Genetics and Rare Diseases

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.

Andrew Dauber

Growth disorder study starts by analyzing DNA

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The National Institutes of Health has awarded Andrew Dauber, M.D., MMSc, the chief of endocrinology at Children’s National Health System, a five-year grant that will allow four pediatric health systems to compile and study clinical and genetic markers of severe pediatric growth disorders.

The study will use the electronic health records of large health systems combined with DNA samples from dozens of children, with the goal of enabling endocrinologists to detect children with previously undiagnosed severe genetic growth disorders.

“If you’re a pediatrician treating an 8-year-old patient who has stopped growing, the first thing you’ll want to do is determine the underlying cause, which could be due to many factors including a genetic mutation,” says Dr. Dauber. “There are many reasons why children grow poorly and it is often very difficult to figure out what is causing the problem. However, the various causes may be treated quite differently and may alert us to other medical issues that we need to watch out for. We need to be able to identify clues from the patient’s clinical presentation that may point us to the right diagnosis.”

Dr. Dauber and endocrinology researchers from Children’s National Health System, Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and The Children’s Hospital of Philadelphia will use electronic health records to identify children who likely have rare genetic growth disorders. They will then use cutting-edge DNA sequencing technologies, whole exome sequences, to identify novel genetic causes of severe growth disorders. Patients with growth hormone resistance, resistance to insulin-like growth factor 1 (IGF-I) and severe short stature inherited from a single parent will be recruited for the initial phases of the study.

“It’s rare to find patients meeting criteria for each of these subgroups, which is why it’s critical to work collaboratively across institutions,” says Dr. Dauber. “This type of genetic sorting and sharing brings us closer to identifying new markers for severe or treatment-resistant growth disorders, which will help alert pediatricians and parents to potential risks earlier on in a child’s life.”

In addition to assessing genetic markers for short stature, the endocrinologists will conduct pilot studies of targeted interventions, such as IGF-I therapy in patients with mutations in the growth hormone pathway, based on these genetic underpinnings.

“Ideally, by identifying markers of severe growth disorders first, we’ll be able to provide targeted treatments and therapies later on to help patients throughout their lifespan,” adds Dr. Dauber.

Typical treatments for atypical growth patterns include growth hormone or less commonly insulin-like growth factor, or IGF-1, for short stature and hormone-inhibiting treatments for precocious puberty.

The multicenter clinical trial is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under grant Ro1HD093622, and runs through June 30, 2023.

Maureen E Lyon

Maureen E. Lyon, Ph.D., ABPP, lauded for outstanding excellence in patient-centered advance care planning

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Maureen E Lyon

Maureen E. Lyon, Ph.D., a principal investigator at Children’s Center for Translational Science, will be honored with a “Recognition Award for Excellence and Innovation in Research” by Respecting Choices for outstanding excellence in patient-centered advance care planning and shared decision-making.

Respecting Choices will present the award on Oct. 26, 2018, during its “National Share the Experience Conference” in Bloomington, Minnesota.

Lyon’s expertise is in advance care planning and shared decision-making for children and adolescents with life-threatening illnesses and their families, a field that has transformed in recent decades in order to pave better paths forward for difficult but necessary conversations.

“It came from my clinical experience,” Lyon says. “In the early days of the human immunodeficiency virus (HIV) epidemic in the U.S., everything, absolutely everything, was done to keep the kids alive in the hopes that some new drug would come around the corner, and we could bring them back from the brink. I remember one of the young boys saying to his case manager that he didn’t want all of these interventions. But he hadn’t told his family.”

That young man’s eye-opening comments – and learning that Children’s National Health System had a policy that teenagers were to be included in conversations about their own advance care planning – inspired Lyon to conduct a series of surveys involving adolescents, families and clinicians.

“I remember sitting down with friends and saying ‘There must be a better way to do this. Everyone is afraid to broach the subject,’ ” Lyon recalls. So, she conducted surveys of all healthy kids coming through Children’s adolescent clinic and kids diagnosed with HIV, cancer and sickle cell disease.

“It turned out the kids did want to talk about it. That was the first thing. Families told us they wanted help breaking the ice. Physicians felt it wasn’t their role – many doctors felt their role was to save people – or, they didn’t have the training,” she says.

Through a series of focus groups with youths living with HIV, families and community members, Lyon adapted the adult-centric Respecting Choices model to create a three-session intervention to better meet the advance care planning needs of youths and adolescents living with HIV.

Lyon’s recent work includes a single-blinded, randomized study published Oct. 19, 2018, in Pediatrics that finds the more families understand the end-of-life treatment preferences expressed by adolescents living with HIV, the less likely these youth are to suffer HIV-related symptoms, compared with youths whose families do not understand their end-of-life care goals.

She also has adapted the Respecting Choices intervention to facilitate its use with children diagnosed with cancer. More recently, she has adapted the model for use by parents of children with rare diseases who cannot communicate on their own.

“For the other life-threatening health conditions, we worked to support adolescents in expressing their advance care planning choices in their own voices. With rare diseases, we’re shifting gears,” she adds.

Published research indicates a sizable proportion of pediatric patients who die in hospitals now have confirmed or suspected rare diseases, she says. During a pilot involving seven families, many parents multitasked during the conversations, taking pauses to attend to various alarms as they sounded, to complete regular feedings and to contend with their child’s petit mal seizures.

“The level of burden of taking care of these children with terminal illnesses was pretty overwhelming,” she says. “Still, families were not too burdened to participate in advance care planning, but first wanted to identify their priority palliative care needs and to develop a support plan to meet those needs. We also had more fathers involved.”

Telemedicine

A rare prescription: Providing children with palliative care

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Telemedicine

A pilot program at Children’s National enabled parents of children with extremely rare diseases to receive in-person or virtual health consultations with a trained provider.

Pediatric advance care planning (pACP) and making complex  medical decisions is especially difficult for parents of children with extremely rare diseases. Imagine if your child is the only person in the world with a rare disease that may limit basic functions: eating, breathing, walking and talking. Now, imagine you are presented with two scenarios: Experiment with a new drug to see if it improves your child’s conditions or plan for near-future, end-of-life care.

While these types of difficult decisions for parents of children with rare diseases are common, a new counseling model, based on a four-session pilot program conducted at Children’s National, aims to ease this process by providing parents with a comprehensive support plan.

On Oct. 15 and 16, Maureen Lyon, Ph.D., a clinical psychologist at Children’s National and a professor of pediatrics at the George Washington University School of Medicine and Health Sciences, will present “Living on the Precipice: The Journey of Children with Rare Diseases and Their Families” at a poster session at the National Organization for Rare Disorders’ Rare Disease and Orphan Products Breakthrough Summit at the Marriott Wardman Park in Washington.

