The Finding:

A team of ear, nose, and throat specialists has demonstrated that eating honey after swallowing a button battery has the potential to reduce serious injuries in small children. The research suggests that this common household product may significantly reduce morbidity and mortality from highly caustic batteries.

Why it matters:

“Button batteries are ingested by children more than 2,500 times a year in the United States, with more than a 12-fold increase in fatal outcomes in the last decade compared to the prior decade,” said Ian N. Jacobs, MD, director of the Center for Pediatric Airway Disorders and a pediatric otolaryngologist at Children’s Hospital of Philadelphia. “Since serious damage can occur within two hours of ingesting a battery, the interval between ingestion and removal is a critical time to act in order to reduce esophageal injury.”

Who conducted the study:

Co-principal investigators Dr. Jacobs and Kris R. Jatana, MD, a pediatric otolaryngologist and director of Pediatric Otolaryngology Quality Improvement at Nationwide Children’s Hospital, led the study.

How they did it:

To determine successful interventions for mitigating these injuries in both home and clinical settings, researchers worked with animal models to test the effectiveness of palatable, viscous liquids that could create a protective barrier between the tissue and the battery, as well as neutralize harsh alkaline levels. The researchers screened various options, including juices, sodas, and sports drinks.

“We explored a variety of common household and medicinal liquid options, and our study showed that honey and sucralfate demonstrated the most protective effects against button battery injury, making the injuries more localized and superficial,” Dr. Jacobs said.

Quick thoughts:

“Our recommendation would be for parents and caregivers to give honey at regular intervals before a child is able to reach a hospital, while clinicians in a hospital setting can use sucralfate before removing the battery,” Dr. Jacobs said. However, the authors caution against using these substances in children who have a clinical suspicion of existing sepsis or perforation of the esophagus, known severe allergy to honey or sucralfate, or in children less than 1-year-old due to a small risk of botulism.

What’s next:

The study’s findings will be put immediately into clinical practice by incorporating them into the latest National Capital Poison Center Guidelines for management of button battery ingestions.

Where the study was published:

The study was published online by The Laryngoscope.

Who helped fund the study:

Funding support came from CHOP’s Frontier Program Grant.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Center for Pediatric Airway Disorders.

The Finding:

A research team led by allergists at Children’s Hospital of Philadelphia discovered that children were nine times more likely to develop an emerging, chronic food allergy called eosinophilic esophagitis (EoE) if they had three allergies other than EoE, as compared with children with no pre-existing allergies. Children with EoE, a painful inflammation of the esophagus also had a higher risk than those without EoE of developing the respiratory allergy allergic rhinitis — commonly referred to as seasonal allergy.

Why it matters:

The study is the first to suggest that EoE was a component of the “allergic march,” a pillar concept in the allergy field, which is usually compressed into the first five years of life. The typical childhood progression is a skin allergy, such as atopic dermatitis, followed by an anaphylactic food allergy, then a respiratory allergy, such as asthma. However, a key implication of the current study is that primary care clinicians should incorporate early EoE screening in children who have other allergies.

Who conducted the study:

David A. Hill, MD, PhD, an allergist at CHOP, and Jonathan M. Spergel, MD, PhD, who leads the hospital’s Food Allergy Center, led the study.

How they did it:

The researchers analyzed health records of more than 130,000 patients in the CHOP pediatric network who were followed from birth to adolescence to determine whether and when patients acquired allergic diseases. The researchers also compared the risk of developing EoE between allergic and non-allergic children.

Quick thoughts:

“The more allergies a child has, the higher is that child’s risk of developing EoE,” Dr. Hill said. “The connection among these allergies suggests a common underlying genetic or biological cause, and also may imply that if we can successfully treat an earlier type of allergy, we may prevent later allergies.”

What’s next:

The next step is to further investigate the underlying biological mechanisms among different allergies. “Ultimately, we hope to find that intervening earlier in the allergic march, for example, in treating allergic skin conditions, may interrupt the march and prevent the child from developing later disorders such as EoE,” Dr. Hill said.

Where the study was published:

The study was published online by the Journal of Allergy and Clinical Immunology: In Practice.

