Genetics and Rare Diseases

Bladder cancer’s unique bacterial “fingerprint”

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

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

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.

Marva Moxey-Mims in her office at Children's National.

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

Marva Moxey-Mims in her office at Children's National.

Marva Moxey-Mims, M.D., FASN, 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.

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.

photos used for facial analysis technology

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

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.

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

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

Staphylococcus

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.

An-Massaro

How EPO saves babies’ brains

An-Massaro

“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,” says An Massaro, M.D.

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.

inhaler

Keeping kids with asthma out of the hospital

inhaler

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

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.

2nd-annual-hackathon

Genetic testing reigns triumphant at health app hackathon

2nd-annual-hackathon

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

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

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.”

Javad Nazarian

Private foundation and researchers partner to cure childhood cancers

Javad Nazarian

Researchers nationally and internally stand the best chance of fulfilling Gabriella Miller’s dream of curing childhood cancers by effectively working together, says Javad Nazarian, Ph.D.

“Thank you for helping me reach my goal.” The handwritten note was penned by Gabriella Miller, a patient treated at Children’s National Health System who ultimately succumbed to an aggressive form of pediatric brain cancer.

Gabriella, then 9 years old, dreamed of curing childhood cancer, including diffuse intrinsic pontine glioma (DIPG), the aggressive pediatric brain tumor that took her life.

Attendees will gather April 14, 2018, for an annual gala held by the Smashing Walnuts Foundation – a group Gabriella started – to celebrate their progress on achieving her goal and to chart future strategic approaches.

“While this foundation was the brainchild of a single person, researchers nationally and internally stand the best chance of fulfilling her dream by working together more effectively,” says Javad Nazarian, Ph.D., M.S.C., the gala’s main speaker. Nazarian is scientific director of Children’s Brain Tumor Institute and is scientific co-chair of the Children’s Brain Tumor Tissue Consortium.

To that end, Children’s National was named a member of a public-private research collective awarded up to $14.8 million by the National Institutes of Health (NIH) to launch a data resource center that cancer sleuths around the world can tap into to accelerate discovery of novel treatments for childhood tumors.

This April, the NIH announced that researchers it funded had completed PanCancer Atlas, a detailed genomic analysis on a data set of molecular and clinical information from more than 10,000 tumors representing 33 types of cancer, including DIPG.

And this January, the NIH announced that it would accept applications from researchers performing whole-genome sequencing studies at one of its Gabriella Miller Kids First research program sequencing facilities. The centers will produce genome, exome and transcriptome sequencing.

Expanding access to these growing troves of data requires a close eye on nuts-and-bolts issues, such as securing sufficient physical data storage space to house the data, Nazarian adds. It’s essential for research teams around the world to have streamlined access to data sets they can analyze as well as contribute to.

“In addition to facilitating researchers’ access to this compiled data, we want to ensure that patients and families feel they are partners in this enterprise by also offering opportunities for them to share meaningful clinical data,” Nazarian says.

Nazarian has been instrumental in expanding the comprehensive biorepository at Children’s National, growing it from just a dozen samples six years ago to thousands of specimens donated by patients with all types of pediatric brain tumors, including DIPG.

“We are so grateful to our patients and families. They share our passion for finding cures and validating innovative treatments for pediatric cancers that defy current treatment. They provide funding through their foundations. Families touched by tragedy offer samples to help the next family avoid reliving their experience,” Nazarian says. “It is in their names – and in Gabriella’s name – that we continue to push ourselves to ‘crack the cure’ for childhood brain cancer.”

Sean Donahue

Pediatric ophthalmology celebrates 75th anniversary in Washington, D.C.

Sean Donahue

Angeline M. Parks Visiting Professor Sean P. Donahue, M.D., Ph.D., (front left) enjoys a light moment during the celebration of the 75th anniversary while Anthony Sandler, M.D., Children’s surgeon in chief, senior vice president of the Joseph E. Robert Jr. Center for Surgical Care and director of the Sheikh Zayed Institute, speaks to the group.

After 75 years dedicated to the eyes of children, the world’s pediatric ophthalmologists gathered in Washington, D.C., the specialty’s birthplace, to share the latest research and innovation in the field. The group gathered for a joint meeting of the International Strabismological Association (ISA) and the American Association for Pediatric Ophthalmology and Strabismus (AAPOS), which was held March 18-22, 2018.

