth disorders, amongst others.

“Researchers, clinicians and medical trainees are pressed for time,” notes Dr. Dauber. “Merging these three arenas into a joint infrastructure powers institutional collaboration and fuels transformative, cutting-edge care.”

To put his real-life hypothesis of providing an engine for innovation into practice, Dr. Dauber led the interdisciplinary growth center at Cincinnati Children’s Hospital Medical Center and organized a Genomics First for Undiagnosed Diseases Program to study genetic clues for undiagnosed diseases. At Boston Children’s Hospital, he was the assistant medical director for the clinical research unit and held academic appointments with Harvard Medical School.

Dr. Dauber finds it’s critically important to merge clinical practice with research and education. He received his medical degree and a Master’s of Medical Sciences in Clinical Investigation from Harvard Medical School. He has published more than 65 studies examining genetic clues to endocrine disorders, with a focus on short stature and growth disorders.

Dr. Dauber conducted the majority of his research – ranging from studying genetic clues for rare growth disorders and causes of precocious puberty to genes that regulate the bioavailability of IGF1, insulin-like growth factor – while counseling patients, advising students and fellows, managing grants, reviewing studies and speaking at international pediatric endocrinology conferences.

He’s harnessing this data by combining genomic insights with electronic health records and patient registries. While some of this information can be used immediately to identify a high-risk patient, other conditions may take years to understand. Dr. Dauber views this as an investment in the future of pediatric endocrinology.

“I’m excited to join Children’s National and to work in Washington, where we can power our city and the nation with premier partnerships and collaboration,” adds Dr. Dauber. “In addition to using genetic clues to investigate growth disorders, we’re just as enthusiastic about investing in and expanding access to youth-focused diabetes education and care.”

The Division of Diabetes and Endocrinology works with the National Institutes of Health, conducts independent research and received support from the Washington Nationals Dream Foundation for its diabetes program, the largest pediatric diabetes program in the region, which provides community education and counsels 1,800 pediatric patients each year.

Research and Education Week awardees embody the diverse power of innovation

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cnmc-research-education-week

“Diversity powers innovation” was brought to life at Children’s National April 16 to 20, 2018, during the eighth annual Research and Education Week. Children’s faculty were honored as President’s Award winners and for exhibiting outstanding mentorship, while more than 360 scientific poster presentations were displayed throughout the Main Atrium.

Two clinical researchers received Mentorship Awards for excellence in fostering the development of junior faculty. Lauren Kenworthy, Ph.D received the award for Translational Science and Murray M. Pollack, M.D., M.B.A., was recognized in the Clinical Science category as part of Children’s National Health System’s Research and Education Week 2018.

Dr. Kenworthy has devoted her career to improving the lives of people on the autism spectrum and was cited by former mentees as an inspirational and tireless counselor. Her mentorship led to promising new lines of research investigating methods for engaging culturally diverse families in autism studies, as well as the impact of dual language exposure on cognition in autism.

Meanwhile, Dr. Pollack was honored for his enduring focus on motivating early-career professionals to investigate outcomes in pediatric critical care, emergency medicine and neonatology. Dr. Pollack is one of the founders of the Collaborative Pediatric Critical Care Research Network. He developed PRISM 1 and 2, which has revolutionized pediatric intensive care by providing a methodology to predict mortality and outcome using standardly collected clinical data. Mentees credit Dr. Pollack with helping them develop critical thinking skills and encouraging them to address creativity and focus in their research agenda.

In addition to the Mentorship and President’s Awards, 34 other Children’s National faculty, residents, interns and research staff were among the winners of Poster Presentation awards. The event is a celebration of the commitment to improving pediatric health in the form of education, research, scholarship and innovation that occurs every day at Children’s National.

Children’s Research Institute (CRI) served as host for the week’s events to showcase the breadth of research and education programs occurring within the entire health system, along with the rich demographic and cultural origins of the teams that make up Children’s National. The lineup of events included scientific poster presentations, as well as a full slate of guest lectures, educational workshops and panel discussions.

“It’s critical that we provide pathways for young people of all backgrounds to pursue careers in science and medicine,” says Vittorio Gallo, Ph.D., Children’s chief research officer and CRI’s scientific director. “In an accelerated global research and health care environment, internationalization of innovation requires an understanding of cultural diversity and inclusion of different mindsets and broader spectrums of perspectives and expertise from a wide range of networks,” Gallo adds.