Dr. Lyon will highlight key take-home points she observed during the pilot program:

  • Background: Eight families were recruited for the pilot program and seven enrolled. Six completed the four-session program, which was spread out over two months.
    • All parents were mothers, but two fathers joined for the goal-planning care conversation sessions. Some families brought their children to visits.
    • Five parents were married and two were single.
    • Four families identified as Caucasian, three families identified as African American, and one family identified as American Indian or Alaska Native.
  • Visits: About half of the families – three – attended the sessions at Children’s National. Four used the telemedicine option. A research nurse, clinical psychologist and advanced practice nurse participated in the 60- to 90-minute sessions.
  • Plans: The families discussed basic palliative care needs, such as comprehensive care coordination, which is highly individualized, before discussing their goals of care. After their needs and goals were discussed, the families created advance care plans to guide them during a medical crisis.
  • Results: Out of the six parents who completed the study, the mean positive caregiver appraisal score increased from 4.5. To 4.7, mean family well-being increased from 3.9 to 4.1, and the mean score for meaning and peace increased from 21.4 to 23.3. The scores were calculated by using the Carer Support Needs Assessment Tool (CSNAT) during the assessment and with modified protocols to assess quality of life and caregiver appraisal after the intervention.
Maureen Lyon

“The goal of palliative care is to optimize quality of life for children with life-threatening illnesses and their families by anticipating, preventing and treating suffering in all its forms,” explains Maureen Lyon, Ph.D. “This is delivered throughout illness and addresses physical, intellectual, emotional, social and spiritual needs.”

“These sessions increased a family’s sense of overall well-being,” says Jessica Thompkins, B.S.N., R.N., C.P.N., a research nurse coordinator with the FAmily CEntered Advanced Care Planning Team (FACE) and a co-author of the poster. “The families felt better just by knowing that they had time scheduled each week to connect with a trained medical provider to discuss a range for options they need as a caregiver, from everyday care at home to long-term health care planning at the hospital.”

The top-rated support need identified by all parents, according to the survey: “Knowing what to expect in the future when caring for their children.”

“The goal of palliative care is to optimize quality of life for children with life-threatening illnesses and their families by anticipating, preventing and treating suffering in all its forms,” says Dr. Lyon. “This is delivered throughout illness and addresses physical, intellectual, emotional, social and spiritual needs.”

The researchers would like to use this pilot to partner with other medical centers to create an evidence-based template to support the palliative care needs of family caregivers who have children with life-limiting rare diseases. Their goal is to improve a family caregiver’s quality of life, over time, and increase the completion and documentation of advance care plans for children of all ethnic and racial groups.

Rare diseases are defined as a disease that affects fewer than 200,000 people in the U.S. Extremely rare diseases, including those observed in this pilot, may affect just one or a few people in the world.

The rare disease pilot program is based on previous pACP models with adolescent HIV and pediatric cancer populations.

Additional poster authors include Jichuan Wang, Ph.D., Karen Fratantoni, M.D., M.P.H., Kate Detwiler, Ph.D., Yao Cheng, M.S., and Marshall Summar, M.D.

Staphylococcus aureus

Understanding antibiotic resistance in patients with cystic fibrosis

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Staphylococcus aureus

Patients with cystic fibrosis who carried antibiotic-resistant bacteria, such as Staphylococcus aureus, in their lungs had significantly lower microbial diversity and more aggressive disease, according to a small study published in Heliyon.

A defective gene causes thick, sticky mucus to build up in the lungs of patients with cystic fibrosis (CF). There, it traps bacteria, causing patients to develop frequent lung infections that progressively damage these vital organs and impair patients’ ability to breathe.

Most patients with this progressive genetic disorder die by the fourth decade of life. A key to helping patients live even that long – a vast improvement from an average lifespan of 10 years  just decades ago – is judicious use of antibiotics, explains Andrea Hahn, M.D., a pediatric infectious diseases specialist at Children’s National Health System.

But antibiotics are a double-edged sword, Dr. Hahn adds: Although they’re necessary to eradicate lung infections, repeated use of these drugs can lead to antibiotic resistance, making it tougher to treat future infections. Also, antibiotic use can kill the nonpathogenic bacteria living in the lungs as well. That decreases the diversity of the microbial community that resides in the lungs, a factor associated with disease progression. But how antibiotic resistance impacts the relationship between lung bacterial diversity and CF patients’ pulmonary function has been unknown.

Dr. Hahn and colleagues investigated this question in a small study that was published online Sept. 17, 2018, in Heliyon. Their findings suggest that the presence of multidrug resistant bacteria in the airways of patients with CF is associated with decreased microbial diversity and decreased pulmonary function.

In the study, the researchers recruited six patients with CF from Children’s National during well-child visits. During those appointments, the research team collected respiratory secretions from these volunteers. They collected more samples at subsequent visits, including:

  • When patients were admitted to the hospital for pulmonary exacerbations (periods when infections inflamed their airways, making it difficult to breathe);
  • Just after intravenous antibiotic courses to treat these infections; and
  • Thirty days after patients completed antibiotic therapy, when their lungs’ bacterial flora had some time to bounce back.

Over the 18-month study period, these patients made multiple visits for exacerbations and antibiotic treatments, leading to samples from 19 patient encounters overall.

The scientists then analyzed each sample in two different ways. They used some to grow cultures in petri dishes, the classic method that labs use to figure out which bacterial species are present and to determine which antibiotics are effective in tamping them down. They used another part of the sample to run genetic analyses that searched for antibiotic resistance genes. Both methods were necessary to gather a complete inventory of which antibiotic-resistant bacteria were present, Dr. Hahn explains.

“Laboratory cultures are designed to grow certain types of bacteria that we know are problematic, but they don’t show everything,” she says. “By genetically sequencing these samples, we can see everything that’s there.”

Their results revealed a host of bacterial species present in these patients’ airways, including methicillin-resistant Staphylococcus aureus, a notoriously hard-to-treat microbe. Patients who carried this or other antibiotic-resistant bacteria had significantly lower microbial diversity in their samples and more aggressive disease. Their samples also were more likely to contain bacteria of the genus Alcaligenes, whose role in CF is not yet known.

Although heavy antibiotic use probably contributed to both the antibiotic resistance and lowered microbial diversity, Dr. Hahn says, the answer isn’t to reduce use of these drugs: They’re necessary to help patients with CF recover after each bout with pulmonary exacerbations. Rather, she says, using methods beyond a simple lab culture can help doctors target infectious bacteria more selectively, perhaps avoiding collateral damage.

“We can’t stop using antibiotics,” she says, “but we can learn to use them better.”

In addition to Dr. Hahn, Children’s co-authors include Aszia Burrell; Hani Fanous; Hollis Chaney, M.D.; Iman Sami Zakhari, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., MPH; and Robert J. Freishtat, M.D., MPH; and Senior Author, Keith A. Crandall, of The George Washington University.

