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Category: Pediatrics

Hot Topics: Asthma Guidelines Inadequate for Black Children

Jackie Werner Hot Topics in Research, Pediatrics

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma

Wechsler, M. E., Szefler, S. J., Ortega, V. E., Pongracic, J. A., Chinchilli, V., Lima, J. J., . . . Israel, E. (2019). Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med, 381(13), 1227-1239. https://doi.org/10.1056/NEJMoa1905560

BACKGROUND

Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

METHODS

We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

RESULTS

When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P=0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol–low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P=0.003]; salmeterol–medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P=0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

CONCLUSIONS

In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA.


Hot Topics: Genetic Testing Can Use Placental Swab

Jackie Werner Hot Topics in Research, Obstetrics and Gynecology, Pediatrics

A Rapid Method for Label-Free Enrichment of Rare Trophoblast Cells from Cervical Samples

Bailey-Hytholt, C., Sayeed, S., Kraus, M., Joseph, R., Shukla, A., & Tripathi, A. (2019). A rapid method for label-free enrichment of rare trophoblast cells from cervical samples. Scientific Reports, 9(1), 12115. http://doi.org/10.1038/s41598-019-48346-3

Extravillous trophoblasts (EVTs) have the potential to provide the entire fetal genome for prenatal testing. Previous studies have demonstrated the presence of EVTs in the cervical canal and the ability to retrieve a small quantity of these cells by cervical sampling. However, these small quantities of trophoblasts are far outnumbered by the population of cervical cells in the sample, making isolation of the trophoblasts challenging. We have developed a method to enrich trophoblast cells from a cervical sample using differential settling of the cells in polystyrene wells. We tested the addition of small quantities of JEG-3 trophoblast cell line cells into clinical samples from standard Pap tests taken at 5 to 20 weeks of gestation to determine the optimal work flow. We observed that a 4 min incubation in the capture wells led to a maximum in JEG-3 cell settling on the surface (71 ± 10% of the initial amount added) with the removal of 91 ± 3% of the cervical cell population, leading to a 700% enrichment in JEG-3 cells. We hypothesized that settling of mucus in the cervical sample affects the separation. Finally, we performed a proof-of-concept study using our work flow and CyteFinder cell picking to verify enrichment and pick individual JEG-3 and trophoblast cells free of cervical cells. Ultimately, this work provides a rapid, facile, and cost-effective method for enriching native trophoblasts from cervical samples for use in subsequent non-invasive prenatal testing using methods including single cell picking.

Hot Topics: Training Muscles Before Surgery Eases Autotransplantation

Jackie Werner Hot Topics in Research, Pediatrics, Sports Medicine, Surgery

Perspectives for the Use of Neurotechnologies in Conjunction With Muscle Autotransplantation in Children

Blagovechtchenski E, Agranovich O, Kononova Y, Nazarova M, Nikulin VV. Perspectives for the use of neurotechnologies in conjunction with muscle autotransplantation in children. Frontiers in Neuroscience. 2019;13:99. https://doi.org/10.3389/fnins.2019.00099

Muscles autotransplantation is an important way to restore motor activity in case of injury or diseases associated with a loss of muscles ability. One of the typical examples of such pathology is arthrogryposis multiplex congenita (AMC). Arthrogryposis is one of the most serious congenital malformations of the musculoskeletal system. It is characterized by the presence of two or more major joint contractures, muscle damage, and motoneuronal dysfunction in the anterior horns of the spinal cord. One of the main problems that determines the limitation or even impossibility of self-care of patients suffering from arthrogryposis is the lack of active movements in the upper limb joints, which can be restored by autotransplantation of the muscles of various donor areas (Hall, 1997Bamshad et al., 2009Loeffler and Lewis, 2016).

Hot Topics: Routine Data Can Quickly Detect Sepsis in Newborns

Jackie Werner Critical Care, Hot Topics in Research, Pediatrics

Machine learning models for early sepsis recognition in the neonatal intensive care unit using readily available electronic health record data

Masino AJ, Harris MC, Forsyth D, et al. Machine learning models for early sepsis recognition in the neonatal intensive care unit using readily available electronic health record data. PLOS ONE. 2019;14(2):e0212665. https://doi.org/10.1371/journal.pone.0212665.