“Here at Children’s National we want our current and future clinician-researchers to reflect the patients we serve, which is why our emphasis this year was on harnessing diversity and inclusion as tools to power innovation,” says Mark L. Batshaw, M.D., physician-in-chief and chief academic officer of Children’s National.

“Research and Education Week 2018 presented a perfect opportunity to celebrate the work of our diverse research, education and care teams, who have come together to find innovative solutions by working with local, national and international partners. This event highlights the ingenuity and inspiration that our researchers contribute to our mission of healing children,” Dr. Batshaw concludes.

Awards for the best posters were distributed according to the following categories:

  • Basic and translational science
  • Quality and performance improvement
  • Clinical research
  • Community-based research and
  • Education, training and program development.

Each winner illustrated promising advances in the development of new therapies, diagnostics and medical devices.

Diversity powers innovation: Denice Cora-Bramble, M.D., MBA
Diversity powers innovation: Vittorio Gallo, Ph.D.
Diversity powers innovation: Mark L. Batshaw, M.D.

test tubes

2016: A banner year for innovation

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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.

It took an act of Congress to save lives

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Boosting research and innovation to find cures and develop new medical devices for children and adults who carry childhood and rare diseases will transform our health system and save lives.

Until now, medical research and innovation have been severely limited in the U.S. by regulations and lack of funding. On behalf of healthcare systems and medical innovators across the U.S., we applaud the House and Senate for their tremendous bipartisan effort to pass the 21st Century Cures Act that will transform our health and research system and enable us to more effectively fight diseases.

We are encouraged by the provisions in the act that break down regulatory barriers and expedite the approvals of drugs and devices. We are particularly excited about the provisions to increase funding to the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), as well as the establishment of precision medicine, the cancer moonshot initiatives and new programs that will improve our mental health system and fight the worsening opioid epidemic. Boosting research and innovation to find cures and develop new medical devices for children and adults who carry childhood and rare diseases is at the core of our mission at Children’s National. Our researchers are working to find new biomarkers, map the human genome, develop medical devices for children and personalize medicine to make treatment and cures more targeted and effective. They are also studying pain and looking at new ways to detect the presence of opioids and cannabinoids. Thanks in large part to funding from the NIH, institutions like ours are able to continue groundbreaking biomedical research. This legislation brings hope to our children and their families, especially those who volunteer to participate in research, that our scientific breakthroughs will be translated to drugs, therapeutics and medical devices safer and faster.

Another victory for all of us in the pediatric medical device field is the expansion of the Humanitarian Use Device program to include devices used by up to 8,000 individuals rather than the current 4,000 individual cap. The hard cap at 4,000 individuals was excessively restrictive and was a significant disincentive blocking the development of devices for rare diseases and conditions, especially those affecting children. The 4,000 limit was also an obstacle for the development of diagnostic devices, since the FDA interprets the limitation to apply to the number of patients that would receive the diagnostic test, rather than the number of individuals affected or manifesting the rare disease.

Currently, medical device development for children lags woefully behind adults. Children have medical device needs that are considerably different from adults. The subtleties of developing devices for pediatric patients are fundamentally different than those for adults. The challenges include small markets, scarce financial incentives, regulatory issues, and the procedural dissimilarities of premarket clinical trials and post-market surveillance. The lack of available pediatric devices often forces clinicians to treat pediatric patients by using or modifying adult devices, adjusting implants designed for other purposes, and using implants designed decades ago. Because devices are being used “off-label,” clinicians and regulators are not able to collect information on their effectiveness. This act promises a faster regulatory approval process, which increases the enthusiasm of the venture community in investing in drug and device development, which in turn can help startup companies in the field secure private capital.

Thank you to everyone who worked tirelessly to create this bill and to those who lobbied on its behalf. It’s efforts like the 21st Century Cures Act, that break down regulatory barriers and provide the resources to expedite the approvals of life-saving drugs and devices, that save children’s lives.

About the Author

Kolaleh Eskandanian, Ph.D.
Executive Director
Sheikh Zayed Institute for Pediatric Surgical Innovation
Research interests: device development, entrepreneurship, innovation in health care