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Anna Penn

Protecting the fetal brain from harm

Anna Penn

Ongoing placental dysfunction and allopregnanolone loss, not the increase that was expected due to stress, may alter cortical development in complicated pregnancies and put babies at risk, says Anna Penn, M.D., Ph.D.

Researchers long have known that allopregnanolone (ALLO), a derivative of the hormone progesterone, is produced in adults’ brains during times of acute stress and modulates how easily the brain’s neurons fire. ALLO also is produced in the placenta during fetal development, one of more than 200 different hormones that each uniquely contribute to fostering a smooth pregnancy and maintaining a fetus’ overall health. Although ALLO is thought to protect the developing brain in pregnancies complicated by conditions that might harm it, such as high blood pressure, how its levels evolve during pregnancy and in newborns shortly after birth has remained unknown.

Now, a new study presented during the Pediatric Academic Societies (PAS) 2018 annual meeting suggests that the placenta ramps up ALLO production over the second trimester, peaking just as fetuses approach full term.

To investigate this phenomenon, Anna Penn, M.D., Ph.D., a neonatologist/neuroscientist at Children’s National Health System, and colleagues created a designer experimental model to study how premature loss of ALLO alters orderly brain development. Knowing more about the interplay between ALLO and normal development of the cortex, the outer layer of the cerebrum, is a first step that could lead to strategies to rescue this vital brain region.

“The cortex is basically the brain’s command-and-control center for higher functions. In our experimental model, it develops from the middle of gestation through to the end of gestation. If ALLO levels are disrupted just as these cells are being born, neurons migrating to the cortex are altered and the developing neural network is compromised,” says Dr. Penn, senior author of the research presented at PAS 2018. “We’re concerned this same phenomenon occurs in human infants whose preterm birth disrupts their supply of this essential hormone.”

To better understand the human placental hormone pattern, the research team analyzed cord blood or serum samples collected within the first 36 hours of life for 61 preterm newborns born between 24 to 36 gestational weeks. They compared those preemie samples with samples drawn from 61 newborns carried to term who were matched by race, gender, size for gestational age, delivery method and maternal demographics.

They used liquid-chromatography-tandem mass spectrometry, a technique that can precisely analyze trace levels of compounds, to compare levels of 27 different steroids, including ALLO and its precursors as well as better-known adrenal gland hormones, such as cortisol and 17-Hydroxyprogesterone.

“Pregnancies complicated by hypertension tended to correlate with lower ALLO levels, though this finding did not reach statistical significance. This suggests that ongoing placental dysfunction and ALLO loss, not the increase that we expected to be caused by stress, may alter cortical development in these pregnancies and put babies at risk,” Dr. Penn adds. “In addition, having the largest neonatal sample set to date in which multiple steroid hormones have been measured can provide insight into the shifting hormone patterns that occur around 36 weeks gestation, just prior to term. Hopefully, restoring the normal hormonal milieu for preemies or other at-risk newborns will improve neurological outcomes in the future.”

In addition to Dr. Penn, study co-authors include Caitlin Drumm, MedStar Georgetown University Hospital; Sameer Desale, MedStar Health Research Institute; and Kathi Huddleston, Benjamin Solomon and John Niederhuber, Inova Translational Medicine Institute.

Baby in the NICU

Getting to the heart of cardiac output

Baby in the NICU

To keep infants in the neonatal intensive care unit (NICU) as healthy as possible, it’s important to keep close tabs on their vital signs. During their NICU stay, most babies have continuous monitoring of their blood pressure, respiratory rate and blood oxygen saturation. And although continuous monitoring of heart rate is also typically standard, other information about heart function – such as cardiac output, a measure of how well the heart is pumping blood – remains a challenge to obtain in these vulnerable babies.

Clinical markers like blood pressure, heart rate and urine output are available, but they are indirect measures of cardiac output, how much blood the heart pumps per minute. Less invasive techniques, such as Doppler ultrasound, can be imprecise. Respiratory mass spectrometry or catherization would provide more precision by directly calcuating cardiac output but carry risks or are not feasible for neonates.