Background

Rapid antibiotic administration is known to improve sepsis outcomes, however early diagnosis remains challenging due to complex presentation. Our objective was to develop a model using readily available electronic health record (EHR) data capable of recognizing infant sepsis at least 4 hours prior to clinical recognition.

Methods and findings

We performed a retrospective case control study of infants hospitalized ≥48 hours in the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital of Philadelphia between September 2014 and November 2017 who received at least one sepsis evaluation before 12 months of age. We considered two evaluation outcomes as cases: culture positive–positive blood culture for a known pathogen (110 evaluations); and clinically positive–negative cultures but antibiotics administered for ≥120 hours (265 evaluations). Case data was taken from the 44-hour window ending 4 hours prior to evaluation. We randomly sampled 1,100 44-hour windows of control data from all times ≥10 days removed from any evaluation. Model inputs consisted of up to 36 features derived from routine EHR data. Using 10-fold nested cross-validation, 8 machine learning models were trained to classify inputs as sepsis positive or negative. When tasked with discriminating culture positive cases from controls, 6 models achieved a mean area under the receiver operating characteristic (AUC) between 0.80–0.82 with no significant differences between them. Including both culture and clinically positive cases, the same 6 models achieved an AUC between 0.85–0.87, again with no significant differences.

Conclusions

Machine learning models can identify infants with sepsis in the NICU hours prior to clinical recognition. Learning curves indicate model improvement may be achieved with additional training examples. Additional input features may also improve performance. Further research is warranted to assess potential performance improvements and clinical efficacy in a prospective trial.

Hot Topics: Bias Minimizes Girls’ Pain

Jackie Werner Ethics, Hot Topics in Research, Pediatrics

Gender bias in pediatric pain assessment

Earp BD, Monrad JT, LaFrance M, Bargh JA, Cohen LL, Richeson JA. Gender bias in pediatric pain assessment. 2019. https://dx.doi.org/10.1093/jpepsy/jsy104.

Objective
Accurate assessment of pain is central to diagnosis and treatment in healthcare, especially in pediatrics. However, few studies have examined potential biases in adult observer ratings of children’s pain. Cohen, Cobb, & Martin (2014. Gender biases in adult ratings of pediatric pain. Children’s Health Care, 43, 87–95) reported that adult participants rated a child undergoing a medical procedure as feeling more pain when the child was described as a boy as compared to a girl, suggesting a possible gender bias. To confirm, clarify, and extend this finding, we conducted a replication experiment and follow-up study examining the role of explicit gender stereotypes in shaping such asymmetric judgments.

Methods
In an independent, pre-registered, direct replication and extension study with open data and materials (https://osf.io/t73c4/), we showed participants the same video from Cohen et al. (2014), with the child described as a boy or a girl depending on condition. We then asked adults to rate how much pain the child experienced and displayed, how typical the child was in these respects, and how much they agreed with explicit gender stereotypes concerning pain response in boys versus girls.

Results
Similar to Cohen et al. (2014), but with a larger and more demographically diverse sample, we found that the “boy” was rated as experiencing more pain than the “girl” despite identical clinical circumstances and identical pain behavior across conditions. Controlling for explicit gender stereotypes eliminated the effect.

Conclusions
Explicit gender stereotypes—for example, that boys are more stoic or girls are more emotive—may bias adult assessment of children’s pain.

Hot Topics: Childhood Cancer Tumor Pathway Discovered Through Zebrafish

Jackie Werner Hot Topics in Research, Oncology, Pediatrics

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis

Kendall GC, Watson S, Xu L, et al. PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. eLife. 2018;7:e33800. https://doi.org/10.7554/eLife.33800.

Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6–19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.

Hot Topics: Communication Difficulties in Children with Autism Linked to Suicidal Behavior

Jackie Werner Developmental Disorders, Hot Topics in Research, Pediatrics

Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study

Culpin I, Mars B, Pearson RM, et al. Autistic traits and suicidal thoughts, plans, and self-harm in late adolescence: Population-based cohort study. Journal of the American Academy of Child & Adolescent Psychiatry. 2018;57(5):320.e6. http://dx.doi.org/10.1016/j.jaac.2018.01.023.

Objective
To examine the hypothesis that autism spectrum disorders (ASD) diagnosis and traits in childhood are associated with suicidal thoughts, plans and self-harm at 16 years, and that any observed associations are explained by depression at 12 years.