Who helped fund the study:

Grants from the National Institutes of Health, the Food Allergy Research & Education Inc. Clinical Network, and the Consortium of Eosinophilic Gastrointestinal Disease Researchers supported this research.

Where to learn more:

You can learn more about this research by reading a Cornerstone post.

The Finding:

Children and adults treated with some oral antibiotics have a significantly higher risk of developing kidney stones, according to new research. This is the first time that these medicines have been linked to this condition, with the strongest risks appearing at younger ages and among patients most recently exposed to antibiotics.

Researchers found that five classes of oral antibiotics were associated with a diagnosis of kidney stone disease: oral sulfas, cephalosporins, fluoroquinolones, nitrofurantoin, and broad-spectrum penicillins. They also discovered that patients who received sulfa drugs were more than twice as likely as those notexposed to sulfa drugs to have kidney stones. For broad-spectrum penicillins, the increased risk was 27 percent higher.

Why it matters:

“The overall prevalence of kidney stones has risen by 70 percent over the past 30 years, with particularly sharp increases among adolescents and young women,” said study leader Gregory Tasian, MD, MSCE, a pediatric urologist at Children’s Hospital of Philadelphia. Dr. Tasian noted that kidney stones were previously rare in children.

Study co-author Michelle Denburg, MD, MSCE, a pediatric nephrologist at CHOP, added, “The reasons for the increase are unknown, but our findings suggest that oral antibiotics play a role, especially given that children are prescribed antibiotics at higher rates than adults.”

Who conducted the study:

Drs. Tasian and Denburg led the study and co-authored the paper with Jeffrey Gerber, MD, PhD, an infectious diseases specialist at CHOP who leads programs in antibiotic stewardship, and Lawrence Copelovitch, MD, a pediatric nephrologist who co-directs the Kidney Stone Center at CHOP with Dr. Tasian.

How they did it:

The study team drew on an electronic health records database from the United Kingdom available through the Center for Clinical Epidemiology and Biostatistics in the Perelman School of Medicine at the University of Pennsylvania. This database included over 13 million people (adults and children) seen by general practitioners between 1994 and 2015. The team analyzed prior antibiotic exposure for nearly 26,000 patients with kidney stones, compared to nearly 260,000 control subjects.

Quick thoughts:

“Our findings suggest that antibiotic prescription practices represent a modifiable risk factor — a change in prescribing patterns might decrease the current epidemic of kidney stones in children,” Dr. Tasian said. In fact, approximately 30 percent of antibiotics prescribed in office visits are inappropriate, and children receive more antibiotics than any other age group, so the new findings reinforce the need for clinicians to be careful in prescribing correct antibiotics, he pointed out.

What’s next:

The researchers are continuing to investigate the microbiomes of children and adolescents with kidney stones at CHOP. They plan to expand their research to better understand how variations in microbiome compositions may influence the development of kidney stones.

Where the study was published:

The study was published online by the Journal of the American Society of Nephrology.

Who helped fund the study:

Grants from the National Institutes of Health supported this research.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Pediatric Kidney Stone Center.

The Finding:

Researchers have discovered gene mutations that severely disrupt crucial functions in mitochondria, the energy-producing structures within cells, are behind a rare but devastating neurological regression in infants. Mutations in the gene PMPCB interfere with the function of the enzyme mitochondrial processing protease (MPP), which cleaves mitochondrial proteins in order to activate these proteins as part of normal biological processing.

It turns out that disrupting that process blocked the production of iron-sulfur clusters that are crucial to energy metabolism and other cellular functions. In infants, diminished MPP activity leads to a potentially catastrophic biological energy deficiency.

Why it matters:

The disease mechanism, in which mutations disrupt a critical mitochondrial enzyme, has not previously been implicated in humans. The discovery offers new hope for a cure. “If we better understand biological pathways and mechanisms, we may be able to start screening for compounds that may suggest potential treatments for this condition,” said Ingo Helbig, MD, a pediatric neurologist at Children’s Hospital of Philadelphia.

Who conducted the study:

Dr. Helbig, who discovered the role of the gene in human disease and who served as the lead investigator, collaborated with researchers from Germany, Australia, and the U.S. on the study.