“This year marks the 75th anniversary of our specialty, which was founded right here, at Children’s National, in Washington, D.C., when Dr. Frank Costenbader restricted his practice exclusively to children and began to train residents in the nuance of treating children’s eyes,” says Mohamad S. Jaafar, M.D., chief of the Division of Ophthalmology at Children’s National Health Center. “It is a tremendous honor to welcome my colleagues back to the birthplace of pediatric ophthalmology on this grand occasion.”

In advance of the larger meeting, Children’s Division of Ophthalmology welcomed some of the international attendees to Children’s National for a special gathering on Saturday, March 17, 2018.

The event at Children’s featured a special lecture by this year’s Angeline M. Parks Visiting Professor, Sean P. Donahue, M.D., Ph.D. Dr. Donahue is the Sam and Darthea Coleman Chair in Pediatric Ophthalmology and Chief of Pediatric Ophthalmology at the Children’s Hospital at Vanderbilt. This Annual Visiting Professorship was established by the members of the Costenbader Society (The Children’s National Pediatric Ophthalmology Alumni Society) in memory of Angeline M. Parks, the wife of pediatric ophthalmologist Marshall M. Parks, M.D., to carry on her legacy of establishing a warm and supportive environment between physician and spouse, which benefits the physicians and their young patients.

Three former division chiefs of Ophthalmology at Children’s National, Drs. Costenbader, Parks and Friendly, have national lectureships established in their names to reflect their contributions to the field. Dr. Frank Costenbader, the society’s namesake, established the sub-specialty of pediatric ophthalmology. Dr. Parks founded the Children’s Eye Foundation and the AAPOS, and David S. Friendly, M.D., codified pediatric ophthalmology fellowship training across the United States.

Honor Awards for Children’s pediatric ophthalmologists at ISA-AAPOS

During the ISA-AAPOS meeting, two current Children’s National pediatric ophthalmologists were recognized with Honor Awards for their long-term dedication to pediatric ophthalmology, their patients, and their engagement in the AAPOS to advance the field.

William Madigan, M.D., vice chief of Ophthalmology at Children’s, a professor of surgery at the Uniformed Services University of the Health Sciences, and a clinical professor of Ophthalmology and Pediatrics at the George Washington University School of Medicine and Health Sciences. He was recognized by AAPOS for his long-time service, including:

  • Chair of the organization’s audit committee and the Costenbader Lecture selection committee.
  • Membership on the fellowship directors’ committee that developed nationwide requirements for pediatric ophthalmology fellowships and established the certification process to insure high quality and uniform education in the specialty.
  • Invited lectures in Shanghai, China; Geneva, Switzerland; and Sao Paolo, Brazil, among others.
  • Many posters and presentations about clinical and research topics of importance for members of the AAPOS and other distinguished professional societies.

Marijean Miller, M.D., director of Neonatal Ophthalmology, division research director at Children’s National and clinical professor of Ophthalmology and Pediatrics at the George Washington University School of Medicine and Health Sciences, was recognized by AAPOS for her cumulative contributions to the society, including:

  • Multiple memberships on vital committees, including AAPOS’s training and accreditation committee and audit committee.
  • Presentation of original research via posters and oral presentations on topics including best practices in neonatal clinical care, innovative tools and applications and advocacy for patients and their families.

“We are so grateful to have a team that continues the tradition of excellence in pediatric ophthalmology here at Children’s National,” Dr. Jaafar says. “Drs. Madigan and Miller exemplify the dedication of our division to caring for the children we serve, and to advancing our field. Congratulations to both!”

Rare Disease Institute director named to Global Commission to End the Diagnostic Odyssey for Children

Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children.

Children’s National Health System has announced that Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children (“the Global Commission”), an alliance dedicated to shortening the multi-year journey that rare disease patients and families endure on the road to diagnosis.

Established in partnership with Shire, Microsoft and EURORDIS, the Global Commission is comprised of a multi-disciplinary team of global experts that have the commitment, creativity and technological expertise required to make a substantial difference in the lives of the millions of children living with a rare disorder.