Method
We examined associations between ASD diagnosis and 4 dichotomized ASD traits (social communication, pragmatic language, repetitive behavior, and sociability) with suicidal and nonsuicidal self-harm, suicidal thoughts, and suicidal plans at age 16 years in 5,031 members of the United Kingdom−based birth cohort study the Avon Longitudinal Study of Parents and Children. We assessed whether any associations were explained by depressive symptoms in early adolescence measured by the Short Moods and Feelings Questionnaire at 12 years.

Results
Children with impaired social communication had a higher risk of self-harm with suicidal intent (relative risk [RR] = 2.14, 95% CI = 1.28–3.58), suicidal thoughts (RR = 1.42, 95% CI = 1.06–1.91), and suicidal plans (RR = 1.95, 95% CI = 1.09–3.47) by age 16 years as compared to those without. There was no evidence for an association between ASD diagnosis and outcomes, although these analyses were imprecise because of small numbers. There was also no evidence of an association between other autism traits and the outcomes. Approximately 32% of the total estimated association between social communication impairment and self-harm was explained by depressive symptoms at 12 years.

Conclusion
Social communication impairments are an important autistic trait in relation to suicidality. Early identification and management of depression may be a preventative mechanism, and future research identifying other potentially modifiable mechanisms may lead to interventions against suicidal behavior in this high-risk group.

Hot Topics: NIH Releases Big Data for Brain Development Research

Jackie Werner Hot Topics in Research, Neurology, Pediatrics, Psychology and Psychiatry

NIH releases first dataset from unprecedented study of adolescent brain development

National Institutes of Health. (2018, February 13). NIH releases first dataset from unprecedented study of adolescent brain development [Press release]. Retrieved from https://www.nih.gov/news-events/news-releases/nih-releases-first-dataset-unprecedented-study-adolescent-brain-development.

The National Institutes of Health Tuesday released to the scientific community an unparalleled dataset from the Adolescent Brain Cognitive Development (ABCD) study. To date, more than 7,500 youth and their families have been recruited for the study, well over half the participant goal.  Approximately 30 terabytes of data (about three times the size of the Library of Congress collection), obtained from the first 4,500 participants, will be available to scientists worldwide to conduct research on the many factors that influence brain, cognitive, social, and emotional development. The ABCD study is the largest long-term study of brain development and child health in the United States.

Hot Topics: Antacids Taken During Pregnancy Linked to Asthma in Children

Jackie Werner Hot Topics in Research, Pediatrics, Pulmonary

Acid-Suppressive Drug Use During Pregnancy and the Risk of Childhood Asthma: A Meta-analysis

Lai T, Wu M, Liu J, et al. Acid-suppressive drug use during pregnancy and the risk of childhood asthma: A meta-analysis. Pediatrics. 2018. doi: 10.1542/peds.2017-0889.

CONTEXT: The association between acid-suppressive drug exposure during pregnancy and childhood asthma has not been well established.

OBJECTIVE: To conduct a systematic review and meta-analysis on this association to provide further justification for the current studies.

DATA SOURCES: We searched PubMed, Medline, Embase, the Cochrane Database of Systematic Reviews, EBSCO Information Services, Web of Science, and Google Scholar from inception until June 2017.

STUDY SELECTION: Observational studies in which researchers assessed acid-suppressive drug use during pregnancy and the risk of childhood asthma were included.

DATA EXTRACTION: Of 556 screened articles, 8 population-based studies were included in the final analyses.

RESULTS: When all the studies were pooled, acid-suppressive drug use in pregnancy was associated with an increased risk of asthma in childhood (relative risk [RR] = 1.45; 95% confidence interval [CI] 1.35–1.56; I2 = 0%; P < .00001). The overall risk of asthma in childhood increased among proton pump inhibitor users (RR = 1.34; 95% CI 1.18–1.52; I2 = 46%; P < .00001) and histamine-2 receptor antagonist users (RR = 1.57; 95% CI 1.46–1.69; I2 = 0%; P < .00001).

LIMITATIONS: None of the researchers in the studies in this meta-analysis adjusted for the full panel of known confounders in these associations.

CONCLUSIONS: The evidence suggests that prenatal, maternal, acid-suppressive drug use is associated with an increased risk of childhood asthma. This information may help clinicians and parents to use caution when deciding whether to take acid-suppressing drugs during pregnancy because of the risk of asthma in offspring.