How they did it:

Researchers studied the DNA of five affected children in four families, including three affected children who died before age 6. The research team used whole-exome sequencing to pinpoint the causative mutations in the gene PMPCB. Because that gene is highly conserved across yeast and humans, the researchers then conducted experiments in yeast to investigate the effects of the mutation.

Quick thoughts:

“We uncovered the cause of this mysterious neurodegenerative disease, and now we understand better what happens in the brains of these children,” Dr. Helbig said. “This new understanding is the very first step toward potentially finding a treatment.”

What’s next:

The current findings set the stage for follow-up research in biological implications, for instance, by further investigation in yeast models of the disease. “We realized that that the disease mechanisms of this condition can be reliably modeled in yeast,” Dr. Heilbig said. “We can therefore use this model to assess for ways to modify the disease process in order to find treatments.”

Where the study was published:

The study was published online by the American Journal of Human Genetics.

Who helped fund the study:

Multiple sources contributed funding support, including the German Research Foundation, the University of Kiel, the German Research Foundation (Deutsche Forschungsgemeinschaft), the Japan Agency for Medical Research and Development, Miracles for Mito, Summits for Samantha, and the Children’s Hospital Colorado Foundation.

Where to learn more:

You can learn more about this research by reading a press release by the Division of Neurology. Dr. Helbig also introduced this finding on this research blog “Beyond the Ion Channel.”

The Finding:

Researchers identified a pathway in brain circuitry that, when stimulated, leads to “antidepressive” behavior in animal models. If such brain stimulation proves to have similar effects in people, it may eventually lead to a novel treatment for depression.

Why it matters:

“Our group was the first to investigate whether stimulating Ent (the entorhinal cortex) could affect mood,” according to Sanghee Yun, PhD, research assistant professor of Anesthesiology and Critical Care at Children’s Hospital of Philadelphia. “Our findings are the first evidence that targeting this particular brain circuit may offer a potential new depression treatment.”

Who conducted the study:

Amelia Eisch, PhD, a neurobiology researcher, led the study, and Dr. Yun was the paper’s first author. Both are from the Department of Anesthesiology and Critical Care at CHOP.

How they did it:

Researchers worked with a mouse model genetically engineered to “knock down” or eliminate a previously identified protein called TRIP8b, which increases during stress and inhibits cell firing. The researchers stimulated a region upstream from the brain’s hippocampus, the entorhinal cortex (Ent). The mice with greater stimulation in their Ent circuits showed antidepressive behaviors.

Quick thoughts:

“Major depressive disorder is a serious health problem worldwide. Existing treatments are helpful for many people, but also have a high rate of relapse and significant side effects,” Dr. Eisch said. “Because scientists consider depression to be caused by malfunctions in brain circuitry, we suggest that ‘tuning’ a specific circuit could set the stage for a targeted treatment.”

What’s next:

The researchers hope the study findings present opportunities to collaborate with translational researchers to pursue promising implications for practical, noninvasive treatments for people with depression.

“Existing brain stimulation therapies for depression are extremely helpful for many patients, but they don’t work for everyone, and they also have side effects such as memory loss and cognitive impairment,” Dr. Eisch said. “It is important to increase the number of tools available to treat depression and find those with fewer side effects as well.”

Where the study was published:

The study was published online by Nature Medicine.

Who helped fund the study:

Grants from the National Institutes of Health, the National Aeronautics and Space Administration, and the National Alliance for Research on Schizophrenia and Depression supported the study.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Department of Anesthesiology and Critical Care Medicine.

The Finding:

Researchers investigating a key signaling protein in Huntington’s disease (HD), an incurable, inherited disease with progressive loss of brain cells and motor function, discovered deleterious effects on heart function beyond the rare disease’s devastating neurological impact.

A defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT protein (mHTT) causes involuntary movements and severe cognitive and emotional disturbances. The study found that adjusting the protein levels improved heart function in mice with HD.