Financial support for the research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075 and the National Heart, Lung and Blood Institute under award number K12HL119994.

Sen Chandra Sreetama and Jyoti K Jaiswal

Modified glucocorticoid stabilizes dysferlin-deficient muscle cell membrane in experimental models

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Sen Chandra Sreetama and Jyoti K Jaiswal

Limb girdle muscular dystrophy type 2B (LGMD2B) – a disease so rare that researchers aren’t even sure how many people it affects – is characterized by chronic muscle inflammation and progressively weakened muscles in the pelvis and shoulder girdle. It can affect able-bodied people during their childbearing years and makes it difficult to tiptoe, walk, run or rise unaided from a squat. Ultimately, many with the muscle-wasting condition require wheelchair assistance. There is no therapy approved by the Food and Drug Administration for this condition.

In a head-to-head trial between the conventional glucocorticoid, prednisolone, and a modified glucocorticoid, vamorolone, in experimental models of LGMD2B, vamorolone improved dysferlin-deficient muscle cell membrane stability and repair. This correlated with increased muscle strength and decreased muscle degeneration, according to a Children’s-led study published online Aug. 27, 2018, in Molecular Therapy. By contrast, prednisolone worsened muscle weakness, impaired muscle repair and increased myofiber atrophy.

“These two steroids differ by only two chemical groups,” says Jyoti K. Jaiswal, MSC, Ph.D., a principal investigator at Children’s National Health System and senior study author. “One made muscle repair better. The other made muscle repair worse or about the same as untreated experimental models. This matches experience in the clinic as patients with LGMD2B experienced increased muscle weakness after being prescribed conventional glucocorticoids, such as prednisolone.”

Healthy muscle cells rely on the protein dysferlin to properly repair the sarcolemmal membrane, a cell membrane specialized for muscle cells that serves a vital role in ensuring that muscle fibers are strong enough and have the necessary resources to contract. Mutations in the DYSF gene that produces this essential protein causes LGMD2B.

Jaiswal likens the plasma membrane to a balloon that sits atop the myofiber, a long cell that when healthy can flex and contract. If, in the process of myofiber contraction, the plasma membrane experiences anything out of sync or overly stressful, it develops a tear that needs to be quickly sealed. An intact balloon keeps air inside; tear it, and air escapes. When the plasma membrane tears, calcium from the outside leaks in, causing the muscle cell to collapse into a ball and die. The body contends with the dead cell by breaking it up into fragments and sending in inflammatory cells to clear the debris.

Lack of dysferlin is associated with increased lipid mobility in the LGMD2B cell membrane

Lack of dysferlin is associated with increased lipid mobility in the limb girdle muscular dystrophy type 2B (LGMD2B) cell membrane, which is further increased by injury and prednisolone treatment, causing failure of these cells to undergo repair. By contrast, vamorolone treatment stabilizes the LGMD2B muscle cell membrane to near healthy cell level, enabling repair of injured cells.

The study team got the idea for the current research project during a previous study of the experimental treatment vamorolone for a different type of muscular dystrophy. “In Duchenne muscular dystrophy (DMD), treatment with vamorolone not only reduced inflammation, but the membranes of muscle fibers were stabilized. That was the team’s ah-hah moment,” he says.

Three different doses of vamorolone were tested on cells derived from patients with LGMD2B with higher cell membrane repair efficacy seen with rising treatment dose. The dysferlinopathic experimental models were treated for three months with daily doses of cherry syrup laced with either 30 mg/kg of vamorolone or prednisolone or cherry syrup alone as the placebo arm.

“Right now there are zero treatments,” he says. People with LGMD2B turn to rehabilitative therapies and movement aids to cope with loss of mobility. Doctors are cautioned not to prescribe steroids. Jaiswal says many patients with LGMD2B grew up doing strenuous exercise, former athletes whose first indication of a problem was muscle cramping and pain. How this progresses to muscle weakness and loss is an area of active research in Jaiswal’s lab. “While additional research is needed, our findings here suggest that modified steroids such as vamorlone may be an option for some patients,” Jaiswal says.

“There is a nuance here: In addition to genomic effects, steroids also have physical effects on the cell membrane which may make some of the approved steroids ‘good’ steroids for dysferlinopathy that could selectively be used for this disease,” adds Sen Chandra Sreetama, lead study author.  Further research could indicate whether vamorolone, which is in Phase II human clinical trials for DMD, or any off-the-shelf drug could slow decline in muscle function for patients with LGMD2B.

Additional Children’s study authors include Goutam Chandra; Jack H. Van der Meulen; Mohammad Mahad Ahmad; Peter Suzuki; Shivaprasad Bhuvanendran; and Kanneboyina Nagaraju and Eric P. Hoffman, both of ReveraGen BioPharma.

Research reported in this news release was supported by the Clark Charitable Foundation; Muscular Dystrophy Association, under award number MDA277389; National Institute of Arthritis and Musculoskeletal and Skin Diseases, under award number R01AR055686; National Institutes of Health (NIH), under award numbers K26OD011171 and R24HD050846; and the District of Columbia Intellectual and Developmental Disabilities Research Center under NIH award number 1U54HD090257.

Understanding individual and collective mechanisms behind cell membrane repair

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Tissue repair signaling illustration

Signals released during plasma membrane repair initiate tissue repair: Extracellular vesicle signaling, an intracellular calcium increase that initiates plasma membrane repair in injured cells and an increase in cytosolic calcium that stimulates release of ATP by vesicle exocytosis or through plasma membrane channels.

PDF Version

What’s known

All cells are surrounded by a cell membrane: a double layer of lipids with embedded proteins that separates the inside of the cell from the outside environment. At only 10 nanometers in thickness, this layer is quite fragile. Any breach can be fatal for a cell, causing chemical imbalances by exposing its interior to the extracellular milieu. Consequently, cells have evolved a set of responses to rapidly restore the integrity of the cell membrane in the event of a rupture, coordinating actions spurred by both immediate and longer-term signals. Research is providing a growing understanding of these repair mechanisms, which could go awry in degenerative diseases.

What’s new

Adam Horn, Ph.D., a postdoctoral fellow, and Jyoti K. Jaiswal, Ph.D., a principal investigator at Children’s Center for Neuroscience Research and the Center for Genetic Medicine Research, recently co-authored a literature review article summarizing these cell membrane repair mechanisms and the signals that trigger them. They delve into a variety of resourceful ways that cells fix tears or holes in this membrane, including one akin to blood clotting that stuffs a tear with proteins, organelles or vesicles; another in which the proteins that give a cell structure (the cytoskeleton) disassemble, relaxing tension that helps pull the damaged membrane together; or one in which the damaged portion in the membrane is shed. These repairs are driven by signals that largely rely on a large calcium influx into the cellular fluid, which spurs into action a variety of repair-related proteins. Better understanding each element could help researchers develop new and better ways to treat degenerative diseases in which cells inadequately repair damage.

