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Staphylococcus

Airway microbial diversity in children with Cystic Fibrosis

Staphylococcus

Despite having less overall microbial richness, children with Cystic Fibrosis displayed a greater presence of Staphylococcus species.

Cystic Fibrosis (CF) is a disease that mainly affects the lungs and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for the CFTR membrane protein located on certain secretory cells. CFTR dysfunction leads to complications such as the production of abnormally viscous mucus which causes chronic suppurative lung infections that require antibiotics to treat. New drugs called CFTR modulators can help improve CFTR protein function and some are even FDA-approved for use in children. In addition to CFTR protein function, the lung’s resident microbiota and its richness of diversity, plays an important role in both health and disease, including CF.

In a new study published in Heliyon, scientists from Children’s National Hospital examined the difference in the upper airway microbiome between children with CF and healthy controls. Age-related differences among children with CF and the impact of CFTR modulators on microbial diversity were also assessed. Seventy-five children between 0-6 years of age participated in the study, including 25 children with CF and 50 healthy controls. For CF participants, oropharyngeal swabs and clinical data were obtained from the biorepository, while data for controls were obtained during a single clinical visit.

Analysis revealed that CF patients had less microbial diversity and different composition of the upper airway microbiome compared to age similar controls, a finding that is consistent with research on the lower airways. Despite having less overall microbial richness, children with CF displayed a greater presence of Staphylococcus species, (a main driver of the pulmonary exacerbations characteristic of CF), three Rothia operational taxonomic units (OTUs) and two Streptococcus OTUs. CF patients received a significantly higher number of antibiotics courses within the previous year compared to healthy controls, and further investigation will be necessary to understand the impact of antibiotics on the upper airway microbiome of infants and children with CF.

Longitudinal comparisons to study effects of age and CFTR modulation on the microbiome of children with CF were also undertaken. Younger CF patients (those 0 to <3 years of age at study enrollment), were more likely to have culturally-normal respiratory flora and more stable microbial composition over time than older CF patients (those ≥ 3–6 years of age at study enrollment), with no significant differences in alpha or beta diversity. Older CF patients were significantly more likely to be receiving a CFTR modulator than younger patients. CF patients receiving CFTR modulators had higher microbial diversity measures than those not receiving CFTR modulators and were closer (but still significantly lower) in microbial richness to healthy controls. No significant differences in beta diversity were found between the three groups.

This study adds to the growing body of evidentiary support for the use of CFTR modulators in improving airway microbial diversity in CF patients. Future studies with a larger cohort and greater focus on the impact on early initiation of CFTR modulators on microbial diversity and clinical outcomes is necessary.

The study, “Airway microbial diversity is decreased in young children with cystic fibrosis compared to healthy controls but improved with CFTR modulation,” was recently published in Heliyon. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Aszia Burrell; Emily Ansusinha; Hollis Chaney, M.D.; Iman Sami, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., M.P.H.; Robert McCarter, Sc.D.; and Robert J. Freishtat, M.D., M.P.H..

Nobuyuki Ishibashi

R01 grant funds white matter protection study for congenital heart disease

Nobuyuki Ishibashi

Nobuyuki Ishibashi, M.D., is the principal investigator on a $3.2 million NIH R01 to study white matter growth and repair in utero for fetal brains affected by congenital heart disease.

Many of the neurological deficits seen in children with congenital heart disease (CHD) are related to abnormal white matter development early in life caused by reduced oxygen supply to the brain while in utero. Children with immature white matter at birth also commonly sustain additional white matter injuries following cardiac surgery.

The NIH recently awarded a prestigious R01 grant totaling more than $3.2 million to a collaborative project led by the Center for Neuroscience Research, the Sheikh Zayed Institute for Pediatric Surgical Innovation and the Children’s National Heart Institute at Children’s National Hospital as well as MedStar Washington Hospital Center.

The research, titled “White matter protection in the fetus with congenital heart disease,” looks specifically at whether providing a supplemental amount of the naturally occurring tetrahydrobiopterin (BH4) for pregnant women could rescue white matter development of fetuses with congenital heart disease whose brains aren’t receiving enough oxygen – or suffering from hypoxic-ischemic events.

Previous preclinical studies have shown that this lack of oxygen depletes the brain’s natural BH4 level, and the researchers hypothesize that BH4 levels play a critical role in the growth and development of white matter in the fetal brain by triggering key cellular/molecular processes. Specifically, the study will focus on three aims:

  1. Establish in a preclinical model the optimal protective regiment for women pregnant with a fetus who has CHD to receive BH4.
  2. Determine the appropriate approach to deliver BH4 to this population
  3. Leverage genetic tools and biochemical techniques in the laboratory to better understand where and how BH4 levels play a role in the growth (or lack thereof) of oligodendrocytes—the primary cells of white matter.

This laboratory-based work is the first step to determining if the neurodevelopment of babies born with CHD can be preserved or recovered by addressing key brain development that occurs before the baby is even born. Findings related to congenital heart disease may also translate to other populations where white matter development is affected by hypoxia-ischemia, including premature infants.

The project is led by principal investigator Nobuyuki Ishibashi, M.D., with co-investigators Vittorio Gallo, Ph.D., Joseph Scafidi, D.O., and Mary Donofrio, M.D. as well as colleagues at MedStar Washington Hospital Center.

child using inhaler

The search for new Cystic Fibrosis clinical biomarkers

child using inhaler

Physician-scientists from Children’s National Hospital are unlocking new insights into Cystic Fibrosis by studying the type and number of bacteria in the lungs.

Cystic Fibrosis (CF) is a genetic disorder that chiefly affects the lungs and results in the production of abnormally dehydrated, viscous mucus. The inability to adequately clear this mucus leads to bacterial retention and both intermittent and chronic lung infections which require antibiotic therapy to treat. Researchers have used 16S rDNA amplicon sequencing for years in the attempts to characterize the airway microbiomes of CF patients, and more recently have used shotgun whole genome sequencing (WGS) techniques to obtain further details regarding bacterial species and strains. Previous studies on the airway microbiomes of CF patients have revealed that inter-person variability is high and can sometimes exceed intra-person variability. This can preclude generalizations regarding the CF population as a whole, which includes more than 30,000 Americans.

A recently published case study examined a young child with advanced and severely aggressive CF over a 12-month period, during which five pulmonary exacerbations occurred. A total of 14 sputum samples were collected across three clinical periods- baseline, exacerbation, and treatment. Samples were subsequently genetically sequenced (via 16s rDNA sequencing and, in three instances, WGS) and volatile metabolites were analyzed. The researchers hypothesized that if signature microbiome and metabolome characteristics correlated with one other and could be identified for each disease state, this data could serve as conglomerate biomarkers for the continuum of CF clinical states within an individual. In turn, this could inform future study design in a larger cohort.

Across all sputum samples, 109 individual operational taxonomic units (OTUs) and 466 distinct volatile metabolites were identified. 16s rDNA sequencing and WGS revealed that Escherichia coli and Staphylococcus aureus were the predominant bacteria during most baseline and exacerbation samples, despite some significant fluctuations in relative abundances. After the patient’s fifth antibacterial course, however, Achromobacter xylosoxidans became the new dominant bacterium.

Analysis revealed that the phylum Bacteroidetes and the genus Stenotrophomonas were significantly more abundant in treatment periods compared to baseline and exacerbation periods. WGS revealed the presence of bacteriophages as well as antibiotic resistance genes (mostly due to multi-drug resistance mechanisms), which can have important clinical ramifications and adds some dimensionality to the genetic analysis.

Volatile metabolite analysis found that observable fluctuations in metabolome composition coincided with fluctuations in the sputum microbiome. In this case, the microbiome and volatile metabolites produced by these bacteria provided an accurate assessment of the child’s clinical state. More specifically, the authors saw a distinct shift in both the microbiome and volatile metabolites with antibiotic treatment across the five independent pulmonary exacerbations. These additional assessments of the bacteria within the CF airway could provide an additional technique beyond standard bacterial cultures to better understand how the patient is responding to antibiotic treatment. Future studies in a larger group of children with CF may provide further insights into bacteria and volatile metabolite combinations that predict pulmonary exacerbation.