Hot Topics: Adolescent Athletes with Limited Hip Range of Motion at Risk for Osteoarthritis

Jackie Werner Hot Topics in Research, Pediatrics, Rheumatology

Cam Deformities and Limited Hip Range of Motion Are Associated With Early Osteoarthritic Changes in Adolescent Athletes: A Prospective Matched Cohort Study

Wyles, C. C., Norambuena, G. A., Howe, B. M., Larson, D. R., Levy, B. A., Yuan, B. J., . . . Sierra, R. J. (2017). Cam deformities and limited hip range of motion are associated with early osteoarthritic changes in adolescent athletes: A prospective matched cohort study. Am J Sports Med, 45(13), 3036-3043. doi:10.1177/0363546517719460

Background:
The natural history of femoroacetabular impingement (FAI) remains incompletely understood. In particular, there is limited documentation of joint damage in adolescent patients with limited range of motion (LROM) of the hip, which is commonly associated with FAI.

Purpose:
To evaluate changes in magnetic resonance imaging (MRI), radiographs, and clinical examinations over 5 years in a group of athletes from a wide variety of sports with asymptomatic LROM of the hip compared with matched controls.

Study Design:
Cohort study (prognosis); Level of evidence, 2.

Methods:
The authors screened 226 male and female athletes aged 12 to 18 years presenting for preparticipation sports physical examinations. Using a goniometer, we identified 13 participants with at least one hip having internal rotation <10° with the hip flexed to 90°. Overall, 21 of 26 hips (81%) had internal rotation <10°. These participants were age- and sex-matched to 13 controls with internal rotation >10°. At the time of enrollment, all participants were asymptomatic and underwent a complete hip examination and radiographic imaging with radiographs (anteroposterior [AP] and von Rosen views) and non-arthrogram MRI. Participants returned at 5-year follow-up and underwent repeat hip examinations, imaging (AP and lateral radiographs and non-arthrogram MRI), and hip function questionnaires. MRI scans were classified as “normal” versus “abnormal” based on the presence of any of 13 scored chondral, labral, or osseous abnormalities. Comparisons between the LROM group and control group were performed using generalized linear models (either linear, logistic, or log-binomial regression as appropriate for the outcome) with generalized estimating equations to account for the within-participant correlation due to patients having both hips included. Relative risk (RR) estimates are reported with 95% CIs.

Results:
At the time of study enrollment, 16 of 26 hips (62%) in the LROM group had abnormal MRI findings within the acetabular labrum or cartilage compared with 8 of 26 hips (31%) in the control group (RR, 2.0; 95% CI, 0.95-4.2; P = .067). The mean alpha angle measured from radial MRI sequences was 58° in the LROM group versus 44° in the control group (P < .0001). In the LROM group, 13 of 26 hips (50%) had a positive anterior impingement sign, whereas 0 of 26 hips (0%) had a positive anterior impingement sign in the control group. At 5-year follow-up, 18 of 19 hips (95%) in the LROM group had abnormal MRI findings compared with 14 of 26 hips (54%) in the control group (RR, 1.7; 95% CI, 1.1-2.7; P = .014). New or progressive findings were documented on MRI in 15 of 20 hips in the LROM group compared with 8 of 26 hips in the control group (RR, 2.4; 95% CI, 1.2-4.8; P = .011). Six of 22 hips (27%) in the LROM group progressed from Tönnis grade 0 to Tönnis grade 1 in degenerative changes, whereas all 26 hips in the control group remained at Tönnis grade 0 on hip radiographs. In the LROM group, 11 of 22 hips (50%) had a positive anterior impingement sign, whereas 1 of 26 hips (4%) had a positive anterior impingement sign in the control group. A cam deformity (alpha angle >55° on lateral radiographs) was present in 20 of 22 hips (91%) in the LROM group and 12 of 26 hips (46%) in the control group (P = .0165). The following variables at baseline were associated with an increased risk of degenerative changes at 5-year follow-up for the entire cohort: decreased hip internal rotation, positive anterior impingement sign, decreased hip flexion, increased alpha angle, and presence of a cam lesion.

Conclusion:
At 5 years, young athletes with LROM of the hip showed increased progressive degenerative changes on MRI and radiographs compared with matched controls. Although the majority of these participants remained asymptomatic, those with features of FAI had radiographic findings consistent with early osteoarthritis. These outcomes suggest that more aggressive screening and counseling of young active patients may be helpful to prevent hip osteoarthritis in those with FAI.