Clinicians at Children’s National Health System hypothesized that COstatus monitors could offer a way to directly measure cardiac output among neonates. The COstatus monitor – a minimally invasive way to measure hemodynamics – captures cardiac output, total end diastolic volume, active circulation volume and central blood volume.

The research team tested the approach by leveraging ultrasound dilution: Injecting saline, which has an ultrasound velocity of 1533m/second, slows the ultrasound velocity of blood from its normal rate of 1580m/second and produces a dilution curve.

“It is feasible to directly measure neonatal cardiac output by ultrasound dilution via the COstatus monitor in the first two weeks of life with no adverse events,” says Khodayar Rais-Bahrami, M.D., a Children’s neonatologist and senior author for the research presented during the Pediatric Academic Societies 2018 annual meeting. “When we took consecutive measurements, we saw very little variance in the parameters.”

The COstatus monitor uses an extracorporeal loop that is connected to arterial and venous catheters. The 12 neonates included in the study already had umbilical venous catheters as well as either a peripheral arterial line or umbilical arterial catheter. The infants ranged in weight from 0.72 to 3.74 kg and were born at 24 to 41.3 gestational weeks.

The infants’ cardiac output was measured 54 times from 1 to 13 days of life. Up to two measurement sessions occurred daily for a maximum of four days. The mean cardiac output was 0.43 L/minute with a mean cardiac index of 197mL/kg/minute.

Future research will describe normal cardiac output ranges for neonates as well as how these measurements evolve during the first week of life.

In addition to Dr. Rais-Bahrami, study co-authors include Simranjeet S. Sran, M.D., and Mariam Said, M.D., a Children’s neonatologist.

Stricter state firearms laws can save children’s lives

In a new study presented at the Pediatric Academic Societies (PAS) 2018 annual meeting, Children’s researchers find that states with stricter firearm laws have lower rates of firearm-related deaths in children. The same cross-sectional analyses also found that states with laws that mandate universal background checks prior to firearm and ammunition purchases were associated with lower rates of firearm-related mortality in children, compared with states that lack these laws.

“Injuries due to firearms are the nation’s third-leading cause of pediatric death,” says Monika Goyal, M.D., M.S.C.E., director of research in the Division of Emergency Medicine and Trauma Services at Children’s National Health System and lead author of the research paper. “Firearm legislation at the state level varies significantly. Our findings underscore the need for further investigation of which types of state-level firearm legislation most strongly correlate with reduction in pediatric injuries and deaths.”

The research team analyzed data from the 2015 Web-based injury statistics query and reporting system maintained by the Centers for Disease Control and Prevention to measure the association between Brady Gun Law Scores – a scorecard that evaluates how strict firearms legislation and policies are in all 50 states – and state-based rates of firearm-related death among children aged 21 years and younger.

In 2015, 4,528 children died from firearm-related injuries. Eighty-seven percent were male; 44 percent were non-Latino black; their mean age was 18.

State-specific firearm-related mortality rates among children were as low as 0 per 100,000 to as high as 18 per 100,000. Median mortality rates were lower among the 12 states requiring universal background checks for firearm purchase at 3.8 per 100,000 children compared with 5.7 per 100,000 children in states that did not require background checks. Similarly, the five states with this requirement had a lower median mortality rate, 2.3 per 100,000 children, when compared with states that did not require background checks for ammunition purchase, 5.6 per 100,000 children.

“Newtown. Orlando. Las Vegas. Parkland. Those are among the mass shootings that have occurred across the nation in recent years. While these tragedies often are covered heavily by the news media, they represent a subset of overall pediatric injuries and deaths due to firearms. Pediatric firearm-related injuries are a critical public health issue across the U.S.,” Dr. Goyal adds.