The article, “Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study,” was published in Frontiers in Cellular and Infection Microbiology. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Iman Sami, M.D., pulmonologist at Children’s National; Anastassios C. Koumbourlis, M.D., M.P.H, director of the Cystic Fibrosis Center; and Robert J. Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research.

doctor and patient filling out paperwork

How advance care planning can improve life in a pandemic and beyond

doctor and patient filling out paperwork

New research, published in AIDS and Behavior, shows the effectiveness of an Advance Care Planning model developed through participatory research with adolescents in improving palliative care among adult people living with HIV (PLWH).

Since the beginning of the COVID-19 pandemic, there has been a dramatic increase in advance care planning (ACP) and the creation of advance directives, also known as living wills, in the United States. New research, published in AIDS and Behavior, shows the effectiveness of an ACP model developed through participatory research with adolescents in improving palliative care among adult people living with HIV (PLWH).

These findings demonstrate that ACP positively contributes to the palliative care of adult PLWH by relieving suffering and maximizing quality of life. The intervention was based on the FAmily CEntered (FACE) Advance Care Model, which was developed and tested by principal investigator Maureen E. Lyon, Ph.D., and her colleagues.

Dr. Lyon’s team used this model successfully with adolescents living with HIV as part of five-year, five-site trial that included Children’s National Hospital. The trial was co-funded by the National Institutes of Health and National Institute of Nursing Research. The success of that study was parlayed into a new five-year study testing a slightly modified ACP intervention in adults, with Children’s National serving as the coordinating center. “The adolescents showed us the way,” says Dr. Lyon.

The paper details the findings of a longitudinal, two arm, randomized controlled clinical trial examining whether an ACP intervention aimed at adult PLWH and their families correlated with higher congruence in treatment preferences, as well as higher congruence over time. Patient-surrogate dyads were randomized to an ACP intervention arm or an active control arm at a 2:1 ratio (86 intervention dyads and 43 control dyads at 18-month follow up), due to prior demonstrated benefit of ACP.

The ACP intervention consisted of two 60-minute, patient-focused sessions. During session 1, Respecting Choices Next Steps® ACP Conversation, both patients and their surrogate decision-makers focused on the patients’ understanding of HIV, experience of symptoms, fears, hopes and worries. Next, a patient’s treatment preferences were explored via the Statement of Treatment Preferences (SoTP), which became a part of the patient’s electronic health record (EHR). Surrogates were questioned on their comprehension and willingness to comply with the patient’s wishes. Session 1 was acknowledged as the beginning of a conversation, and continued conversation between the dyad was encouraged.

Session 2, Five Wishes©, involved a facilitator guiding the dyad through a Five Wishes© advance directive. Session 2 resulted in legal documentation of a patient’s preferences in five specific areas: The patient’s preferred health care decision-maker, the kind of medical treatment the patient wants, how comfortable the patient wants to be, how the patient wants people to treat him/her and what the patient wants loved ones to know. The patient, surrogate and treating physicians all received a copy, and a copy was also submitted to the patient’s EHR.

Dyads in the control arm participated in two 60-minute sessions entitled Developmental or Relationship History (excluding any medical questions) and Nutrition & Exercise.

The researchers then assessed treatment preference congruence for each patient-surrogate dyad by presenting them with five different hypothetical scenarios. After the first session, congruence across all scenarios was significantly higher among ACP intervention dyads compared to control dyads. ACP patients were also significantly more likely to give their surrogates leeway in treatment decision making compared to control patients.

Compared to control dyads, ACP dyads were significantly more likely to maintain High → High congruence transition and significantly less likely to experience Low → Low congruence transition as measured from immediately post-intervention to 12-months post-intervention. The only two cases of Low → High congruence transition occurred in the intervention arm. Of note, ACP surrogates accurately reported on changes in patient preferences over one year, showing the positive impact of early conversation on longitudinal congruence.

Dr. Lyon hopes these results will encourage people to talk to their loved ones as soon as possible about ACP, not only during the current pandemic but into the future. “People can use what’s happening in the news as a trigger to begin these conversations,” she says. “The 1990 Patient Self-Determination Act (PSDA) encourages persons of all ages– including children and their parents– to decide the type and extent of medical care they want to accept or refuse if they become unable to make those decisions due to illness. Our research shows conversations matter.”

The original research paper, “Effect of FAmily CEntered (FACE®)Advance Care Planning on Longitudinal Congruence in End-of-Life Treatment Preferences: A Randomized Clinical Trial,” was recently published in AIDS and Behavior. Dr. Maureen E. Lyon, Ph.D., FABPP, of the Center for Translational Research/Children’s Research Institute, was the principal investigator of the trial and a co-senior of the paper.

Vittorio Gallo and Mark Batshaw

Children’s National Research Institute releases annual report

Vittorio Gallo and Marc Batshaw

Children’s National Research Institute directors Vittorio Gallo, Ph.D., and Mark Batshaw, M.D.

The Children’s National Research Institute recently released its 2019-2020 academic annual report, titled 150 Years Stronger Through Discovery and Care to mark the hospital’s 150th birthday. Not only does the annual report give an overview of the institute’s research and education efforts, but it also gives a peek in to how the institute has mobilized to address the coronavirus pandemic.

“Our inaugural research program in 1947 began with a budget of less than $10,000 for the study of polio — a pressing health problem for Washington’s children at the time and a pandemic that many of us remember from our own childhoods,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director at Children’s National Research Institute. “Today, our research portfolio has grown to more than $75 million, and our 314 research faculty and their staff are dedicated to finding answers to many of the health challenges in childhood.”

Highlights from the Children’s National Research Institute annual report

  • In 2018, Children’s National began construction of its new Research & Innovation Campus (CNRIC) on 12 acres of land transferred by the U.S. Army as part of the decommissioning of the former Walter Reed Army Medical Center campus. In 2020, construction on the CNRIC will be complete, and in 2012, the Children’s National Research Institute will begin to transition to the campus.
  • In late 2019, a team of scientists led by Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, traveled to the Democratic Republic of Congo to collect samples from 60 individuals that will form the basis of a new reference genome data set. The researchers hope their project will generate better reference genome data for diverse populations, starting with those of Central African descent.
  • A gift of $5.7 million received by the Center for Translational Research’s director, Lisa Guay-Woodford, M.D., will reinforce close collaboration between research and clinical care to improve the care and treatment of children with polycystic kidney disease and other inherited renal disorders.
  • The Center for Neuroscience Research’s integration into the infrastructure of Children’s National Hospital has created a unique set of opportunities for scientists and clinicians to work together on pressing problems in children’s health.
  • Children’s National and the National Institute of Allergy and Infectious Diseases are tackling pediatric research across three main areas of mutual interest: primary immune deficiencies, food allergies and post-Lyme disease syndrome. Their shared goal is to conduct clinical and translational research that improves what we know about those conditions and how we care for children who have them.
  • An immunotherapy trial has allowed a little boy to be a kid again. In the two years since he received cellular immunotherapy, Matthew has shown no signs of a returning tumor — the longest span of time he’s been tumor-free since age 3.
  • In the past 6 years, the 104 device projects that came through the National Capital Consortium for Pediatric Device Innovation accelerator program raised $148,680,256 in follow-on funding.
  • Even though he’s watched more than 500 aspiring physicians pass through the Children’s National pediatric residency program, program director Dewesh Agrawal, M.D., still gets teary at every graduation.

Understanding and treating the novel coronavirus (COVID-19)

In a short period of time, Children’s National Research Institute has mobilized its scientists to address COVID-19, focusing on understanding the virus and advancing solutions to ameliorate the impact today and for future generations. Children’s National Research Institute Director Mark Batshaw, M.D., highlighted some of these efforts in the annual report:

  • Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, is looking at whether or not the microbiome of bacteria in the human nasal tract acts as a defensive shield against COVID-19.
  • Catherine Bollard, M.D., MBChB, director of the Center for Cancer and Immunology Research, and her team are seeing if they can “train” T cells to attack the invading coronavirus.
  • Sarah Mulkey, M.D., Ph.D., an investigator in the Center for Neuroscience Research and the Fetal Medicine Institute, is studying the effects of, and possible interventions for, coronavirus on the developing brain.