Why it matters:

“Heart disease is the second leading cause of death in Huntington’s disease patients, but its biology remains poorly understood,” said Beverly Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at Children’s Hospital of Philadelphia, where she is an expert on gene therapy for inherited brain disorders. “Better knowledge of the underlying biology of Huntington’s disease will improve the development of effective therapies.”

About 30,000 Americans have HD.

Who conducted the study:

Dr. Davidson led the study team.

How they did it:

The study focused on heart function in mice with HD. The mutant protein mHTT disrupts functioning along the mTORC1 pathway, named for the signaling protein complex mTORC1 that promotes cellular growth and metabolism and plays a key role in the neurology of HD.

Researchers found mTORC1 activity was lower in HD mice than in healthy mice and that the HD mice also had smaller-than-normal hearts. The study team discovered that HD mice were less able to adapt to stress on their hearts and had higher mortality from that stress. However, when the researchers restored mTORC1 activation in the HD mice by using genetic techniques to knock down the mutant HTT protein, the mice were better able to adapt to cardiac stress and had higher survival over the course of the study.

Quick thoughts:

“We know from our previous studies that improving mTORC1 functioning may have a protective effect in HD, but this would require carefully adjusting the pathway to restore normal mTORC1 levels,” Dr. Davidson said. The new study suggests that improving mTOR function in hearts would also be beneficial.

What’s next:

The researchers hope that future studies will investigate whether the mHTT protein has a similar effect on human hearts as in the mice, which may help explain the heart-related mortality seen in patients with HD.

Where the study was published:

The study was published online in Cell Reports.

Who helped fund the study:

Several grants from the National Institutes of Health supported the study.

Where to learn more:

You can learn more by reading a press release by CHOP’s Division of Neurology.

The Finding:

New research shows drivers with attention-deficit/hyperactivity disorder (ADHD) symptoms are more likely to be involved in a crash. In fact, researchers found the more inattention symptoms a teen reported, the more mistakes they made in a driving simulator.

Why it matters:

Teenage drivers ages 16 to 19 are three times more likely to get into fatal accidents than their older counterparts. Approximately 20 percent of U.S. teens in this age group have been affected by symptoms associated with mental health disorders, including 9 percent with a lifetime history of ADHD. This study seeks to shed light on the relationship between these findings.

Who conducted the study:

Catherine McDonald, PhD, RN, FAAN, a senior fellow at Children’s Hospital of Philadelphia’s Center for Injury Research and Prevention (CIRP) and assistant professor in the Department of Family and Community Health at the University of Pennsylvania School of Nursing, led the research study.

How they did it:

The research team recruited drivers aged 16 to 17 years old and asked them to complete a questionnaire that assessed their symptoms of ADHD and other mental health disorders. The teens were then asked to go for a virtual drive in the CIRP Driving Simulator Core to assess their driving skills.

Quick thoughts:

“Previous studies have shown increases in crash-risk related to an ADHD diagnosis,” Dr. McDonald said. “We wanted to tease apart the nuances behind that. Is it about risk-taking, skill, or performance deficits? Is it about decision-making? In the capacity of a simulator as well as self-reported behaviors, we wanted to see if our data could get at the why of what is happening around driving behaviors.”

What’s next:

“We would like to learn more about the relationship of mental health symptoms to driving behavior in a sample with higher rates and severity of ADHD so we can examine the impact of inattention and hyperactivity-impulsivity symptom severity across the full range of these dimensions,” Dr. McDonald said. That next step could move the research toward its ultimate goal: tailoring interventions for teen drivers at risk in different ways.

Where the study was published: The findings were published online in the journal Nursing Research.

Who helped fund the study:

Grants from the National Institutes of Health and Penn Nursing’s Dorothy Mereness Endowed Research Fund supported the research study.

Where to learn more:

You can learn more by reading CIRP’s Research in Action post.

The Finding:

Researchers discovered a “missing mutation” in severe infant epilepsy that leads to epileptic seizures. They also found early indications that specific medications might prevent disabling brain injury by controlling epilepsy during a crucial period shortly after birth.

Why it matters:

“These are still early days, but we may be able to use this knowledge to protect the newborn brain and improve a child’s long-term outcome,” said Ethan Goldberg, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia.