“Pediatricians have helped to educate parents about other public health concerns, such as the danger posed by second-hand exposure to tobacco smoke or non-use of seat belts and car seats. In addition to presenting our most recent study results, members of our research group also hosted a workshop at PAS aimed at inspiring pediatric clinicians to similarly tackle this latest public health challenge and to advocate for firearm safety,” she says.

In addition to Dr. Goyal, study co-authors include Gia Badolato; Shilpa Patel, M.D.; Sabah Iqbal; Katie Donnelly, M.D.; and Kavita Parikh, M.D., M.S.H.S.

Cara Lichtenstein

Children’s Community Health Track receives prestigious APA Teaching Program Award

Cara Lichtenstein

“As a community-focused health system, one of our central missions is to train a new generation of residents to create successful community partnerships and integrate public health concepts into the everyday practice of medicine to improve the health of underserved communities,” says Cara Lichtenstein, M.D., MPH.

The Children’s National Community Health Track (CHT) has been recognized by the Academic Pediatric Association with its prestigious Teaching Program Award. The honor was made public at the Pediatric Academic Societies (PAS) annual meeting on May 7, 2018 in Toronto, Ontario. The purpose of the award is to foster interest in the teaching of general pediatrics by giving national recognition to an outstanding general pediatric program. The PAS selection committee chose Children’s CHT for demonstrating excellence in educational teaching methods, acceptance by the community, its adaptability and the outstanding quality of residents trained in the program.

“As a community-focused health system, one of our central missions is to train a new generation of residents to create successful community partnerships and integrate public health concepts into the everyday practice of medicine to improve the health of underserved communities,” says Cara Lichtenstein, M.D., MPH and director of Children’s Community Health Track.

Children’s CHT focuses on underserved populations and the development of skills in health policy, advocacy and community healthcare delivery. Residents spend their outpatient time learning to use public health techniques to identify and address community health needs, becoming a physician advocate and learning more about the sociocultural determinants of health and health disparities. Training for CHT is integrated with Children’s overall pediatrics residency program to ensure excellence in attainment of clinical skills, and to allow residents the opportunity to work with Children’s top-rated primary care, specialty and hospital-based physicians and care teams.

This is the third time in recent years that Children’s National has been honored by the Academic Pediatric Association. In 2013, Mary Ottolini, M.D., MPH and vice chair of medical education was recognized for her leadership of Children’s Master Teacher Leadership Development program. In 2009, Denice Cora-Bramble, M.D., MBA accepted the APA Health Care Delivery Award for the Goldberg Center for Community Pediatric Health at Children’s National.

Children’s offers up to eight residency positions each year designated as Community Health Track positions. The goals of the track are centered on the core competencies of community pediatrics as described by the American Academy of Pediatrics. Primarily to train residents to:

  • Grasp the breadth of diversity inherent in the pediatric population and be familiar with health-related implications of cultural beliefs and practices of groups represented in the community.
  • Recognize the role of the pediatrician in identifying needs and facilitating access to resources for patients, families and communities.
  • Be aware of the risks to health and barriers to care for underserved children in Washington, D.C., and demonstrate skill in improving access to continuous comprehensive health maintenance.
  • Appreciate key issues related to the pediatrician’s role and interactions with local community agencies and advocacy groups.
  • Value the role of schools and childcare settings in supporting the educational and psychosocial development of children and adolescents.
  • Apply key principles about health promotion and disease prevention for children and adolescents over a set period of time.
  • Observe, interpret and report observations about the communities in which they serve.

The fundamental difference in this track compared to the more traditional Categorical Track lies in the outpatient experiences that occur in all three years of training. The CHT utilizes these outpatient experiences to help residents to attain a well-rounded community pediatrics experience.

“Washington, D.C. is an incredibly diverse community with large numbers of vulnerable children and families from D.C. and all over the world. Given our location in our nation’s capital, residents and faculty have the unique opportunity to work with national professional and advocacy organizations that are influencing policy – both locally and nationally – as it relates to children, families and health care,” says Mark Weissman, M.D., chief of general pediatrics and community health at Children’s National. “We’re thrilled to be recognized with the Academic Pediatric Association’s Teaching Program Award and grateful to Dr. Lichtenstein for her leadership and commitment to improving the health of D.C.’s children and training the next generation of pediatricians and advocates.”