Questions for future research

Q: How do the different types of signals coordinate individual and collective mechanisms of cell membrane repair?

Q: How is cell membrane repair coordinated among populations of cells at the tissue level?

Source: “Cellular Mechanisms and Signals That Coordinate Plasma Membrane Repair.” A. Horn and J.K. Jaiswal. Published by Cellular and Molecular Life Sciences July 26, 2018.

Bladder cancer’s unique bacterial “fingerprint”

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Michael H. Hsieh, M.D., Ph.D.

Michael H. Hsieh, M.D., Ph.D.

Decades ago, researchers thought that the native bacteria scattered throughout the human body—such as in the gut, the oral cavity and the skin—served little useful purpose. This microbiota, whose numbers at least match those of the cells in the body they live on and in, were considered mostly harmless hitchhikers.

More recently, research has revealed that these natural flora play key roles in maintaining and promoting health. In addition, studies have shown that understanding what a “typical” microbiome looks like and how it might change over time can provide an early warning system for some health conditions, including cancer.

Now, a small, multi-institutional study conducted in experimental models suggests that as bladder cancer progresses, it appears to be associated with a unique bacterial fingerprint within the bladder—a place thought to be bacteria-free except in the case of infection until just a few years ago. The finding opens the possibility of a new way to spot the disease earlier.

Bladder cancer is the fourth-most common malignancy among U.S. men but, despite its prevalence, mortality rates have remained stubbornly high. Patients often are diagnosed late, after bladder cancer has advanced. And, it remains difficult to discern which patients with non-invasive bladder cancer will go on to develop muscle-invasive disease.

Already, researchers know that patients with grade 4 oral squamous cell carcinoma, women with increasingly severe grades of cervical cancer and patients with cirrhosis who develop liver cancer have altered oral, vaginal and gut microbiomes, respectively.

New technological advances have led to identification of a diverse community of bacteria within the bladder, the urinary microbiome. Leveraging these tools, a research team that includes Children’s National Health System investigators studied whether an experimental model’s urinary bacterial community changed as bladder cancer progressed, evolving from a microbiome into a urinary “oncobiome.”

To test the hypothesis, the research team led by Michael H. Hsieh, M.D., Ph.D., a Children’s urologist, exposed an experimental model of bladder cancer to a bladder-specific cancer-causing agent, n-butyl-n-(4-hydroxybutyl) nitrosamine (BBN). Bladder cancers induced by BBN closely resemble human cancers in tissue structure at the microscopic level and by gene expression analyses. Ten of the preclinical models received a .05 percent concentration of BBN in their drinking water over five months and were housed together. Ten other experimental models received regular tap water and shared a separate, adjacent cage.

Researchers collected urine samples ranging from 10 to 100 microliters at the beginning of the longitudinal study, one week after it began, then once monthly. They isolated microbial DNA from the urine and quantified it to determine how much DNA was microbial. All of the bladders from experimental models exposed to BBN and two bladders from the control group were analyzed by a pathologist trained in bladder biology.

According to the study published online July 5, 2018, by the biology preprint server Biorxiv, they found a range of pathologies:

  • Five of the experimental models that received BBN did not develop cancer but had histology consistent with inflammation. Three had precancer on histology: urothelial dysplasia, hyperplasia or carcinoma in situ. Two developed cancer: invasive urothelial carcinomas, one of which had features of a squamous cell carcinoma.
  • The experimental model that developed invasive carcinoma had markedly different urinary bacteria at baseline, with Rubellimicrobium, a gram negative organism found in soil that has not been associated with disease previously, Escherichia and Kaistobacter, also found in soil, as the most prominent bacteria. By contrast, in the other experimental models the most common urinary bacteria were Escherichia, Prevotella, Veillonella, Streptococcus, Staphyloccoccus and Neisseria.
  • By month four, the majority of experimental models exposed to BBN had significantly higher proportion of Gardnerella and Bifidobacterium compared with their control group counterparts.

“Closely analyzing the urinary bacterial community among experimental models exposed to BBN, we saw distinct differences in microbial profiles by month four that were not present in earlier months,” Dr. Hsieh says. “While Gardnerella is associated with the development of cancer, Bifidobacterium has been shown to exert antitumor immunity, and its increasing abundance points to the need for additional research to understand its precise role in oncogenesis.”

Dr. Hsieh adds that although the study is small, its findings are of significance to children who are prone to developing urinary tract infections (UTIs), including children with spina bifida, due to the association between UTIs and bladder cancer. “This work is important because it not only suggests that the urinary microbiome could be used to diagnose bladder cancer, but that it could also perhaps predict cancer outcomes. If the urinary microbiome contributes to bladder carcinogenesis, it may be possible to favorably change the microbiome through antibiotics and/or probiotics in order to treat bladder cancer.”

In addition to Dr. Hsieh, co-authors include Catherine S. Forster, M.D., M.S., and Crystal Stroud, of Children’s National; James J. Cody, Nirad Banskota, Yi-Ju Hsieh and Olivia Lamanna, of the Biomedical Research Institute; Dannah Farah and Ljubica Caldovic, of The George Washington University; and Olfat Hammam, of Theodor Bilharz Research Institute.

Research reported in this news release was supported by the National Institutes of Health under award number R01 DK113504 and the Margaret A. Stirewalt Endowment.

vitamins

Use of dietary supplements in children with Down syndrome

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vitamins

There is a widespread practice of parents giving dietary supplements to children with Down syndrome in the hope of improving intelligence or function, according to new research published in The Journal of Pediatrics. The study, conducted by experts at Children’s National Rare Disease Institute (CNRDI), examined the prevalence, perceived impact, cost and other factors related to dietary supplement use in children with Down syndrome.

The survey finds nearly half of 1,167 respondents – 49 percent – have given or currently give dietary supplements to their children in an effort to improve health and development. On average, children receive three of the more than 150 supplements reported, with nearly 30 percent of users beginning supplementation before the child’s first birthday.

Amy Feldman Lewanda, M.D., a medical geneticist at CNRDI and lead author on the study, notes that the results also reveal a troubling trend – nearly 20 percent of parents who report using dietary supplements do not inform their pediatrician.

“While we know supplements are given by parents in hopes of improving developmental outcomes for children with Down syndrome, many of these supplements contain concerning ingredient profiles that can have adverse effects in infants and children that are too young to communicate their symptoms,” says Dr. Lewanda. “Additionally, these supplements have no proven safety or efficacy, so it’s important for families to consult with their pediatrician or primary care provider to help determine any risk, ill effects or conflicts with existing treatment.”