The study focused on mutations in the gene SCN3A, which had been previously linked to less severe forms of epilepsy but had not clearly been proven to be an epilepsy gene. SCN3A encodes the sodium channel Nav1.3 which regulates electrical activity in neurons of the developing brain. The current research solidified this link and was the first to establish that SCN3A mutations cause the severe infantile form, known as epileptic encephalopathy. Researchers also found that existing anti-seizure medications — lacosamide and phenytoin — could help treat this condition.

Who conducted the study:

Dr. Goldberg along with Ingo Helbig, MD, physician in the Division of Neurology, led the study team of European and American researchers, including several from CHOP.

How they did it:

The researchers reported on a cohort of four unrelated children from different countries, all of whom had severe epilepsy with a particularly early onset that did not respond to medication and resulted in expected lifelong disability. The researchers used whole-exome sequencing to pinpoint mutations in the SCN3A gene, which were present in the affected children, but not inherited from their parents. Cell studies further revealed detailed properties of the electrical signaling process.

Quick thoughts:

Precise, early diagnosis may be crucial because of the highly regulated timetable of early-life neurological events. “The mutation’s activity in the Nav1.3 sodium ion channel occurs during a short period in newborns, but if we can intervene during that window, we may be able to help prevent long-term neurological injury and benefit patients,” Dr. Goldberg said.

What’s next:

Further research in stem cell-derived neurons from patients with SCN3A encephalopathy and in animal models will be necessary to test possible precision-medicine treatments for safety and efficacy before they can be investigated in patients. Dr. Goldberg’s team is actively pursuing these leads. Drs. Goldberg and Helbig have a growing cohort of more than 20 patients with SCN3A encephalopathy who have been identified since the initial publication.

The current research has resulted in the addition of the SCN3A gene to an existing diagnostic test, CHOP’s Epilepsy Panel, which uses next-generation sequencing to rapidly test for more than 100 genetic causes of childhood epilepsy.

Where the study was published:

The study was published online by the Annals of Neurology.

Who helped fund the study:

The National Institutes of Health and the Burroughs Wellcome Fund Career Award for Medical Scientists provided funding for this study.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Pediatric Epilepsy Program and on Dr. Helbig’s blog.

The Finding:

Researchers found important differences in how cancers develop in children compared to how they develop in adults. For instance, they identified 142 genes that drive pediatric cancers, but only 45 percent of those genes match genes found in adult pan-cancer studies. This implies that precise treatments need to be better customized for children.

Why it matters:

Physician-scientists from Children’s Hospital of Philadelphia contributed crucial data and expertise to the first pan-cancer analysis of children’s cancer. Pan-cancer analyses identify similarities and differences among the biological changes across diverse types of cancer to discover insights for improved care.

Who conducted the study:

Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital, led the study team. Co-authors of the study from CHOP lead the two largest datasets in the study: Stephen Hunger, MD, CHOP’s chief of Oncology, leads the TARGET team for acute lymphoblastic leukemia, and John M. Maris, MD, leads the neuroblastoma TARGET team. Sharon Diskin, PhD, a faculty member of the Division of Oncology and the Center for Childhood Cancer Research at CHOP, was also an author of the study.

How they did it:

The researchers analyzed DNA samples from nearly 1,700 patients from multiple centers across five groups of pediatric cancers: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, Wilms’ tumor and osteosarcoma.

Quick thoughts:

“As pediatric centers have developed precision medicine strategies, many have relied on diagnostic panels developed to detect mutations common in adult cancers. In contrast, CHOP has developed diagnostic panels specific to mutations common in pediatric cancers — many of which occur only rarely in adult cancers,” Dr. Hunger said.

What’s next:

“This collaborative project proves the concept that childhood cancers are not ‘small adult tumors.’ They show unique genetic changes. Thus, precision diagnostic and therapeutic strategies for childhood cancers will be very different than those being developed for common adult malignancies,” Dr. Maris said.

Where the study was published:

The study was published online and in print by the journal Nature.

Who helped fund the study:

Patients were in clinical trials sponsored by the Children’s Oncology Group.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Cancer Center.