You can view the entire Children’s National Research Institute academic annual report online.

Newborn baby laying in crib

How a baby with classic galactosemia was nearly missed: When the test succeeds but system fails

Newborn baby laying in crib

Run at the state-level, mandatory newborn screening (NBS) programs detect a host of hereditary disorders so that infants can be treated before further damage, or even death, occurs.

Newborn screening (NBS) programs are critical to public health. Run at the state-level, mandatory NBS programs detect a host of hereditary disorders so that infants can be treated before further damage, or even death, occurs.

While much attention is paid to testing technology, programs must still meet basic minimum requirements to reliably identify and treat all affected individuals including minimum reporting requirements, case surveillance and a dedicated short-term follow-up program. In newborn screening, success is systematic.

A new report “How a baby with classic galactosemia was nearly missed: When the test succeeds but system fails,” published in the American Journal of Medical Genetics, takes a look at an individual case that almost slipped through the cracks of a local NBS program.

One disorder detected by NBS is classic galactosemia (CG), which arises from a deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme, leaving infants unable to metabolize galactose-1-phosophate, a monosaccharide abundantly present in milk. CG can result in fatal liver failure, sepsis and coagulopathy if the affected infant is not switched to soy-based formula within the first week of life.

CG can be detected through a combination of enzyme assay, DNA analysis and galactose quantification. However, NBS programs differ in testing protocols for CG by state, and not all NBS programs conduct all of these tests. This is of particular relevance to the Washington, D.C., metropolitan area, a regional nexus where crossing state and district lines for medical care is common.

The report describes how a D.C.-born infant was screened for CG through all three tests. While his galactose levels were normal, his GALT was low and DNA testing revealed homozygosity for a CG mutation known as K285N. In tandem, the latter two indicators constitute a true positive result for CG, and necessitate the proper issuance of referrals, precautions and follow-up, which failed to occur in this case.

The infant breastfed and displayed notable lethargy, and parents were directed to a local emergency department in a neighboring state which does not screen for CG with DNA testing.

The providers there were unfamiliar with the DNA results, and after new labs came back normal, the NBS results were deemed as “likely falsely positive” for CG. Fortunately, a provider at the community hospital forwarded the NBS results to the Children’s National Rare Disease Institute (CNRDI). Upon review, CNRDI metabolic specialists immediately sought to rectify the situation by reaching out to the family with proper instructions and arranging a clinical evaluation, which occurred 10 days after birth.

While this case had a fortunate ending, the report highlights the potential deficiencies in NBS programs, which have historically been among America’s most successful public health initiatives. The proper and timely functioning of NBS systems is contingent upon the functioning of its constituent parts, including testing, diagnosis, follow-up, management and stakeholder education.

While test results were accurate in this case, systemic shortcomings left a patient in danger. As the authors state, “Programs must keep in mind that the true success of newborn screening extends beyond just the test itself…to improve safety and care outcomes we must focus on the system.”

A clinical report by a team of authors, mainly comprised of Children’s National clinicians, was published earlier this month in the American Journal of Medical Genetics. Authors include Sarah Viall, PPCNP, MSN, a pediatric nurse practitioner in the Rare Disease Institute; Nicholas Ah Mew, M.D., director of the Inherited Metabolic Disorders Program; and Beth A. Tarini, M.D., M.S., associate director of the Center for Translational Research.

muscle cells

Experimental model mimics early-stage myogenic deficit in boys with DMD

muscle cells

Muscle regeneration marked by incorporation of muscle stem cell nuclei (green) in the myofibers (red) in dystrophic muscles with low TGFβ level (upper image), but not with high TGFβ level (lower image). Inflammatory and other nuclei are labeled blue.

Boys with Duchenne muscular dystrophy (DMD) experience poor muscle regeneration, but the precise reasons for this remain under investigation. An experimental model of severe DMD that experiences a large spike in transforming growth factor-beta (TGFβ) activity after muscle injury shows that high TGFβ activity suppresses muscle regeneration and promotes fibroadipogenic progenitors (FAPs). This leads to replacement of the damaged muscle fibers by calcified and connective tissue, compromising muscle structure and function. While blocking FAP buildup provides a partial solution, a Children’s National Hospital study team identifies correcting the muscle micro-environment caused by high TGFβ as a ripe therapeutic target.

The team’s study was published online March 26, 2020, in JCI Insight.

DMD is a chronic muscle disease that affects 1 in 6,200 young men in the prime of their lives. The disorder, caused by genetic mutations leading to the inability to produce dystrophin protein, leads to ongoing muscle damage, chronic inflammation and poor regeneration of lost muscle tissue. The patients experience progressive muscle wasting, lose the ability to walk by the time they’re teenagers and die prematurely due to cardiorespiratory failure.

The Children’s National team finds for the first time that as early as preadolescence (3 to 4 weeks of age), their experimental model of severe DMD disease showed clear signs of the type of spontaneous muscle damage, regenerative failure and muscle fiber loss seen in preadolescent boys who have DMD.

“In boys, the challenge due to muscle loss exists from early in their lives, but had not been mimicked previously in experimental models,” says Jyoti K. Jaiswal, MSc, Ph.D., principal investigator in the Center for Genetic Medicine Research at Children’s National, and the study’s co-senior author. “TGFβ is widely associated with muscle fibrosis in DMD, when, in fact, our work shows its role in this disease process is far more significant.”

Research teams have searched for experimental models that replicate the sudden onset of symptoms in boys who have DMD as well as its complex progression.

“Our work not only offers insight into the delicate balance needed for regeneration of skeletal muscle, but it also provides quantitative information about muscle stem cell activity when this balanced is disturbed,” says Terence A. Partridge, Ph.D., principal investigator in the Center for Genetic Medicine Research at Children’s National, and the study’s co-senior author.

This schematic depicts the fate of injured myofibers in healthy or dystrophic muscle

This schematic depicts the fate of injured myofibers in healthy or dystrophic muscle (WT or mdx experimental models) that maintain low TGFβ level, compared with D2-mdx experimental models that experience a large increase in TGFβ level. As the legend shows, various cells are involved in this regenerative response.

“The D2-mdx experimental model is a relevant one to use to investigate the interplay between inflammation and muscle degeneration that is seen in humans with DMD,” adds Davi A.G. Mázala, co-lead study author.  “This model faithfully recapitulates many features of the complex disease process seen in humans.”

Between 3 to 4 weeks of age in the experimental models of severe DMD disease, the level of active TGFβ spiked up to 10-fold compared with models with milder disease. Intramuscular injections of an off-the-shelf drug that inhibits TGFβ signaling tamped down the number of FAPs, improving the muscle environment by lowering TGFβ activity.

“This work lays the foundation for studies that could lead to future therapeutic strategies to improve patients’ outcomes and lessen disease severity,” says James S. Novak, Ph.D., principal investigator in Children’s Center for Genetic Medicine Research, and co-lead study author. “Ultimately, our goal is to improve the ability of patients to continue to maintain muscle mass and regenerate muscle.”

In addition to Mázala, Novak, Jaiswal and Partridge, Children’s National study co-authors include Marshall W. Hogarth; Marie Nearing; Prabhat Adusumalli; Christopher B. Tully; Nayab F. Habib; Heather Gordish-Dressman, M.D.; and Yi-Wen Chen, Ph.D.

Financial support for the research described in this post was provided by the National Institutes of Health under award Nos. T32AR056993, R01AR055686 and U54HD090257; Foundation to Eradicate Duchenne; Muscular Dystrophy Association under award Nos. MDA295203, MDA480160 and MDA 477331; Parent Project Muscular Dystrophy; and Duchenne Parent Project – Netherlands.

Vittorio Gallo

Special issue of “Neurochemical Research” honors Vittorio Gallo, Ph.D.

Vittorio Gallo

Investigators from around the world penned manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Vittorio Gallo, Ph.D., for his leadership in the field of neural development and regeneration.