Reasons for not informing pediatricians about supplement use vary, according to the study results. The most common reason reported was that the doctor has never specifically asked about nutritional supplements. While some parents indicate they do not view supplement use as important medical information to divulge, others feel that their pediatrician may not be knowledgeable about these types of supplements or may dismiss the practice entirely, as some reportedly have done in the past.

Amy Feldman Lewanda

Amy Feldman Lewanda, M.D., a medical geneticist at CNRDI and lead author on the study.

The most popular class of products reported by 25.8 percent of respondents taking supplements are antioxidants, such as curcumin, a byproduct of turmeric, and epigallocatechin-3-gallate (ECGC), the polyphenol compound in green tea. Vitamins, both single and multivitamins, rank second, accounting for 18.9 percent of supplement use. B vitamins were the most popular among single vitamin use. The third most popular supplement category, reported by 15.8 active or previous supplement users, contains proprietary products or combination supplements, such as Nutrivene-D or HAP-CAPS (High Achievement Potential Capsules).

According to Dr. Lewanda, chemical analyses of herbal supplements find some contain anabolic steroids or pharmaceuticals that aren’t listed in the ingredients. Hepatoxicity has been cited among 60 herbs, herbal drugs and herbal supplements. The problem, she notes, is that these products aren’t regulated, like pharmaceuticals are, and similarly, they aren’t thoroughly tested for their safety and efficacy.

The study also notes potential concerns about consuming hyper-concentrated forms of fat-soluble vitamins, including vitamin E and vitamin K, which stay in the body until the vitamins are used. One particular supplement, Speak, provides 5,000 percent of the recommended daily value limits of vitamin E. Fat-soluble vitamins and/or herbal supplements pose unknown health risks – including liver damage.

Among study respondents who actively provide supplements to their children, roughly 87 percent feel they are effective. Those who stopped administering supplements to their children cite lack of efficacy and cost – approximately $90.53 per month on average – as leading reasons for discontinuing use. Approximately 17 percent of respondents note side-effects of supplement use, specifically gastrointestinal disturbance, which was the most common side effect among active and previous supplement users.

“This research gives pediatricians a bit of a wake-up call on what’s trending in the Down syndrome community and the dialogue taking place online, in parent support groups and outside of the doctor’s office,” says Marshall Summar, M.D., director of CNRDI and co-author on the study. “The goal is for pediatricians and parents to work as a team in providing the best care possible for every child, so we hope this research provides physicians greater insight and encourages more open dialogue with patient families about supplement use.  Since many of these supplements have active ingredients, it is vitally important that the primary care provider be aware of them.”

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

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

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

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

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

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

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

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

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

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Potential to replace race as a risk factor for kidney-transplant failure

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Right now, more than 100,000 adult and pediatric patients in the U.S. are waiting for a life-saving kidney donation. Thirteen of them die each day while awaiting a transplant. However, a significant portion of kidneys from deceased donors are discarded because they literally don’t make the grade – a scoring system known as the kidney donor profile index (KDPI) that aims to predict how long a donor kidney will last in an intended recipient based on a variety of factors, including the donor’s age, size and health history.

Ethnicity and race are also part of that scoring system, explains Marva Moxey-Mims, M.D., FASN, chief of the Division of Nephrology at Children’s National Health System. That’s partly because research over the years has suggested that kidneys from certain racial groups, including African-Americans, may not have the same longevity as those from other groups.

But race might not be the right marker to consider, Dr. Moxey-Mims counters. More recent studies have shown that a particular gene known as APOL1 might better predict risk of kidney-transplant failure. APOL1 high-risk variants are associated with a wide range of kidney diseases, with retrospective studies suggesting that they could be a key cause of failure in some donated kidneys. Although this gene is found almost exclusively in people of recent African descent, only about 13 percent of that population has high-risk APOL1 variants that might cause kidney problems.

“Instead of putting all African-American donor kidneys in one proverbial ‘bucket,’ we might be able to use this gene to determine if they truly carry a higher risk of early failure,” Dr. Moxey-Mims says.

To more definitively confirm whether this gene could be used as a proxy for heightened kidney-failure risk, Dr. Moxey-Mims and colleagues across the country are participating in the APOL1 Long-Term Kidney Transplantation Outcomes Network (APOLLO) study, she and Dr. Barry Freedman explain in a perspective published online April 27, 2018, in Clinical Journal of the American Society of Nephrology. The APOLLO study will tap people accessing the hundreds of transplant centers scattered across the nation, prospectively genotyping deceased and living African-American kidney donors as well as kidney-transplant recipients to assess whether they carry high-risk APOL1 gene variants. Living donors and transplant recipients will be followed for years to gauge how their kidneys fare over time.

The researchers, Dr. Moxey-Mims explains, hope to answer whether the APOL1 high-risk gene variants in donor kidneys could replace race as a risk factor when calculating the KDPI score and whether recipients’ own APOL1 gene variants impact transplant failure risk. They also hope to better understand the risk to living donors. “If a living donor has an increased risk of kidney failure,” she adds, “he or she can make a more educated decision about whether to donate a kidney.”

Dr. Moxey-Mims plays a pivotal role as the chair of the study’s steering committee, a group made up of the study’s principal investigators at all 13 clinical sites and the Data Coordinating Center, as well as the program officials from the National Institutes of Health funding institutes (National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, and National Institute on Minority Health and Health Disparities). She will play a key part in helping to ensure that the study stays on track with recruitment goals, as well as publicizing the study at national meetings.

The study also includes a Community Advisory Council, a group made up of stakeholders in this study: 26 African-Americans who either have donated a kidney, received a kidney donation, are on dialysis awaiting a kidney transplant, or have a close relative in one of those categories. This group has helped to steer the study design in multiple ways, Dr. Moxey-Mims explains. For example, they have worked with study leaders to simplify the language on consent forms, helped to delineate which data study participants might want to receive when the study is completed, and helped to publicize the study in their communities by giving talks at churches and other venues.

Eventually, Dr. Moxey-Mims says APOLLO study researchers hope that clarifying the role of the APOL1 gene in kidney-transplant failure could lead to fewer discarded kidneys, which could boost the number of available kidneys for patients awaiting transplants.

“Down the road, the pool of patients awaiting transplant might have access to more kidneys because available organs aren’t getting a bad score simply because the donor is African-American,” she says. “We hope this might shorten the wait for some patients and their families who are desperate to get that call that a kidney is finally available.”

Financial support for research reported in the post was provided by the National Institutes of Health under grant numbers R01 DK084149, R01 DK070941 and U01 DK116041.

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Facial analysis technology successful in identifying Williams-Beuren syndrome in diverse populations

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photos used for facial analysis technology

Image Credit: Darryl Leja, NHGRI.