The Finding:

A study team identified a new cell lineage, which they called alveolar epithelial progenitor (AEP) cells. Researchers focused on the alveoli — tiny compartments in the lung in which gas exchange occurs — as oxygen is taken up by the blood and carbon dioxide is removed. They discovered that certain powerful stem cell signaling pathways act on AEP cells in the lung to orchestrate their response to injury. Activated AEP cells multiply rapidly and differentiate into alveolar cells, thereby regenerating lung tissue.

Why it matters:

The discovery could provide an opportunity to develop innovative future treatments that harness the body’s ability to regenerate. AEP cells could be used to treat lung diseases in individuals of all ages, from premature infants to the elderly.

Who conducted the study:

Edward Morrisey, PhD, director of the Penn Center for Pulmonary Biology and Scientific Director of Penn’s Institute for Regenerative Medicine, led the research team, and David Frank, MD, PhD, a pediatric cardiologist at Children’s Hospital of Philadelphia, was the study’s co-first author.

How they did it:

The researchers studied a mouse model of lung injury caused by influenza virus. The researchers found that AEP cells share similar characteristics in both mice and humans, which allowed them to perform experiments in organoid models — three-dimensional cell cultures that simulated specific ways that lungs regenerate in living lower organisms.

Quick thoughts:

“These cells sit quietly, but poised, in the lung until an injury activates them to proliferate and differentiate,” Dr. Frank said. “If we can learn to manipulate the biological signals in this process, we may be able to regenerate lung tissue in patients.”

What’s next:

The researchers hope to translate their findings into eventual treatments for lung diseases such as bronchopulmonary dysplasia, a severe, sometimes fatal disability in infants with underdeveloped lungs; chronic obstructive pulmonary disease in adults; and severe lung damage from influenza in individuals of any age. The findings might even play a part in developing future tissue engineering treatments for premature babies or patients needing lung transplantation.

Where the study was published:

The study was published online in the journal Nature.

Who helped fund the study:

Several grants from the National Institutes of Health supported this study.

Where to learn more:

You can learn more about this research by reading a press release by CHOP’s Pulmonary Hypertension Program.

The Finding:

Researchers found that, when judged by both practical and clinical outcomes, narrow-spectrum antibiotics performed just as well or better than broad-spectrum ones, and result in fewer disruptions to family routines, such as adverse drug effects and missed school days.

In treating earaches, strep throat, and other common infections, researchers discovered a significantly higher risk of adverse events for broad-spectrum antibiotics compared to narrow-spectrum antibiotics (3.7 percent vs. 2.7 percent as documented by clinicians, and 35.6 percent vs. 25.1 percent, as reported by patients and families). However, the rates of treatment failure were not significantly different between both types of antibiotics.

Why it matters:

The study reflects an “antimicrobial stewardship” approach, guiding healthcare providers to prescribe the most appropriate antibiotic for a patient’s specific type of infection, with the aim of improving individual outcomes and reducing the overall risk of antibiotic resistance — in which disease-causing microorganisms develop resistance to commonly used antibiotics.

“Many children unnecessarily receive broad-spectrum antibiotics for common infections, which can lead to antibiotic resistance and unnecessary side effects,” said study leader Jeffrey Gerber, MD, PhD, associate director for Inpatient Research Activities in the Center for Pediatric Clinical Effectiveness (CPCE) at Children’s Hospital of Philadelphia. “This study showed that inappropriate prescribing of antibiotics also affects families at a much more practical level, such as missed days from school and work, side effects of the drugs, and costs for extra childcare. These can be a real burden for families.”

Who conducted the study:

Dr. Gerber led the study.

How they did it:

The study team performed two complementary studies in 31 primary care practices in CHOP’s pediatric network in Pennsylvania and New Jersey, between January 2015 and April 2016. They drew on electronic health records of infants and children up to age 12, who were diagnosed with an acute respiratory tract infection (ARTI) and prescribed an oral antibiotic. In a retrospective cohort of approximately 30,000 patients, 14 percent received broad-spectrum drugs, and 86 percent received narrow-spectrum drugs. In a a prospective cohort of 2,472 children, researchers conducted telephone interviews with caregivers to measure outcomes that parents had identified as their highest concerns: adverse drug effects, additional childcare costs, lingering symptoms, and missed school days.