At a pivotal moment early in his career, Vittorio Gallo, Ph.D., was accepted to work with Professor Giulio Levi at the Institute for Cell Biology in Rome, a position that leveraged courses Gallo had taken in neurobiology and neurochemistry, and allowed him to work in the top research institute in Italy directed by the Nobel laureate, Professor Rita Levi-Montalcini.

For four years as a student and later as Levi’s collaborator, Gallo focused on amino acid neurotransmitters in the brain and mechanisms of glutamate and GABA release from nerve terminals. Those early years cemented a research focus on glutamate neurotransmission that would lead to a number of pivotal publications and research collaborations that have spanned decades.

Now, investigators from around the world who have worked most closely with Gallo penned tributes in the form of manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Gallo “for his contributions to our understanding of glutamatergic and GABAergic transmission during brain development and to his leadership in the field of neural development and regeneration,” writes guest editor Arne Schousboe, of the University of Copenhagen in Denmark.

Dr. Gallo as a grad student

Vittorio Gallo, Ph.D. as a 21-year-old mustachioed graduate student.

“In spite of news headlines about competition in research and many of the negative things we hear about the research world, this shows that research is also able to create a community around us,” says Gallo, chief research officer at Children’s National Hospital and scientific director for the Children’s National Research Institute.

As just one example, he first met Schousboe 44 years ago when Gallo was a 21-year-old mustachioed graduate student.

“Research can really create a sense of community that we carry on from the time we are in training, nurture as we meet our colleagues at periodic conferences, and continue up to the present. Creating community is bi-directional: influencing people and being influenced by people. People were willing to contribute these 17 articles because they value me,” Gallo says. “This is a lot of work for the editor and the people who prepared papers for this special issue.”

In addition to Gallo publishing more than 140 peer-reviewed papers, 30 review articles and book chapters, Schousboe notes a number of Gallo’s accomplishments, including:

  • He helped to develop the cerebellar granule cell cultures as a model system to study how electrical activity and voltage-dependent calcium channels modulate granule neuron development and glutamate release.
  • He developed a biochemical/neuropharmacological assay to monitor the effects of GABA receptor modulators on the activity of GABA chloride channels in living neurons.
  • He and Maria Usowicz used patch-clamp recording and single channel analysis to demonstrate for the first time that astrocytes express glutamate-activated channels that display functional properties similar to neuronal counterparts.
  • He characterized one of the spliced isoforms of the AMPA receptor subunit gene Gria4 and demonstrated that this isoform was highly expressed in the cerebellum.
  • He and his Children’s National colleagues demonstrated that glutamate and GABA regulate oligodendrocyte progenitor cell proliferation and differentiation.
Purkinje cells

Purkinje cells are large neurons located in the cerebellum that are elaborately branched like interlocking tree limbs and represent the only source of output for the entire cerebellar cortex.

Even the image selected to grace the special issue’s cover continues the theme of continuity and leaving behind a legacy. That image of Purkinje cells was created by a young scientist who works in Gallo’s lab, Aaron Sathyanesan, Ph.D. Gallo began his career working on the cerebellum – a region of the brain important for motor control – and now studies with a team of scientists and clinician-scientists Purkinje cells’ role in locomotor adaptive behavior and how that is disrupted after neonatal brain injury.

“These cells are the main players in cerebellar circuitry,” Gallo says. “It’s a meaningful image because goes back to my roots as a graduate student and is also an image that someone produced in my lab early in his career. It’s very meaningful to me that Aaron agreed to provide this image for the cover of the special issue.”

bacterial extracellular vesicle

Once overlooked cellular messengers could combat antibiotic resistance

bacterial extracellular vesicle

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors. The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors, a critical step to better understanding the way gut bacteria communicate with the rest of the body via the bloodstream.

For decades, researchers considered circulating bacterial extracellular vesicles as bothersome flotsam to be jettisoned as they sought to tease out how bacteria that reside in the gut whisper messages to the brain.

There is a growing appreciation that extracellular vesicles – particles that cells naturally release – actually facilitate intracellular communication.

“In the past, we thought they were garbage or noise,” says Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute. “It turns out what we throw away is not trash.”

Kylie Krohmaly, a graduate student in Dr. Freishtat’s laboratory, has isolated from blood, extracellular vesicles from Escherichia coli and Haemophilus influenzae, common bacteria that colonize the gut, and validated the results via electron microscopy.

“The images are interesting because they look like they have a bit of a halo around them or penumbra,” Krohmaly says.

The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

“It’s the first time anyone has pulled them out of blood. Detecting them is one thing. Pulling them out is a critical step to understanding the language the microbiome uses as it speaks with its human host,” Dr. Freishtat adds.

Krohmaly’s technique is so promising that the Children’s National team filed a provisional patent.

The Children’s research team has devised a way to gum up the cellular works so that bacteria no longer become antibiotic resistant. Targeted bacteria retain the ability to make antibiotic-resistance RNA, but like a relay runner dropping rather than passing a baton, the bacteria are thwarted from advancing beyond that step. And, because that gene is turned off, the bacteria are newly sensitive to antibiotics – instead of resistant bacteria multiplying like clockwork these bacteria get killed.

“Our plan is to hijack this process in order to turn off antibiotic-resistance genes in bacteria,” Dr. Freishtat says. “Ultimately, if a child who has an ear infection can no longer take amoxicillin, the antibiotic would be given in tandem with the bacteria-derived booster to turn off bacteria’s ability to become antibiotic resistant. This one-two punch could become a novel way of addressing the antibiotic resistance process.”

ISEV2020 Annual Meeting presentation
(Timing may be subject to change due to COVID-19 safety precautions)
Oral with poster session 3: Neurological & ID
Saturday May 23, 2020, 5 p.m. to 5:05 p.m. (ET)
“Detection of bacterial extracellular vesicles in blood from healthy volunteers”
Kylie Krohmaly, lead author; Claire Hoptay, co-author; Andrea Hahn, M.D., MS, infectious disease specialist and co-author; Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute and senior author.

preterm baby

Validating a better way to stratify BPD risk in vulnerable newborns

preterm baby

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia severity.

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia (BPD) severity, a research team led by Children’s National Hospital writes in Scientific Reports. What’s more, the researchers defined a brand-new category (level IV) for newborns who receive supplemental oxygen more than 120 days as a reliable way to predict which infants are at the highest risk of returning to the hospital due to respiratory distress after discharge.

About 1 in 10 U.S. infants is born preterm, before 37 weeks gestation, according to the Centers for Disease Control and Prevention. That includes extremely preterm infants who weigh about 1 lb. at birth. These very low birthweight newborns have paper thin skin, frail hearts and lungs that are not yet mature enough to deliver oxygen throughout the body as needed. Thanks to advances in neocritical care, an increasing number of them survive prematurity, and many develop BPD, a chronic lung disease characterized by abnormal development of the lungs and pulmonary vasculature.

“About half of the babies born prematurely will come back to the hospital within the first year of life with a respiratory infection. The key is identifying them and, potentially, preventing complications in this high-risk population,” says Gustavo Nino, M.D., a Children’s National pulmonologist and the study’s lead author.

For decades, the most common way to stratify BPD risk in these vulnerable newborns has been to see if they require supplemental oxygen at 36 weeks corrected gestational age.

“The problem with this classification is it doesn’t take into account the very premature babies who are on oxygen for much longer than other babies. So, we asked the question: Can we continue risk stratification beyond 36 weeks in order to identify a subset of babies who are at much higher risk of complications,” Dr. Nino says.

The longitudinal cohort study enrolled 188 infants born extremely preterm who were admitted to the neonatal intensive care unit (NICU) at Children’s National and tracked their data for at least 12 months after discharge. The team used a multidimensional approach that tracked duration of supplemental oxygen during the newborns’ NICU stay as well as scoring lung imaging as an independent marker of BPD severity. To validate the findings, these U.S.-born newborns were matched with 130 infants who were born preterm and hospitalized at two NICUs located in Bogotá, Colombia.