In an international study led by the National Human Genome Research Institute (NHGRI), researchers have successfully identified Williams-Beuren syndrome in diverse populations using clinical information and objective facial analysis technology developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National.

The technology, which was featured by STAT as an ‘Editor’s Pick’ finalist in their recent competition to find the best innovation in science and medicine, enables users to compare the most relevant facial features characteristic of Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome affects an estimated 1 in 7,500 to 10,000 people, with the most significant medical problems being cardiovascular, including high blood pressure. Though the syndrome is a genetic condition, most cases are not inherited. Signs and symptoms include intellectual disability and distinctive facial features including puffiness around the eyes, a short nose with a broad tip, full cheeks and a wide mouth with full lips.

Using the facial analysis technology, the researchers compared 286 African, Asian, Caucasian and Latin American children and adults with Williams-Beuren syndrome with 286 people of the same age, sex and ethnicity without the disease. They were able to correctly identify patients with the disease from each ethnic group with 95 percent or higher accuracy.

“Our algorithm found that the angle at the nose root is the most significant facial feature of the Williams-Beuren syndrome in all ethnic groups and also highlighted facial features that are relevant to diagnosing the syndrome in each group,” said Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are working to create a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

The technology was also highly accurate in identifying Noonan syndrome according to a study published in Sept. 2017, DiGeorge syndrome (22q11.2 deletion syndrome) in April 2017 and Down syndrome in Dec. 2016. The next study in the series will focus on Cornelia de Lange syndrome.

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For hemorrhagic cystitis, harnessing the power of a parasite

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Schistosoma haematobium egg

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D.

Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.

Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.

In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”

S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.

“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”

Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.

In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.

Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.

Staphylococcus

How our bladder’s microbiota affect health

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The presence of bacteria such as Staphylococcus in the urine is linked to the incidence and severity of urge urinary incontinence as well as treatment success.

About half of the cells in our bodies aren’t really “ours” at all. They’re the microbiota: The vast array of microorganisms that live in our gut, skin, oral cavity and other places. Decades ago, researchers thought that these organisms simply happened to colonize these areas, playing only a tangential role in health, for example, helping to break down food in the intestines or causing cavities. More recent work has revealed the incredibly complex role they play in diseases ranging from diabetes and schizophrenia.

The bladder is no exception. Just a single decade ago, the bladder was thought to be a sterile environment. But that view has shifted radically, with more sensitive cultivation methods and precise 16S rRNA gene-sequencing techniques revealing a significant bladder microbiome that could have an enormous impact on pediatric urologic diseases. These findings have opened brand new fields of research aimed at clarifying the role that the bladder’s microbiome plays in common urological diseases that affect children, according to a review article published online Feb. 22, 2018, by Current Urology Reports.

“There is a growing appreciation for the role of diverse bacteria in contributing to improved health as well as triggering disease processes or exacerbating illness,” says Michael H. Hsieh, M.D., Ph.D., director of the Clinic for Adolescent and Adult Pediatric Onset Urology (CAPITUL) at Children’s National Health System and study senior author. “Already, we know that probiotics and dietary modifications have the potential to play powerful roles in preventing urinary diseases that commonly occur among pediatric patients,” Dr. Hsieh says. This underscores the importance of conducting even more studies to improve our understanding and to identify new therapies for health conditions that resist current treatment options.”

The review conducted by Dr. Hsieh and co-authors highlights the effects of the microbiome on a number of urologic diseases that affect children, including:

  • Urinary tract infection A number of studies point to the association between decreased microbial diversity and the incidence of what is commonly called urinary tract infection (UTI) or “dysbiosis.” This relationship suggests that using probiotics to replace or supplement antibiotics could favorably alter the urinary microbiome. Future research will focus on the pathophysiological role of the microbiome to determine whether it can be manipulated to prevent or treat UTIs.
  • Urge urinary incontinence While data vary by study, the presence of bacteria in the urine, especially certain bacterial species – such as Gardnerella, Staphylococcus, Streptococcus, Actinomyces, Aerococcus, Corynebacterium and Oligella – are linked to the incidence and severity of urge urinary incontinence (UUI) as well as treatment success. Most studies find an association between greater genitourinary biodiversity and reduced incidence and lessened severity of UUI as well as improved treatment response. Future research will focus on further clarifying this relationship.
  • Urolithiasis Calcium oxalate stones, the most common type of kidney stone, have a microbiome that differs from the urinary microbiome leading researchers to question whether the stone’s own bacterial makeup could help to predict recurrence of future kidney stones. What’s more, Oxalobacter formigenes, a gram-negative bacterium, lowers oxalate levels in the blood and are associated with a 70 percent reduction in the risk of kidney stones forming. In an experimental model, fecal transplants with the full microbiome represented had a pronounced and persistent effect on oxalate production. Patients who receive some antibiotics often have reduced rates of formigenes colonization. However, the bacteria are resistant to amoxicillin, augmentin, ceftriaxone and vancomycin, which could point to preferential use of these antibiotics to stave off disease and ward off kidney stone formation.

Additional authors include Daniel Gerber, study lead author, The Georgetown University School of Medicine and Health Sciences; and Catherine Forster, M.D., study co-author, Children’s National.

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How EPO saves babies’ brains

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Researchers have discovered that treating premature infants with erythropoietin can help protect and repair their vulnerable brains.

The drug erythropoietin (EPO) has a long history. First used more than three decades ago to treat anemia, it’s now a mainstay for treating several types of this blood-depleting disorder, including anemia caused by chronic kidney disease, myelodysplasia and cancer chemotherapy.

More recently, researchers discovered a new use for this old drug: Treating premature infants to protect and repair their vulnerable brains. However, how EPO accomplishes this feat has remained unknown. New genetic analyses presented at the Pediatric Academic Societies 2018 annual meeting that was conducted by a multi-institutional team that includes researchers from Children’s National show that this drug may work its neuroprotective magic by modifying genes essential for regulating growth and development of nervous tissue as well as genes that respond to inflammation and hypoxia.

“During the last trimester of pregnancy, the fetal brain undergoes tremendous growth. When infants are born weeks before their due dates, these newborns’ developing brains are vulnerable to many potential insults as they are supported in the neonatal intensive care unit during this critical time,” says An Massaro, M.D., an attending neonatologist at Children’s National Health System and lead author of the research. “EPO, a cytokine that protects and repairs neurons, is a very promising therapeutic approach to support the developing brains of extremely low gestational age neonates.”

The research team investigated whether micro-preemies treated with EPO had distinct DNA methylation profiles and related changes in expression of genes that regulate how the body responds to such environmental stressors as inflammation, hypoxia and oxidative stress.  They also investigated changes in genes involved in glial differentiation and myelination, production of an insulating layer essential for a properly functioning nervous system. The genetic analyses are an offshoot of a large, randomized clinical trial of EPO to treat preterm infants born between 24 and 27 gestational weeks.