Sarah Mulkey Columbia Zika Study

Damage may lurk in “normal” Zika-exposed brains

Sarah Mulkey Columbia Zika Study

An international study that includes Sarah B. Mulkey, M.D., Ph.D., aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions? Dr. Mulkey presented preliminary findings at PAS2017.

It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.

Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.

Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?

“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”

According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.

“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.

Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.

“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”

As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.

The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.

Among the 48 study participants, 45 had “normal” fetal MRIs.

Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:

  • One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
  • One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
  • One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.

“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”

Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”

Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.

“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.

Sabah IqbShilpa Patel, Monika Goyal

Stronger firearm laws reduce ED visits

Sabah Iqbl, Shilpa Patel, Monika Goyal

Children’s National researchers Sabah F. Iqbal, M.D., Shilpa J. Patel, M.D., and Monika K. Goyal, M.D., M.S.C.E., found that regions of the United States with the strictest gun laws also have fewer emergency department visits for pediatric firearm-related injuries.

A new study by researchers from Children’s National Health System find that regions of the United States with the strictest gun laws also have the fewest emergency department visits for pediatric firearm-related injuries. The work is among the few studies to evaluate the association between local laws and firearm-related injury to children and youth. The results, presented at the 2017 annual meeting of the Pediatric Academic Societies, could inform policies at the state and regional levels.

“Our results suggest an association between regional gun laws and firearm-related injuries in children,” says Monika K. Goyal, M.D., M.S.C.E., director of research within Children’s Division of Emergency Medicine and senior author of the poster. “Regions with stricter gun laws had lower incidence rates of firearm-related emergency department visits by children.”

Firearm-related injuries are a leading cause of death and disability among children and adolescents in the United States. It is well established that states with more restrictive gun laws have fewer firearm-related fatalities. However, it has been unclear how these laws affect the rates of firearm-related injuries among children.

To investigate this question, Children’s National researchers gathered data from the Nationwide Emergency Department Sample (NEDS), a set of hospital-based emergency department databases created by the federal Agency for Healthcare Research and Quality to aggregate data about emergency department visits across the country. The researchers matched NEDS data from 2009 to 2013 in patients 21 and younger with state-level Brady Gun Law Scores, a measure of the strength of firearm laws, in four geographic regions: The Midwest, Northeast, South and West.

The researchers found that during this five-year study period, there were 111,839 emergency department visits for pediatric firearm-related injuries nationwide, an average of 22,368 per year. The mean age of patients was 18 years, and the vast majority was male. Just over one-third were publicly insured. About 30 percent of these recorded injuries resulted in hospital admission, and about 6 percent resulted in death.

Overall, firearm-related visits to emergency departments remained consistent over time at a rate of 65 per every 100,000 visits until 2013, when they decreased slightly to 51 per 100,000 visits. However, these rates varied significantly by geographic region. The Northeast had the lowest rate at 40 per 100,000 visits. This was followed by the Midwest, West and South at 62, 68 and 71 per 100,000 visits, respectively.

These numbers roughly matched the Brady Gun Law Scores for each region. The Northeast had the highest Brady score at 45, followed by 8, 9 and 9 for the South, West and Midwest.

These findings, the study authors say, suggest that stricter gun laws might lead to fewer fatalities as well as fewer gun-related injuries among children. Future studies about the role of regional gun culture and its impact on firearm legislation at the regional level, they say, is an important next step in advocating for changes to firearm legislation and reducing pediatric firearm-related injuries.

“Future research work should seek to elucidate the association of specific gun laws with the incidence rates of pediatric firearm-related injuries,” says Shilpa Patel, M.D., M.P.H., an assistant professor of pediatrics and emergency medicine at Children’s National and co-author of the poster. “This work also could evaluate how regional differences — such as social gun culture, gun ownership and other factors — contribute to the significant regional variation in firearm legislation.”