“Babies who are born very preterm and require oxygen beyond 120 days should have expanded ventilation of the lungs and cardiovascular pulmonary system before going home,” he notes. “We need to identify these newborns and optimize their management before they are discharged.”

And, the babies with level IV BPD risk need a different type of evaluation because the complications they experience – including pulmonary hypertension – place them at the highest risk of developing sleep apnea and severe respiratory infection, especially during the first year of life.

“The earlier we identify them, the better their outcome is likely to be,” Dr. Nino says. “We really need to change the risk stratification so we don’t call them all ‘severe’ and treat them the same when there is a subset of newborns who clearly are at a much higher risk for experiencing respiratory complications after hospital discharge.”

In addition to Dr. Nino, Children’s National study co-authors include Awais Mansoor, Ph.D., staff scientist at the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI); Geovanny F. Perez, M.D., pediatric pulmonologist; Maria Arroyo, M.D., pulmonologist; Xilei Xu Chen, M.D., postdoctoral fellow; Jered Weinstock, pediatric pulmonary fellow; Kyle Salka, MS, research technician; Mariam Said, M.D., neonatologist, and Marius George Linguraru, DPhil, MA, MSc, SZI principal investigator and senior author. Additional co-authors include Ranniery Acuña-Cordero, Universidad Militar Nueva Granada, Bogotá, Colombia; and Monica P. Sossa-Briceño and Carlos E. Rodríguez-Martínez, both of Universidad Nacional de Colombia.

Funding for research described in this post was provided by the National Institutes of Health (NIH) under award Nos. HL145669, AI130502 and HL141237. In addition, the NIH has awarded Dr. Nino an RO1 grant to continue this research.

Vote for STAT Madness

It’s a three-peat! Children’s National again competes in STAT Madness

Vote for STAT Madness

Children’s National Hospital collects patients’ blood, extracts T-cells and replicates them in the presence of specific proteins found on cancer cells which, in essence, teaches the T-cells to target specific tumor markers. Training the T-cells, growing them to sufficient quantities and ensuring they are safe for administration takes weeks. But when patients return to the outpatient clinic, their T-cell infusion lasts just a few minutes.

For the third consecutive year, Children’s National was selected to compete in STAT Madness, an annual bracket-style competition that chooses the year’s most impactful biomedical innovation by popular vote. Children’s entry, “Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes,” uses the body’s own immune system to attack and eliminate cancer cells in pediatric and adult patients with solid tumor malignancies.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

An estimated 11,000 new cases of pediatric cancer were diagnosed in children 14 and younger in the U.S. in 2019. And, when it comes to disease, cancer remains the leading cause of death among children, according to the National Institutes of Health. An enterprising research team led by Children’s National faculty leveraged T-cells – essential players in the body’s immune system – to treat pediatric and adult patients with relapsed or refractory solid tumors who had exhausted all other therapeutic options.

“We’re using the patient’s own immune system to fight their cancer, rather than more traditional chemotherapy drugs,” says Catherine M. Bollard, M.D., director of the Center for Cancer & Immunology Research at Children’s National and co-senior author of the study. “It’s more targeted and less toxic to the patient. These T-cells home in on any cancer cells that might be in the body, allowing healthy cells to continue to grow,” Dr. Bollard adds.

That means patients treated in the Phase I, first-in-human trial didn’t lose their hair and weren’t hospitalized for the treatment. After a quick clinical visit for their treatment, they returned to normal activities, like school, with good energy levels.

“With our specially trained T-cell therapy, many patients who previously had rapidly progressing disease experienced prolonged disease stabilization,” says Holly J. Meany, M.D., a Children’s National oncologist and the study’s co-senior author. “Patients treated at the highest dose level showed the best clinical outcomes, with a six-month, progression-free survival of 73% after tumor-associated antigen cytotoxic T-cell (TAA-T) infusion, compared with 38% with their immediate prior therapy.”

The multi-institutional team published their findings from the study online July 29, 2019, in the Journal of Clinical Oncology.

“Our research team and our parents are delighted that some patients treated in our study continue to do well following T-cell therapy without additional treatment. In some cases, two years after treatment, patients do not appear to have active disease and are maintaining an excellent quality of life,” says Amy B. Hont, M.D., the study’s lead author. “One of these was a patient whose parents were told his only other option was palliative care. Our innovation gives these families new hope,” Dr. Hont adds.

The 2020 STAT Madness #Core64 bracket opened March 2, and the champion will be announced April 6.

In addition to Drs. Hont, Meany and Bollard, Children’s National co-authors include C. Russell Cruz, M.D., Ph.D., Robert Ulrey, MS, Barbara O’Brien, BS, Maja Stanojevic, M.D., Anushree Datar, MS, Shuroug Albihani, MS, Devin Saunders, BA, Ryo Hanajiri, M.D., Ph.D., Karuna Panchapakesan, MS, Payal Banerjee, MS, Maria Fernanda Fortiz, BS, Fahmida Hoq, MBBS, MS, Haili Lang, M.D., Yunfei Wang, DrPH, Patrick J. Hanley, Ph.D., and Jeffrey S. Dome, M.D., Ph.D.; and Sam Darko, MS, National Institute of Allergy and Infectious Diseases.

Financial support for the research described in this post was provided by the Children’s National Hospital Heroes Gala, Alex’s Army Foundation, the Children’s National Board of Visitors and Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, the Children’s National Research Institute Bioinformatics Unit, the Clinical and Translational Science Institute and the National Institutes of Health under award No. UL1-TR001876.

kidney ultrasound

Using computers to enhance hydronephrosis diagnosis

kidney ultrasound

Researchers at Children’s National Hospital are using quantitative imaging and machine intelligence to enhance care for children with a common kidney disease, and their initial results are very promising. Their technique provides an accurate way to predict earlier which children with hydronephrosis will need surgical intervention, simplifying and enhancing their care.

We live in a time of great uncertainty yet great promise, particularly when it comes to harnessing technology to improve lives. Researchers at Children’s National Hospital are using quantitative imaging and machine intelligence to enhance care for children with a common kidney disease, and their initial results are very promising. Their technique provides an accurate way to predict earlier which children with hydronephrosis will need surgical intervention, simplifying and enhancing their care.

Hydronephrosis means “water in the kidney” and is a condition in which a kidney doesn’t empty normally. One of the most frequently detected abnormalities on prenatal ultrasound, hydronephrosis affects up to 4.5% of all pregnancies and is often discovered prenatally or just after birth.

Although hydronephrosis in children sometimes resolves by itself, identifying which kidneys are obstructed and more likely to need intervention isn’t particularly easy. But it is critical. “Children with severe hydronephrosis over long periods of time can start losing kidney function to the point of losing a kidney,” says Marius George Linguraru, DPhil, MA, MSc, principal investigator of the project; director of Precision Medical Imaging Group at the Sheikh Zayed Institute for Pediatric Surgical Innovation; and professor of radiology, pediatrics and biomedical engineering at George Washington University.

Children with hydronephrosis face three levels of examination and intervention: ultrasound, nuclear imaging testing called diuresis renogram and surgery for the critical cases. “What we want to do with this project is stratify kids as early as possible,” Dr. Linguraru says. “The earlier we can predict, the better we can plan the clinical care for these kids.”

Ultrasound is used to see whether there is a blockage and try to determine hydronephrosis severity. “Ultrasound is non-invasive, non-radiating, and does not expose the child to any risk prenatally or postnatally,” Dr. Linguraru says. Ultrasound evaluations require a trained radiologist, but there’s a lot of variability. Radiologists have a grading system based on the ultrasound appearance of the kidney to determine whether the hydronephrosis is mild, moderate or severe, but studies show this isn’t predictive of longer term outcomes.

Children whose ultrasounds show concern will be referred to diuresis renogram. Costly, complex, invasive and irradiating, it tests how well the kidney empties. Although appropriate for good clinical indications, doctors try to minimize its use. “Management of hydronephrosis is complex,” Dr. Linguraru says. “We want to use ultrasound as much as possible and much less diuresis renogram.”