The DNA of 18 newborns enrolled in the clinical trial was isolated from specimens drawn within 24 hours of birth and at day 14 of life. Eleven newborns were treated with EPO; a seven-infant control group received placebo.

DNA methylation and whole transcriptome analyses identified 240 candidate differentially methylated regions and more than 50 associated genes that were expressed differentially in infants treated with EPO compared with the control group. Gene ontology testing further narrowed the list to five candidate genes that are essential for normal neurodevelopment and for repairing brain injury:

“These findings suggest that EPO’s neuroprotective effect may be mediated by epigenetic regulation of genes involved in the development of the nervous system and that play pivotal roles in how the body responds to inflammation and hypoxia,” Dr. Massaro says.

In addition to Dr. Massaro, study co-authors include Theo K. Bammler, James W. MacDonald, biostatistician, Bryan Comstock, senior research scientist, and Sandra “Sunny” Juul, M.D., Ph.D., study principal investigator, all of University of Washington.

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Keeping kids with asthma out of the hospital

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Pediatric asthma takes a heavy toll on patients and families alike. Affecting more than 7 million children in the U.S., it’s the most common nonsurgical diagnosis for pediatric hospital admission, with costs of more than $570 million annually. Understanding how to care for these young patients has significantly improved in the last several decades, leading the National Institutes of Health (NIH) to issue evidence-based guidelines on pediatric asthma in 1990. Despite knowing more about this respiratory ailment, overall morbidity – measured by attack rates, pediatric emergency department visits or hospitalizations – has not decreased over the last decade.

“We know how to effectively treat pediatric asthma,” says Kavita Parikh, M.D., M.S.H.S., a pediatric hospitalist at Children’s National Health System. “There’s been a huge investment in terms of quality improvements that’s reflected in how many papers there are about this topic in the literature.”

However, Dr. Parikh notes, most of those quality-improvement papers do not focus on inpatient discharge, a particularly vulnerable time for patients. Up to 40 percent of children who are hospitalized for asthma-related concerns come back through the emergency department within one year. One-quarter of those kids are readmitted.

“It’s clear that we need to do better at keeping kids with asthma out of the hospital. The point at which they’re being discharged might be an effective time to intervene,” Dr. Parikh adds.

To determine which interventions hold promise, Dr. Parikh and colleagues recently performed a systematic review of studies involving quality improvements after inpatient discharge. They published their findings in the May 2018 edition of the journal, Pediatrics. Because May is National Asthma and Allergy Awareness month, she adds, it’s a timely fit.

The researchers combed the literature, looking for research that tested various interventions at the point of discharge for their effect on hospital readmission anywhere from fewer than 30 days after discharge to up to one year later. They specifically searched for papers published from 1991, the year after the NIH issued its original asthma care guidelines, until November 2016.

Their search netted 30 articles that met these criteria. A more thorough review of each of these studies revealed common themes to interventions implemented at discharge:

  • Nine studies focused on standardization of care, such as introducing or revising a specific clinical pathway
  • Nine studies focused on education, such as teaching patients and their families better self-management strategies
  • Five studies focused on tools for discharge planning, such as ensuring kids had medications in-hand at the time of discharge or assigning a case manager to navigate barriers to care and
  • Seven studies looked at the effect of multimodal interventions that combined any of these themes.

When Dr. Parikh and colleagues examined the effects of each type of intervention on hospital readmission, they came to a stunning conclusion: No single category of intervention seemed to have any effect. Only multimodal interventions that combined multiple categories were effective at reducing the risk of readmission between 30 days and one year after initial discharge.

“It’s indicative of what we have personally seen in quality-improvement efforts here at Children’s National,” Dr. Parikh says. “With a complex condition like asthma, it’s difficult for a single change in how this disease is managed to make a big difference. We need complex and multimodal programs to improve pediatric asthma outcomes, particularly when there’s a transfer of care like when patients are discharged and return home.”

One intervention that showed promise in their qualitative analysis of these studies, Dr. Parikh adds, is ensuring patients are discharged with medications in hand—a strategy that also has been examined at Children’s National. In Children’s focus groups, patients and their families have spoken about how having medications with them when they leave the hospital can boost compliance in taking them and avoid difficulties is getting to an outside pharmacy after discharge. Sometimes, they have said, the chaos of returning home can stymie efforts to stay on track with care, despite their best efforts. Anything that can ease that burden may help improve outcomes, Dr. Parikh says.

“We’re going to need to try many different strategies to reduce readmission rates, engaging different stakeholders in the inpatient and outpatient side,” she adds. “There’s a lot of room for improvement.”

In addition to Dr. Parikh, study co-authors include Susan Keller, MLS, MS-HIT, Children’s National; and Shawn Ralston, M.D., M.Sc., Children’s Hospital of Dartmouth-Hitchcock.

Funding for this work was provided by the Agency for Healthcare Research and Quality (AHRQ) under grant K08HS024554. The content is solely the responsibility of the authors and does not necessarily represent the official views of AHRQ.

Research and Education Week awardees embody the diverse power of innovation

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“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.

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Genetic testing reigns triumphant at health app hackathon

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The growing popularity of genetic testing has one large hurdle: There are fewer than 4,000 genetic counselors in the United States, and people who use commercial genetic testing kits may receive confusing or inaccurate information.

To combat this problem, a team of doctors from the Rare Disease Institute at Children’s National Health System created the framework for a smartphone application that would house educational videos and tools that provide reputable information about genetic disorders and genetic testing.

On April 13, 2018, Debra Regier, M.D., Natasha Shur, M.D., and their teammates presented the app “Bear Genes” at the 2nd Annual Medical & Health App Development Workshop, a competition sponsored by the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and the Milken Institute School of Public Health (Milken Institute SPH) at the George Washington University. Bear Genes won first place, and the team received $10,000 to develop a working prototype of the app.

The Bear Genes team was one of 10 who presented their ideas for smartphone apps to a panel of judges at the competition. Ideas covered a variety of topics, including emergency room visits and seizures related to menstrual cycles. Sean Cleary, Ph.D., M.P.H., an associate professor of epidemiology and biostatistics at the Milken Institute SPH, and his teammates proposed an app called “MyCommunicationPal” that would assist autistic individuals in reporting their symptoms to healthcare providers.

Sean Cleary and Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, created the hackathon to bring together professionals from various fields to create technology-based solutions for public health and medical challenges. Interested participants submit applications and app proposals in the fall, and 10 ideas are selected to be fleshed out at the half-day hackathon. Participants join teams to develop the selected ideas, and on the day of the event, create a five-minute presentation to compete for the top prize. About 90 people attended this year’s hackathon.