“Providing more help to children born with rare genetic diseases continues to be one of the core challenges of 21st century medicine,” says Dr. Summar, who notes that patients typically visit up to eight doctors and often receive two or three misdiagnoses along the way. “Even upon diagnosis, patients are hindered by scarce treatment options and approximately a third of patients die before their fifth birthday. We are committed to changing this trend at the CNRDI and are excited to have the opportunity to share our expertise with this alliance on a global stage.”

The Global Commission is focused on developing an actionable roadmap for the field of rare disease that offers recommendations to address core challenges that prevent timely diagnosis for rare disease patients, including improving physicians’ ability to identify and diagnose rare disorders, empowering patients to take an active role in their healthcare and providing high-level policy guidance to help rare disease patients achieve better health outcomes.

Beginning its work in 2018, the Global Commission expects to publish a roadmap that encapsulates the collective findings in early 2019. Over the course of the next year, the alliance will gather input from patients, families and other experts to gain key insights and develop solutions to shorten the diagnostic odyssey.

In the United States, it is estimated that one in 10 people has a rare disease – approximately 80 percent of which are genetically based. Additionally, the National Institutes of Health reports that more than 80 percent are childhood diseases and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

banner year

2017: A banner year for innovation at Children’s National

banner year

In 2017, clinicians and research faculty working at Children’s National Health System published more than 850 research articles about a wide array of topics. A multidisciplinary Children’s Research Institute review group selected the top 10 articles for the calendar year considering, among other factors, work published in high-impact academic journals.

“This year’s honorees showcase how our multidisciplinary institutes serve as vehicles to bring together Children’s specialists in cross-cutting research and clinical collaborations,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “We’re honored that the National Institutes of Health and other funders have provided millions in awards that help to ensure that these important research projects continue.”

The published papers explain research that includes using imaging to describe the topography of the developing brains of infants with congenital heart disease, how high levels of iron may contribute to neural tube defects and using an incisionless surgery method to successfully treat osteoid osteoma. The top 10 Children’s papers:

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2018 at Children’s National, a weeklong event that begins April 16, 2018. This year’s theme, “Diversity powers innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Horizon Pharma gifts $3M to establish Horizon Pharma Clinical Care Endowment at Children’s National Rare Disease Institute

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D., director of the CNRDI.

Children’s National Health System and Horizon Pharma plc are pleased to announce the creation of the Horizon Pharma Clinical Care Endowment, the first clinical team endowment at the Children’s National Rare Disease Institute (CNRDI). The endowment is made possible by a generous six-year, $3 million commitment from Horizon Pharma USA, Inc., a wholly owned subsidiary of Horizon Pharma plc –a biopharmaceutical company dedicated to improving the lives of people living with rare diseases.

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D. , director of the CNRDI.  “We are grateful for Horizon and their support of our mission to make the Children’s National Rare Disease Institute that place. This endowment will support a dedicated team that can provide optimal, comprehensive care to more patients and ensure that families have a trusted source for all aspects of their health care.”

The Horizon Pharma Clinical Care Endowment will generate revenue annually, providing stable support for an expert care team at the CNRDI. Each team will be comprised of a clinical geneticist and support team members – such as genetic counselors, nutritionists and social workers – all specializing in the care of children with rare disease.

The long-term support provided by the Horizon Pharma Clinical Care Endowment will give the CNRDI a firm foundation for treating patients earlier, more consistently and over the course of their lifetime. Horizon’s commitment marks the first donor-funded endowment at the CNRDI.

Currently, it is estimated that one in 10 Americans has a rare disease – approximately 80 percent of which are genetically based. Additionally, the NIH reports that more than 80 percent are childhood diseases, and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

The CNRDI is a first-of-its-kind center focused exclusively on advancing the care and treatment of children and adults with rare genetic diseases. It is the first National Organization for Rare Disorders (NORD) Center of Excellence and aims to provide a medical home for patients and families seeking the most advanced care and expertise for rare genetic conditions that remain largely unknown to the general medical community.

foods rich in folate

An ironclad way to prevent neural tube defects? Not yet

foods rich in folate

Researchers have known for decades that folate, a vitamin enriched in dark, leafy vegetables; fruit; nuts; and other food sources, plays a key role in preventing neural tube defects.

Every year, about 3,000 pregnancies in the U.S. are affected by neural tube defects (NTDs) –  birth defects of the brain, spine and spinal cord. These include anencephaly, in which a major part of the brain, skull and scalp is missing; and spina bifida, in which the backbone and membranes around the spinal cord don’t close properly during fetal development. These structural birth defects can have devastating effects: In the best cases, they might lead to mild but lifelong disability; in the worst cases, babies don’t survive.