For those patients whose kidney is obstructed and eventually need surgical intervention, the sooner that decision can be made the better. “The more you wait for a kidney that is severely obstructed, the more function may be lost. If intervention is required, it’s preferable to do it early,” Dr. Linguraru says. Of course for the child whose hydronephrosis will likely resolve itself, intervention is not the best option.

Marius George Linguraru

“With our technique we are measuring physiological and anatomical changes in the ultrasound image of the kidney,” says Marius George Linguraru, DPhil, MA, MSc. “The human eye may find it difficult to put all this together, but the machine can do it. We use quantitative imaging to do deep phenotyping of the kidney and machine learning to interpret the data.”

Dr. Linguraru and the multidisciplinary team at Children’s National Hospital, including radiology and urology clinicians, are putting the power of computers to work interpreting subtleties in the ultrasound data that humans just can’t see. In their pilot study they found that 60% of the nuclear imaging tests could have been safely avoided without missing any of the critical cases of hydronephrosis. “With our technique we are measuring physiological and anatomical changes in the ultrasound image of the kidney,” Dr. Linguraru says. “The human eye may find it difficult to put all this together, but the machine can do it. We use quantitative imaging to do deep phenotyping of the kidney and machine learning to interpret the data.”

Results of the initial study indicate that kids who have a mild condition can be safely discharged earlier and the model can predict all those kids with obstructions and accelerate their diagnosis by sending them earlier to get further investigation. Dr. Linguraru says. “There are only benefits: some kids will get earlier diagnosis, some earlier discharges.”

The team also has a way to improve the interpretation of diuresis renograms. “We analyze the dynamics of the kidney’s drainage curve in quantifiable way. Using machine learning to interpret those results, we showed we can potentially discharge some kids earlier and accelerate intervention for the most severe cases instead of waiting and repeating the invasive tests,” he says. The framework has 93% accuracy, including 91% sensitivity and 96% specificity, to predict surgical cases, a significant improvement over clinical metrics’ accuracy.

The next step is a study connecting all the protocols. “Right now we have a study on ultrasound, a study on nuclear imaging, but we need to connect them so a child with hydronephrosis immediately benefits,” says Dr. Linguraru. Future work will focus on streamlining and accelerating diagnosis and intervention for kids who need it, both in prospective studies and hopefully clinically as well.

Hydronephrosis is an area in which machine learning can be applied to pediatric health in meaningful ways because of the sheer volume of cases.

“Machine learning algorithms work best when they are trained well on a lot of data,” Dr. Linguraru says. “Often in pediatric conditions, data are sparse because conditions are rare. Hydronephrosis is one of those areas that can really benefit from this new technological development because there is a big volume of patients. We are collecting more data, and we’re becoming smarter with these kinds of algorithms.”

Learn more about the Precision Medical Imaging Laboratory and its work to enhance clinical information in medical images to improve children’s health.

2019 pitch competition

Pediatric medical device pitch competition deadline extended

2019 pitch competition

Pediatric innovators pitch for up to $250,000 in FDA-funded grant awards.

The National Capital Consortium for Pediatric Device Innovation (NCC-PDI) announced today that the application deadline for its annual “Make Your Medical Device Pitch for Kids!” competition is extended one week to Feb. 22 at midnight EST. Innovators and startup companies with devices in the pediatric cardiovascular, orthopedic and spine, or NICU sectors are invited to apply for a share of up to $250,000 in FDA-funded awards and access to a newly created NCC-PDI pediatric device accelerator program led by MedTech Innovator. Submissions are being accepted now.

Up to 30 companies will be selected for the first round of competition scheduled for March 23, 2020 at the University of Maryland, College Park. Up to 10 finalists chosen from that event will compete for up to $250,000 in grant awards in Toronto, Canada on October 4. Finalists also receive a spot in the MedTech Innovator 2020 Accelerator – Pediatric Track, which provides a customized curriculum and in-depth mentorship.  Finalists will be announced in May, 2020.

This is the ninth competition in seven years hosted by NCC-PDI, one of five FDA Pediatric Device Consortia Grant Program members supporting the development and commercialization of pediatric medical devices. NCC-PDI is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital and the A. James Clark School of Engineering at the University of Maryland. Additional consortium members include accelerators Medtech Innovator, BioHealth Innovation and design firm partner Archimedic.

“This year’s competition focuses on three medical device areas of critical need for pediatric patients, so we want to give innovators as much time as possible to prepare their submissions,” said Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National Hospital and principal investigator of NCC-PDI . “Our goal is to support devices that will improve care for children by helping them advance on the pathway to commercialization. We have seen how this competition can provide significant momentum for pediatric innovations, so we want to encourage as much participation as possible.”

To date, NCC-PDI has mentored over 100 medical device sponsors to help advance their pediatric innovations, notes Eskandanian, with six devices having received either their FDA market clearance or CE marking. Along with the positive exposure of presenting at this competition, she notes that the success of NCC-PDI’s portfolio companies is attributed to funding, mentorship, support from partners and facilitated interactions between device innovators and potential investors.

Eskandanian notes that enhancing access to resources for pediatric innovators is one aim of the Children’s National Research & Innovation Campus, a first-of-its-kind campus focused on pediatric healthcare innovation, currently under development on the former Walter Reed Army Medical Center campus in Washington, D.C. With its proximity to federal research institutions and agencies, universities, academic research centers, as well as on site accelerator Johnson & Johnson Innovation – JLABS, the campus will create a rich ecosystem of public and private partners which, like the NCC-PDI network, will help bolster pediatric innovation and commercialization. Opening is scheduled for December 2020.

Pediatric device competition

Premier annual pediatric medical device competition now accepting submissions

Pediatric device competition

Pediatric innovators pitch for grant awards and participation in a special accelerator program.

The official call for submissions is underway for the premiere annual pediatric medical device competition, sponsored by National Capital Consortium for Pediatric Device Innovation (NCC-PDI). The competition is led by Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital, the A. James Clark School of Engineering at the University of Maryland and non-profit accelerator MedTech Innovator. The three organizations are all an integral part of the FDA-funded NCC-PDI, which aims to facilitate the development, production and distribution of pediatric medical devices. Additional NCC-PDI members include accelerator BioHealth Innovation and design firm Archimedic.

The competition focuses on pediatric devices in three areas of critical need: cardiovascular, orthopedic and spine, and neonatal intensive care (NICU) and is now accepting applications. Contestants will pitch for a share of up to $250K in grant awards and the opportunity to participate in the MedTech Innovator 2020 Accelerator – Pediatric Track.

The first stage of competition will be held on March 23 at the University of Maryland and will include up to 30 companies selected from all submissions received. Up to 10 finalists selected from that event will move on to the “Make Your Medical Device Pitch for Kids!” finals on October 4, 2020 in Toronto, Canada. Finalists from the March qualifying round will be notified in May, 2020.

“While there is a great need for pediatric devices in many specialty areas, the development and commercialization process is very challenging because of the small market size and dynamic characteristics of the patient population,” says Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National Hospital and principal investigator of NCC-PDI. “To provide pediatric innovators with greater support in meeting these unique challenges, we must go beyond grant funding, which is why we are collaborating with MedTech Innovator to offer an accelerator program with a pediatric track.”

To date, NCC-PDI has mentored over 100 medical device sponsors to help advance their pediatric innovations, notes Eskandanian, with six devices having received either their FDA market clearance or CE marking. She says the success of NCC-PDI’s portfolio companies is attributed to funding, mentorship, support from partners, facilitated interactions between device innovators and potential investors, and being discovered during their presentations at the signature “Make Your Medical Device Pitch for Kids!” competitions.

While advancements have been made in some pediatric specialties, there is still a critical need for novel devices in cardiovascular, orthopedic and spine, and NICU areas. On average over the past decade, only 24 percent of life-saving medical devices approved by FDA – those that go through PMA and HDE regulatory pathways – have an indication for pediatric use. Of those, most are designated for children age 12 or older. “Devices designed specifically for the younger pediatric population are vitally needed and, at this early stage of the intervention, can significantly improve developmental outcomes for a child,” Eskandanian said.