“The workshop provides us with the opportunity to collaborate with healthcare providers, public health professionals and community members to develop an appropriate user-friendly app for those in need,” said Sean Cleary. “The event also fosters future collaborations between important stakeholders.”

This article originally appeared in the Milken Institute SPH pressroom.

Gustavo Nino

New method may facilitate childhood respiratory research

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Gustavo Nino

“The use of CRC is a potentially powerful translational approach to shed light on the molecular mechanisms that control airway epithelial immune responses in infants and young children. This novel approach enables us to study the origins of respiratory disease and its chronic progression through childhood and beyond,” observes Gustavo Nino, M.D., a Children’s pulmonologist and study senior author.

A new method perfected by a team at Children’s National Health System may help expand research into pulmonary conditions experienced by infants and children, an understudied but clinically important age group. The study describing the new technique was published in the December 2017 print edition of Pediatric Allergy and Immunology.

Using conditionally reprogrammed cells (CRCs), a technique that enables indefinite proliferation of cells in the lab, the team was able to produce cell cultures that have a number of advantages over standard cultures and that may make it easier and more efficient to conduct research into pediatric respiratory immune responses.

The epithelial cells that line human airways are crucial in controlling immune responses to viruses, allergens and other environmental factors. The function and dysfunction of these airway epithelial cells (AECs) play a key role in asthma, cystic fibrosis and other pulmonary conditions, many of which begin in early life.

To generate enough of these cells for research, scientists culture AECs from primary nasal and bronchial cell samples. Cells derived from adults have fueled research leading to new therapies and the discovery of key biomarkers. But little comparable research has been conducted in infants. Airway sampling in premature infants has not been reported, likely to due to airway size limitations and underlying comorbidities. Similarly, sampling in infants is limited by the need for bronchoscopy and sedation.

“A major barrier has been the lack of a good system to culture epithelial cells, since airway sampling in infants and children is a challenge,” says co-lead author, Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program. “We needed a better way to culture cells in this age group.”

While primary AECs do not survive long in the lab, that hurdle was recently overcome by a process that generates CRCs from the primary AECs of adults, making it possible to quickly generate cell cultures from specimens.

In this study, the Children’s team adapted that approach, producing CRCs from primary AECs of neonates and infants. The CRC induction successfully enabled AEC cultures from infants born prematurely and from bronchial specimens of young children.

Geovanny Perez

“A major barrier has been the lack of a good system to culture epithelial cells, since airway sampling in infants and children is a challenge,” says co-lead author, Geovanny F. Perez, M.D., co-director of Children’s Severe Bronchopulmonary Dysplasia Program. “We needed a better way to culture cells in this age group.”

“We found that the CRCs have longer cell life and greater proliferation ability than standard cultures of epithelial cells. They preserved their original characteristics even after multiple experiments. And, they presented an innate immune response similar to that seen in primary human epithelial cells during viral respiratory responses in children,” says Dr. Perez.

“The use of CRC is a potentially powerful translational approach to shed light on the molecular mechanisms that control airway epithelial immune responses in infants and young children. This novel approach enables us to study the origins of respiratory disease and its chronic progression through childhood and beyond,” observes Gustavo Nino, M.D., a Children’s pulmonologist and study senior author.

The authors note that further studies are needed to define more precisely the differences and similarities in the immune responses of CRC and non-CRC derived from primary AEC. However, they conclude that CRC represents a new, effective method to study AEC innate immune responses in infants.

In addition to Drs. Perez and Nino, Children’s Center for Genetic Medicine Research co-authors include Co-Lead Author S. Wolf; Lana Mukharesh; Natalia Isaza Brando, M.D.; Diego Preciado, M.D., Ph.D.; Robert J. Freishtat, M.D., M.P.H.; Dinesh Pillai, M.D.; and M. C. Rose.

Financial support for this research was provided by the National Institute of Allergy and Infectious Diseases under grant number R21AI130502; Eunice Kennedy Shriver National Institute of Child Health and Human Development under grant number HD001399; National Heart, Lung and Blood Institute under grant number HL090020; and National Center for Advancing Translational Sciences under grant number UL1TR000075.

STAT Madness

Voters select Children’s National innovation as runner-up in national competition

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STAT Madness

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner-up in this year’s STAT Madness 2018 competition.

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner up in this year’s STAT Madness 2018 competition. Garnering more than 33,000 overall votes in the bracket-style battle that highlights the best biomedical advances, the Children’s National entry survived five rounds and made it to the championship before falling short of East Carolina University’s overall vote count.

Children’s entry demonstrates the potential widespread utility of digital dysmorphology technology to diverse populations with genetic conditions. The tool enables doctors and clinicians to identify children with genetic conditions earlier by simply taking the child’s photo with a smartphone and having it entered into a global database for computer analyses.

The researchers partnered with the National Institutes of Health National Human Genome Research Institute and clinicians from 20 different countries to acquire pictures from local doctors for the study. Using the facial analysis technology, they compared groups of Caucasians, Africans, Asians and Latin Americans with Down syndrome, 22q11.2 deletion syndrome (also called DiGeorge syndrome) and Noonan syndrome to those without it. Based on more than 125 individual facial features, they were able to correctly identify patients with the condition from each ethnic group with more than a 93 percent accuracy rate. Missed diagnoses of genetic conditions can negatively impact quality of life and lead to premature death.

Children’s National also was among four “Editor’s Pick” finalists, entries that span a diverse range of scientific disciplines. Journalists at the digital publication STAT pored through published journal articles for 64 submissions in the single-elimination contest to honor a select group of entries that were the most creative, novel, and most likely to benefit the biomedical field and the general public.

Each year, 1 million children are born worldwide with a genetic condition that requires immediate attention. Because many of these children experience serious medical complications and go on to suffer from intellectual disability, it is critical that doctors accurately diagnose genetic syndromes as early as possible.

“For years, research groups have viewed facial recognition technology as a potent tool to aid genetic diagnosis. Our project is unique because it offers the expertise of a virtual geneticist to general health care providers located anywhere in the world,” says Marius George Linguraru, D.Phil., M.A., M.S., a Sheikh Zayed Institute for Pediatric Surgical Innovation principal investigator who invented the technology. “Right now, children born in under-resourced regions of the U.S. or the world can wait years to receive an accurate diagnosis due to the lack of specialized genetic expertise in that region.”

In addition to providing patient-specific benefits, Marshall Summar, M.D., director of Children’s Rare Disease Institute that partners in the facial recognition technology research, says the project offers a wider societal benefit.

“Right now, parents can endure a seemingly endless odyssey as they struggle to understand why their child is different from peers,” says Dr. Summar. “A timely genetic diagnosis can dispel that uncertainty and replace it with knowledge that can speed patient triage and deliver timely medical interventions.”