Researchers have known for decades that folate, a vitamin enriched in dark, leafy vegetables; fruit; nuts; and other food sources, plays a key role in preventing NTDs. To help get more folate into pregnant women’s diets, wheat flour in the U.S. and many other countries is often fortified with folic acid, a synthetic version of this vitamin, as part of an intervention credited with significantly reducing the incidence of NTDs.

But folic acid supplementation isn’t enough, says Irene E. Zohn, Ph.D., a principal investigator at the Center for Neuroscience Research at Children’s National Health System who studies how genes and the environment interact during development. A significant number of NTDs still occur, suggesting that other approaches – potentially, other nutrients in the maternal diet – might provide further protection.

That’s why Zohn and colleagues decided to investigate iron. Iron deficiency is one of the most common micronutrient deficiencies in women of childbearing age, Zohn explains. Additionally, iron and folate deficiencies often overlap and signal overall poor maternal diets.

The idea that iron deficiency might play a role in NTDs came from studies by Zohn and colleagues of the flatiron mutant line of experimental models. This experimental model line has a mutation in a gene that transports iron across cell membranes, including the cells that supply embryos with this critical micronutrient.

To determine if NTDs develop in these mutant experimental models because of reduced iron transport, the researchers devised a simple experiment: They took female adult experimental models with the mutation and separated them into four groups. For several weeks, one group ate a diet that was high in folic acid. Another group ate a diet high in iron. The third group ate a diet high in both folic acid and iron. The fourth group ate standard chow. All of these experimental models then became pregnant with embryos that harbored the flatiron mutation, and the researchers assessed the offspring for the presence of NTDs.

Irene Zohn

“We were hoping that iron supplements would be the next folic acid, but it did not turn out that way,” says Irene E. Zohn, Ph.D. “Even though our results demonstrate that iron is important for proper neural tube development, giving extra iron definitely has its downsides.”

As they reported in Birth Defects Research, the dietary interventions successfully increased iron stores: Experimental model mothers whose diets were supplemented with iron, folic acid or both had increased concentrations of these micronutrients in their blood.

The dietary interventions also affected their offspring. While about 80 percent of flatiron mutant embryos fed a standard diet during pregnancy had NTDs, feeding a diet high in iron prevented NTDs in half of the offspring. This lower rate was similar in the offspring of mothers fed a diet high in both folic acid and iron, but not for those whose mothers ate just a diet high in folic acid. Those embryos had NTD rates as high as those who ate just the standard chow, suggesting that low iron was the cause of the high rates, not low folic acid.

Together, Zohn says, these experiments show that iron plays an important role in the development of the neural tube and that deficits in iron might cause some cases of NTDs. However, she notes, reducing NTDs isn’t nearly as simple as supplementing pregnant women’s diets with iron. In the same study, the researchers found that when they gave normal experimental models that didn’t have the flatiron mutation concentrated iron supplements – amounts akin to what doctors might prescribe for human patients with very severe iron-deficiency anemia – folate stores dropped.

That’s because these two micronutrients interact in the body with similar sites for absorption and storage in the intestines and liver, Zohn explains. At either the intestines or liver or at both locations, an iron overload might interfere with the body’s ability to absorb or use folate.

At this point, she says, giving high doses of iron routinely during pregnancy doesn’t look like a feasible way to prevent NTDs.

“We were hoping that iron supplements would be the next folic acid, but it did not turn out that way,” Zohn says. “Even though our results demonstrate that iron is important for proper neural tube development, giving extra iron definitely has its downsides.”

Zohn’s team plans to continue to investigate the role of iron, as well as the role of other micronutrients that might influence neural tube development.

Zohn’s coauthors include Bethany A. Stokes, The George Washington University, and Julia A. Sabatino, Children’s National.

Research reported in this story was supported by a grant from the Board of Visitors, Eunice Kennedy Shriver National Institute of Child Health & Human Development under award number R21-HD076202, the National Center for Research Resources under award number UL1RR031988, Children’s Research Institute and the National Institutes of Health under grant P30HD040677.

Eric Vilain

Exploring differences of sex development

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

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

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

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

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

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

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

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

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

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

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

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

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