For more information and to apply for the upcoming NCC-PDI pitch competition, visit https://medtechinnovator.org/pediatricapply/.

Enhancing access to resources for pediatric innovators is also one of the aims of the Children’s National Research and Innovation Campus, a first-of-its-kind focused on pediatric healthcare innovation, currently under development on the former Walter Reed Army Medical Center campus in Washington, D.C. and opening in December, 2020. With its proximity to federal research institutions and agencies, universities, academic research centers, as well as on site accelerator Johnson and Johnson Innovation – JLABS, the campus will create a rich ecosystem of public and private partners which, like the NCC-PDI network, will help bolster pediatric innovation and commercialization.

NOTE: The deadline for submissions has been extended to February 22 at midnight EST.

Gilbert Vezina

Gilbert Vezina, M.D., recognized with American Society of Pediatric Neuroradiology Gold Medal Award

Gilbert Vezina

Gilbert Vezina, M.D., Director of Neuroradiology in the Division of Diagnostic Imaging and Radiology at Children’s National Hospital, is being recognized at the 2020 American Society of Pediatric Neuroradiology 2nd Annual Meeting with the society’s most distinguished honor, the Gold Medal Award.

The American Society of Pediatric Neuroradiology (ASPNR) Gold Medal is awarded for both professional and personal excellence, honoring individuals who are superb pediatric neuroradiologists, scientists, and/or physicians, and mentors and who also are truly outstanding people. Recipients have consistently extended themselves beyond self-interest to make contributions to the field of pediatric neuroradiology and as such, have elevated the subspecialty. This medal recognizes the exceptional service and achievements of these individuals.

Dr. Vezina completed his undergraduate degree at the Collège Jean-de-Brébeuf, Montréal, Canada and medical school at McGill Medical School, Montréal, Canada. He completed a mixed internship at Montreal General Hospital, Montreal, Canada; residency in Diagnostic Radiology, Massachusetts General Hospital, Boston, Massachusetts followed by a fellowship in Neuroradiology, Boston, Massachusetts.

He began his career at Children’s National Hospital in 1990. He is currently the Director of the Neuroradiology Program at Children’s National Hospital and Professor of Radiology and Pediatrics at George Washington University School of Medicine and Health Sciences, Washington DC. He created the Neuroradiology Fellowship Program in 1993 where he impacted medical students, residents and fellows from around the world. He served as president of ASPNR from 2001-2002 and past President from 2002-2005. He also served as the Interim Chief, Diagnostic Imaging and Radiology at Children’s National for a brief period in 2017.

Congratulations, Dr. Vezina!

Catherine Limperopoulos

Stressful pregnancies can leave fingerprint on fetal brain

Catherine Limperopoulos

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author.

When a diagnosis of fetal congenital heart disease causes pregnant moms to test positive for stress, anxiety and depression, powerful imaging can detect impaired development in key fetal brain regions, according to Children’s National Hospital research published online Jan. 13, 2020, in JAMA Pediatrics.

While additional research is needed, the Children’s National study authors say their unprecedented findings underscore the need for universal screening for psychological distress as a routine part of prenatal care and taking other steps to support stressed-out pregnant women and safeguard their newborns’ developing brains.

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author. “Equally concerning is how prevalent psychological distress is among pregnant women generally. We report for the first time that this challenging prenatal environment impairs regions of the fetal brain that play a major role in learning, memory, coordination, and social and behavioral development, making it all the more important for us to identify these women early during pregnancy to intervene,” Limperopoulos adds.

Congenital heart disease (CHD), structural problems with the heart, is the most common birth defect. Still, it remains unclear how exposure to maternal stress impacts brain development in fetuses with CHD.

The multidisciplinary study team enrolled 48 women whose unborn fetuses had been diagnosed with CHD and 92 healthy women with uncomplicated pregnancies. Using validated screening tools, they found:

  • 65% of pregnant women expecting a baby with CHD tested positive for stress
  • 27% of women with uncomplicated pregnancies tested positive for stress
  • 44% of pregnant women expecting a baby with CHD tested positive for anxiety
  • 26% of women with uncomplicated pregnancies tested positive for anxiety
  • 29% of pregnant women expecting a baby with CHD tested positive for depression and
  • 9% women with uncomplicated pregnancies tested positive for depression

All told, they performed 223 fetal magnetic resonance imaging sessions for these 140 fetuses between 21 and 40 weeks of gestation. They measured brain volume in cubic centimeters for the total brain as well as volumetric measurements for key regions such as the cerebrum, cerebellum, brainstem, and left and right hippocampus.

Maternal stress and anxiety in the second trimester were associated with smaller left hippocampi and smaller cerebellums only in pregnancies affected by fetal CHD. What’s more, specific regions — the hippocampus head and body and the left cerebellar lobe – were more susceptible to stunted growth. The hippocampus is key to memory and learning, while the cerebellum controls motor coordination and plays a role in social and behavioral development.

The hippocampus is a brain structure that is known to be very sensitive to stress. The timing of the CHD diagnosis may have occurred at a particularly vulnerable time for the developing fetal cerebellum, which grows faster than any other brain structure in the second half of gestation, particularly in the third trimester.

“None of these women had been screened for prenatal depression or anxiety. None of them were taking medications. And none of them had received mental health interventions. In the group of women contending with fetal CHD, 81% had attended college and 75% had professional educations, so this does not appear to be an issue of insufficient resources,” Limperopoulos adds. “It’s critical that we routinely to do these screenings and provide pregnant women with access to interventions to lower their stress levels. Working with our community partners, Children’s National is doing just that to help reduce toxic prenatal stress for both the health of the mother and for the future newborns. We hope this becomes standard practice elsewhere.”

Adds Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author: “Our next goal is exploring effective prenatal cognitive behavioral interventions to reduce psychological distress felt by pregnant women and improve neurodevelopment in babies with CHD.”

In addition to Limperopoulos and Wu , Children’s National study co-authors include Kushal Kapse, MS, staff engineer; Marni Jacobs, Ph.D., biostatistician; Nickie Niforatos-Andescavage, M.D., neonatologist; Mary T. Donofrio, M.D., director, Fetal Heart Program; Anita Krishnan, M.D., associate director, echocardiography; Gilbert Vezina, M.D., director, Neuroradiology Program; David Wessel, M.D., Executive Vice President and Chief Medical Officer; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Jessica Lynn Quistorff, MPH, Catherine Lopez, MS, and Kathryn Lee Bannantine, BSN, assisted with subject recruitment and study coordination.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. R01 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

Drs. Tarini, Steinhorn, and Beers

Children’s National Hospital: Starting the new year with strong leadership

Drs. Tarini, Steinhorn, and Beers

Drs. Tarini, Steinhorn and Beers are also in leadership roles within professional societies, elected by their peers, further highlighting the strength of the leadership at Children’s National and professional respect within the health care community.

Three Children’s National Hospital executives are also in leadership roles within professional societies, elected by their peers, further highlighting the strength of the leadership at Children’s National and professional respect within the health care community.

Lee Savio Beers, M.D., FAAP, medical director of Community Health and Advocacy at the Child Health Advocacy Institute (CHAI) at Children’s National, was elected by her peers to become president-elect of the American Academy of Pediatrics (AAP) beginning Jan. 1, 2020. Dr. Beers will then serve as AAP president in 2021 for a one-year term.

“I am humbled and honored to have the support of my peers in taking on this newest leadership role,” says Dr. Beers. “AAP has been a part of my life since I first became a pediatrician, and my many leadership roles in the DC chapter and national AAP have given me a glimpse of the collective good we pediatricians can accomplish by working together toward common strategic goals.”

Dr. Beers is looking forward to continuing her work bringing together the diverse voices of pediatricians, children and families as well as other organizations to support improving the health of all children.

Robin Steinhorn, M.D., senior vice president of the Center for Hospital-Based Specialties at Children’s National was elected by her peers to become Vice President and President-elect of the American Pediatric Society (APS) in May 2018 and she is currently serving her role as the Society’s president, which began in May 2019.

“This is a tremendous honor. I look forward to leveraging the collective leadership and research accomplishments by our members to improve the health of infants and children throughout the U.S.,” said Dr. Steinhorn.