The ARTIs in the analysis were acute otitis media (earache), Group A streptococcal pharyngitis (strep throat) and sinusitis (sinus infection), which account for the majority of antibiotic exposures in children.

Quick thoughts:

“Research tells us that antibiotic stewardship programs not only reduce the overall burden of antibiotic resistance, but also improve patient outcomes,” Dr. Gerber said. “Our previous research has also shown that these programs can lower costs for insurers and families that pay for prescriptions. These programs are a win-win-win for public health, families, and insurers.”

What’s next:

Researchers will use the study findings to build on CHOP’s seven years of research to continuing developing an effective clinical practice model for antibiotic stewardship in pediatric outpatient settings.

Where the study was published:

The study was published online in the Journal of the American Medical Association.

Who helped fund the study:

An award from the Patient-Centered Outcomes Research Institute funded the study.

Where to learn more:

You can learn more about this research by reading a press release by CPCE.

The Finding:

Researchers studying a rare genetic disorder that causes severe, progressive neurological problems in childhood have discovered new insights into the biological mechanisms that drive the disease. TBCK-encephaloneuropathy (TBCKE) is caused by a mutation in the TBCK gene. TBCKE results in progressive neurodegeneration involving the brain as well as progressive muscle weakness.

The researchers found that abnormalities in a biological waste-disposal process called autophagy links the mechanisms underlying rare pediatric neurogenetic disorders including TBCKE to more common neurodegenerative disorders, such as Huntington’s or Parkinson’s disease. They also discovered that an amino acid supplement might offer a targeted therapy.

Why it matters:

Scientists already knew that the TBCK protein regulates signals along a biological pathway known as mTOR. Abnormal mTOR signaling has been linked to epilepsy, autism, intellectual disability, and other neurological conditions. A key role for mTOR signaling is in autophagy, the normal cleanup process in which cells dispose of damaged proteins, lipids, and other biological objects. When autophagy doesn’t function normally, neurodegenerative diseases may result.

Researchers in the current study found that a specific mutation on the TBCK gene, called the Boricua mutation, leads to abnormal autophagy. Patients with this mutation are usually of Puerto Rican (Boricua) descent. They also found a potential biomarker for TBCKE — abnormal levels of chemicals called oligosaccharides in the patients’ urine.

Oligosaccharide levels improved when the researchers added the amino acid leucine to the patients’ cells in laboratory cultures.

Who conducted the study:

Xilma R. Ortiz-Gonzalez, MD, PhD, a pediatric neurogeneticist at Children’s Hospital of Philadelphia, led the study.

How they did it:

The researchers studied a cohort of eight unrelated boys, ranging from age 9 to 14 years, all of Puerto Rican descent. All had the Boricua mutation at the same location on the TBCK gene. They all share a very severe presentation of the disease, including profound intellectual disability, epilepsy, low muscle tone, and progressive dysfunction in both the central and peripheral nervous systems.

Quick thoughts:

“Leucine activates mTOR signaling that was disrupted by the mutation, so this finding suggests that leucine might offer some improvement in disease symptoms if used in patients,” Ortiz-Gonzalez said. This is consistent with previous CHOP research in a TBCK-related disease, which showed potential therapeutic benefits in using leucine in affected cells.

What’s next:

Dr. Ortiz-Gonzalez and her CHOP collaborators are continuing to investigate the biology of TBCKE, while working to establish a patient registry of children with the rare disorder. Her goal is to identify more patients and perform studies that could set the stage for a clinical trial to test leucine or a similar compound as a personalized treatment for this severe childhood disease.

Where the study was published:

The study was published online by the Annals of Neurology.

Who helped fund the study:

The Robert Wood Johnson Harold Amos Faculty Development Award and several grants from the National Institutes of Health funded the research.

Where to learn more:

You can learn more by reading a press release by CHOP’s Division of Neurology. You can also learn more about Dr. Ortiz-Gonzalez’ research by visiting her CHOP Research profile.