The American Academy of Pediatrics, an organization of 66,000 pediatricians, has repeatedly advocated for stricter gun laws, violence prevention programs, research for gun violence prevention and public health surveillance, physician counseling to patients on the health hazards of firearms and mental health access to address exposure to violence.

Fat Cells

Cellular signals may increase atherosclerosis risk

Fat Cells

Fat cells from obese patients have the ability to send signals that can accelerate biological processes leading to atherosclerosis.

Obesity has been linked to a variety of adverse health conditions, including Type 2 diabetes, cancer, heart attack and stroke – conditions that may begin as early as childhood in patients whose obesity also begins early. While this much is known, it has been unclear how extra fat mass might lead to these chronic health conditions.

New research from Children’s National Health System scientists might help answer this question. In findings presented at the 2017 annual meeting of the Pediatric Academic Societies, the research team shows that exosomes – nanosized chemical messages that cells send to each other to regulate protein production – isolated from very obese teenage patients behave very differently from those derived from lean patients and could be key players in heightening the risk of developing atherosclerosis. This hardening of the arteries can, in turn, increase the risk of heart disease and stroke in adulthood.

A research team led by Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National, is exploring possible links between extra belly fat and obesity-related diseases, such as atherosclerosis, a buildup of plaque in arteries that can harden and restrict blood flow. More precise knowledge of the mechanisms by which obesity ratchets up heart risks holds the promise of helping the next generation of kids avoid experiencing chronic disease.

The working theory is that exosomes derived from belly fat from obese patients have the distinct ability to accelerate biological processes leading to atherosclerosis.

The research team isolated exosomes from five obese teenagers and compared them to five sex-matched lean adolescents. It turns out that exosomes derived from fat pick up their marching orders from microRNA content likely to target cholesterol efflux genes, which help reduce cholesterol buildup in cells.

The research team looked at differences in cholesterol efflux gene expression in THP-1 macrophages. Uptake of low-density lipoprotein cholesterol, “bad” cholesterol, was 92 percent higher than in those exposed to exosomes from obese patients compared with their lean counterparts. Exposure to obese exosomes also reduced cholesterol efflux.

“Atherogenic properties of fat-cell derived exosomes from obese patients differ markedly from the non-atherogenic profile of exosomes from lean patients. It is especially concerning that we see biological clues of heightened risk in teenagers, and the finding underscores how the seeds for atherosclerosis can be planted very early in life,” Dr. Freishtat says.

The presentation is the latest finding from a research team that, over years of work, is unraveling the mechanisms of cellular signaling by fat cells.  By closely examining very obese children – who have the most severe cardiometabolic disease – the team identified strong molecular signals of disease risk that they can search for in leaner patients who may be at risk for disease years from now.

“We know that morbidly obese patients have cardiovascular issues,” explains Dr. Freishtat. “An unanswered question is for patients with no clinical symptoms who are a little overweight. Can we look at them and say whether they are at risk for developing atherosclerosis, insulin resistance or Type 2 diabetes five or 10 years down the line? That’s the whole rationale for doing this work.”

The critical issue is what exosomes are up to. Dr. Freishtat says in lean people, they’re active and are very important in maintaining stable metabolism and homeostatic processes.

“When a person becomes obese, however, exosomes evolve,” he says. “They no longer support insulin signaling, which is helpful, and drive processes in the reverse direction, repressing insulin signaling – which can be harmful,” he adds.

Ultimately, the research team aims to revolutionize how chronic diseases like Type 2 diabetes are diagnosed. For far too long, clinicians have relied on symptoms like high glucose levels and excess urination to diagnose diabetes.

“By the time you have symptoms, it’s too late,” says Dr. Freishtat. “In many cases, damage has been done by relentless exposure to high sugar levels. The biological processes that underlie the Type 2 diabetes process began five, 10, 15 years earlier. If we can detect it earlier, before symptoms arise, intervention is going to have a more significant impact on improving and extending patients’ lives.”