Dr. Steinhorn is particularly passionate about mentoring faculty and supporting the growth and career development of young neonatologists and scientists, with several having developed their own research laboratories and assumed division and department leadership positions. She was selected as a ‘Top Doctor’ by Northern Virginia Magazine in 2019.

Beth A. Tarini, M.D., MS, associate director, Center for Translational Research at The Children’s Research Institute, became vice president of the Society for Pediatric Research (SPR) in May 2019. Dr. Tarini will transition to President-Elect in May 2020 and become President in May 2021.

Dr. Tarini’s personal mission during this tenure will be to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini.

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Joseph Letzelter

Offering more options for children with hand and upper extremity ailments

Joseph Letzelter

The Children’s National Hand and Upper Extremities Program is one of few dedicated pediatric programs in the country, and it just added another hand surgeon to the team of extensively trained and experienced specialists.

Joseph Letzelter III, M.D., joined Children’s National Hospital and Pediatric Specialists of Virginia in September 2019 following comprehensive medical training in orthopaedic surgery with a focus on pediatric hand and upper extremity surgery. Dr. Letzelter received his undergraduate and medical degrees from Georgetown University, and also completed his internship and orthopaedic surgery residency there. He then completed a fellowship in hand and upper extremity surgery at New York University before continuing his studies with Dr. Michael Boland at the prestigious Hand Institute of New Zealand in Auckland. To round out his fellowship training, Dr. Letzelter focused purely on pediatric hand and upper extremity surgery at Shriner’s Hospital in Sacramento.

With the addition of Dr. Letzelter, the combined Hand and Upper Extremities Program expands its capacity to treat children with pediatric hand disorders. The joint orthopaedic surgery and plastic surgery program, led by Emily Hattwick, M.D., and Gary Rogers, M.D., uses pediatric-specific surgical methods to treat children without affecting their growth. Partnering with the world-class researchers at the Sheikh Zayed Institute for Surgical Innovation at Children’s National, the team is part of new discoveries that change the way we care for rare conditions. Learn more about the Hand and Upper Extremities Program here.

brain network illustration

$2.5M to protect the brain from metabolic insult

brain network illustration

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, which makes this organ particularly vulnerable to changes in metabolism.

More than 30 million Americans have diabetes, with the vast majority having Type 2 disease. Characterized by insulin resistance and persistently high blood sugar levels, poorly controlled Type 2 diabetes has a host of well-recognized complications: compared with the general population, a greatly increased risk of kidney disease, vision loss, heart attacks and strokes and lower limb amputations.

But more recently, says Nathan A. Smith, MS, Ph.D., a principal investigator in Children’s National Research Institute’s Center for Neuroscience Research, another consequence has become increasingly apparent. With increasing insulin resistance comes cognitive damage, a factor that contributes significantly to dementia diagnoses as patients age.

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, Smith explains – which makes this organ particularly vulnerable to changes in metabolism. Type 2 diabetes and even prediabetic changes in glucose metabolism inflict damage upon this organ in mechanisms with dangerous synergy, he adds. Insulin resistance itself stresses brain cells, slowly depriving them of fuel. As blood sugar rises, it also increases inflammation and blocks nitric oxide, which together narrow the brain’s blood vessels while also increasing blood viscosity.

When the brain’s neurons slowly starve, they become increasingly inefficient at doing their job, eventually succumbing to this deprivation. These hits don’t just affect individual cells, Smith adds. They also affect connectivity that spans across the brain, neural networks that are a major focus of his research.

While it’s well established that Type 2 diabetes significantly boosts the risk of cognitive decline, Smith says, it’s been unclear whether this process might be halted or even reversed. It’s this question that forms the basis of a collaborative Frontiers grant, $2.5 million from the National Science Foundation split between his laboratory; the lead institution, Stony Brook University; and Massachusetts General Hospital/Harvard Medical School.

Smith and colleagues at the three institutions are testing whether changing the brain’s fuel source from glucose to ketones – byproducts from fat metabolism – could potentially save neurons and neural networks over time. Ketones already have shown promise for decades in treating some types of epilepsy, a disease that sometimes stems from an imbalance in neuronal excitation and inhibition. When some patients start on a ketogenic diet – an extreme version of a popular fat-based diet – many can significantly decrease or even stop their seizures, bringing their misfiring brain cells back to health.

Principal Investigator Smith and his laboratory at the Children’s National Research Institute are using experimental models to test whether ketones could protect the brain against the ravages of insulin resistance. They’re looking specifically at interneurons, the inhibitory cells of the brain and the most energy demanding. The team is using a technique known as patch clamping to determine how either insulin resistance or insulin resistance in the presence of ketones affect these cells’ ability to fire.

They’re also looking at how calcium ions migrate in and out of the cells’ membranes, a necessary prerequisite for neurons’ electrical activity. Finally, they’re evaluating whether these potential changes to the cells’ electrophysiological properties in turn change how different parts of the brain communicate with each other, potentially restructuring the networks that are vital to every action this organ performs.

Colleagues at Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital and Harvard Medical School, led by Principal Investigator Eva-Maria Ratai, Ph.D.,  will perform parallel work in human subjects. They will use imaging to determine how these two fuel types, glucose or ketones, affect how the brain uses energy and produces the communication molecules known as neurotransmitters. They’re also investigating how these factors might affect the stability of neural networks using techniques that investigate the performance of these networks both while study subjects are at rest and performing a task.

Finally, colleagues at the Laufer Center for Physical and Quantitative Biology at Stony Brook University, led by Principal Investigator Lilianne R. Mujica-Parodi, Ph.D., will use results generated at the other two institutions to construct computational models that can accurately predict how the brain will behave under metabolic stress: how it copes when deprived of fuel and whether it might be able to retain healthy function when its cells receive ketones instead of glucose.

Collectively, Smith says, these results could help retain brain function even under glucose restraints. (For this, the research team owes a special thanks to Mujica-Parodi, who assembled the group to answer this important question, thus underscoring the importance of team science, he adds.)

“By supplying an alternate fuel source, we may eventually be able to preserve the brain even in the face of insulin resistance,” Smith says.

Xanxin Pei

Dr. Yanxin Pei receives prestigious grant from V Foundation for Cancer Research

Xanxin Pei

When asked about this award, Dr. Pei noted “I am so deeply grateful to receive this support from the V Foundation for Cancer Research…I will use these resources to aid our goal of discovering new therapies to treat medulloblastoma.”

Yanxin Pei, Ph.D., assistant professor in the Brain Tumor Institute and the Children’s Research Institute at Children’s National Hospital in Washington, D.C., has recently been awarded a prestigious grant by the V Foundation for Cancer Research to support her groundbreaking work in finding new treatments for childhood medulloblastoma.

Dr. Pei, who joined Children’s National in 2014 after training in the Wechsler-Reya lab at the Sanford-Burnham Institute in La Jolla, CA, has focused her work on the biology of medulloblastoma, the most common malignant brain tumor in children, with a major emphasis on the study of the medulloblastoma subtype most resistant to treatment. Children with this form of medulloblastoma have less than a 30% chance of survival five years from their diagnosis.

Having already developed one of the most important mouse models of this disease, Dr. Pei’s present V Foundation for Cancer Research Award, which includes becoming a V scholar, will explore the role of metabolism in the development of metastasis in MYC-amplified medulloblastomas (the most virulent form of medulloblastoma).

The V Foundation for Cancer Research Award is one of a series of prestigious awards Dr. Pei has received over the past 18 months for her work, including an NIH-sponsored 5-year award (ROI) evaluating other aspects of medulloblastoma development and resistance to therapy, and grants from the Rally Foundation, the Meghan Rose Bradley Foundation and the Children’s Cancer Foundation.

When asked about this award, Dr. Pei noted “I am so deeply grateful to receive this support from the V Foundation for Cancer Research…I will use these resources to aid our goal of discovering new therapies to treat medulloblastoma.”

Her cutting-edge work is generating national and international attention and firmly places Dr. Pei as an international leader in medulloblastoma research.