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Category: Pediatrics

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.

Hot Topics: Shaming Overweight Children is Harmful

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

Stigma Experienced by Children and Adolescents With Obesity

Pont, S. J., Puhl, R., Cook, S. R., Slusser, W., Section on Obesity , & The Obesity Society. (2017). Stigma experienced by children and adolescents with obesity. Pediatrics, doi:10.1542/peds.2017-3034

The stigmatization of people with obesity is widespread and causes harm. Weight stigma is often propagated and tolerated in society because of beliefs that stigma and shame will motivate people to lose weight. However, rather than motivating positive change, this stigma contributes to behaviors such as binge eating, social isolation, avoidance of health care services, decreased physical activity, and increased weight gain, which worsen obesity and create additional barriers to healthy behavior change. Furthermore, experiences of weight stigma also dramatically impair quality of life, especially for youth. Health care professionals continue to seek effective strategies and resources to address the obesity epidemic; however, they also frequently exhibit weight bias and stigmatizing behaviors. This policy statement seeks to raise awareness regarding the prevalence and negative effects of weight stigma on pediatric patients and their families and provides 6 clinical practice and 4 advocacy recommendations regarding the role of pediatricians in addressing weight stigma. In summary, these recommendations include improving the clinical setting by modeling best practices for nonbiased behaviors and language; using empathetic and empowering counseling techniques, such as motivational interviewing, and addressing weight stigma and bullying in the clinic visit; advocating for inclusion of training and education about weight stigma in medical schools, residency programs, and continuing medical education programs; and empowering families to be advocates to address weight stigma in the home environment and school setting.

Hot Topics: Mothers with Anti-Vaccine Friends and Family Delay Babies’ Shots

Jackie Werner Hot Topics in Research, Pediatrics

Vaccine Education During Pregnancy and Timeliness of Infant Immunization

Veerasingam P, Grant CC, Chelimo C, et al. Vaccine education during pregnancy and timeliness of infant immunization. Pediatrics. 2017. doi: 10.1542/peds.2016-3727

OBJECTIVES: Pregnant women routinely receive information in support of or opposing infant immunization. We aimed to describe immunization information sources of future mothers’ and determine if receiving immunization information is associated with infant immunization timeliness.

METHODS: We analyzed data from a child cohort born 2009–2010 in New Zealand. Pregnant women (N = 6822) at a median gestation of 39 weeks described sources of information encouraging or discouraging infant immunization. Immunizations received by cohort infants were determined through linkage with the National Immunization Register (n = 6682 of 6853 [98%]). Independent associations of immunization information received with immunization timeliness were described by using adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

RESULTS: Immunization information sources were described by 6182 of 6822 (91%) women. Of these, 2416 (39%) received information encouraging immunization, 846 (14%) received discouraging information, and 565 (9%) received both encouraging and discouraging information. Compared with infants of women who received no immunization information (71% immunized on-time), infants of women who received discouraging information only (57% immunized on time, OR = 0.49, 95% CI 0.38–0.64) or encouraging and discouraging information (61% immunized on time, OR = 0.51, 95% CI 0.42–0.63) were at decreased odds of receiving all immunizations on time. Receipt of encouraging information only was not associated with infant immunization timeliness (73% immunized on time, OR = 1.00, 95% CI 0.87–1.15).

CONCLUSIONS: Receipt, during pregnancy, of information against immunization was associated with delayed infant immunization regardless of receipt of information supporting immunization. In contrast, receipt of encouraging information is not associated with infant immunization timeliness.

Hot Topics: Customized 3-D Models Effectively Train Children’s Surgeons

Jackie Werner Hot Topics in Research, Pediatrics, Surgery

Patient-specific 3D models aid planning for triplane proximal femoral osteotomy in slipped capital femoral epiphysis

Cherkasskiy L, Caffrey JP, Szewczyk AF, et al. Patient-specific 3D models aid planning for triplane proximal femoral osteotomy in slipped capital femoral epiphysis. J Child Orthop. 2017;11(2):147-153. https://doi.org/10.1302/1863-2548-11-170277.

Purpose
Slipped capital femoral epiphysis (SCFE) can result in a complex three-dimensional (3D) deformity of the proximal femur. A three-plane proximal femoral osteotomy (TPFO) has been described to improve hip mechanics. The purpose of this study was to evaluate the benefits of using 3D print technology to aid in surgical planning.

Patients and Methods
Fifteen children treated with TPFO for symptomatic proximal femoral deformity due to SCFE were included in this study. Ten patients were treated by a single surgeon with (model group, n = 5) or without (no-model group, n = 5) a 3D model for pre-operative planning, and compared with patients treated by two senior partners without the use of a model (senior group, n = 5) to evaluate for a learning curve. Peri-operative data including patient body mass index (BMI), surgical time and fluoroscopy time were recorded.

Results
Children in all three groups had similar BMIs at the time of the TPFO. Post-operative radiographic parameters were equally improved in all three groups. On average, surgical time decreased by 45 minutes and 38 minutes, and fluoroscopy time decreased by 50% and 25%, in the model group compared with the no-model and senior groups, respectively.

Conclusions
Patient-specific 3D models aid in surgical planning for complex 3D orthopaedic deformities by enabling practice of osteotomies. Results suggest that 3D models may decrease surgical time and fluoroscopy time while allowing for similar deformity correction. These models may be especially useful to overcome steep learning curves for complex procedures or in trainee education through mock surgical procedures.

Hot Topics: SIDS Infants Show High Levels of Serotonin in Blood

Jackie Werner Hot Topics in Research, Pediatrics

High serum serotonin in sudden infant death syndrome

Haynes RL, Frelinger AL, Giles EK, et al. High serum serotonin in sudden infant death syndrome. Proceedings of the National Academy of Sciences. 2017. doi: 10.1073/pnas.1617374114.

Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon postmortem investigation. Previously, we reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL] (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum 5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.

Mental Health of Transgender Children Who Are Supported in Their Identities

PJ Grier Hot Topics in Research, March, Pediatrics

Mental Health of Transgender Children Who Are Supported in Their Identities

OBJECTIVE: Transgender children who have socially transitioned, that is, who identify as the gender “opposite” their natal sex and are supported to live openly as that gender, are increasingly visible in society, yet we know nothing about their mental health. Previous work with children with gender identity disorder (GID; now termed gender dysphoria) has found remarkably high rates of anxiety and depression in these children. Here we examine, for the first time, mental health in a sample of socially transitioned transgender children.

METHODS: A community-based national sample of transgender, prepubescent children (n= 73, aged 3–12 years), along with control groups of nontransgender children in the same age range (n = 73 age- and gender-matched community controls; n = 49 sibling of transgender participants), were recruited as part of the TransYouth Project. Parents completed anxiety and depression measures.

RESULTS: Transgender children showed no elevations in depression and slightly elevated anxiety relative to population averages. They did not differ from the control groups on depression symptoms and had only marginally higher anxiety symptoms.

CONCLUSIONS: Socially transitioned transgender children who are supported in their gender identity have developmentally normative levels of depression and only minimal elevations in anxiety, suggesting that psychopathology is not inevitable within this group. Especially striking is the comparison with reports of children with GID; socially transitioned transgender children have notably lower rates of internalizing psychopathology than previously reported among children with GID living as their natal sex.

 

Kristina R. Olson, Lily Durwood, Madeleine DeMeules, Katie A. McLaughlin

Copyright © 2016 by the American Academy of Pediatrics

March 2016, VOLUME 137 / ISSUE 3