Faculty Bibliography

Socioeconomic disadvantage (SED) experienced in early life is linked to a range of risk behaviors and diseases. Neuroimaging research indicates that this association is mediated by functional changes in corticostriatal reward systems that modulate goal-directed behavior, reward evaluation, and affective processing. Existing research has focused largely on adults and within-household measures as an index of SED, despite evidence that broader community-level SED (e.g., neighborhood poverty levels) has significant and sometimes distinct effects on development and health outcomes. Here, we test effects of both household- and community-level SED on resting-state functional connectivity (rsFC) of the ventral striatum (VS) in 100 racially and economically diverse children and adolescents (ages 6-17). We observed unique effects of household income and community SED on VS circuitry such that higher community SED was associated with reduced rsFC between the VS and an anterior region of the medial prefrontal cortex (mPFC), whereas lower household income was associated with increased rsFC between the VS and the cerebellum, inferior temporal lobe, and lateral prefrontal cortex. Lower VS-mPFC rsFC was also associated with higher self-reported anxiety symptomology, and rsFC mediated the link between community SED and anxiety. These results indicate unique effects of community-level SED on corticostriatal reward circuitry that can be detected in early life, which carries implications for future interventions and targeted therapies. In addition, our findings raise intriguing questions about the distinct pathways through which specific sources of SED can affect brain and emotional development.

Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry-derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = -0.05, p = 3.9 × 10^-10 ), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10^-11 ) and near RAB11FIP5 (rs58649746, p = 4.8 × 10^-9 ) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton. © 2017 American Society for Bone and Mineral Research.

BACKGROUND:Sleep disturbances, in particular insomnia, represent a common problem in children with neurodevelopmental disabilities (NDDs). Currently, there are no approved medications for insomnia in children by the US Food and Drug Administration or European Medicines Agency and therefore they are prescribed off-label. We critically reviewed pediatric literature on drugs as well as nonpharmacological (behavioral) interventions used for sleep disturbances in children with NDDs. METHODS:, and Embase), and Web of Knowledge databases were searched through February 12, 2017, with no language restrictions. Two authors independently and blindly performed the screening. RESULTS:Good sleep practices and behavioral interventions, supported by moderate-to-low level evidence, are the first recommended treatments for pediatric insomnia but they are often challenging to implement. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice but evidence supporting their use is still limited. An increasing body of evidence supports melatonin as the safest choice for children with NDDs. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Only few studies have been carried out in children's and adolescents' zolpidem, zaleplon, and eszopiclone, with contrasting results. Limited evidence supports the use of alpha-agonists such as clonidine to improve sleep onset latency, especially in attention deficit/hyperactivity disorder subjects. Tricyclic antidepressants, used in adults with insomnia, are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies. CONCLUSIONS:Here, we provided a tentative guide for the use of drugs for insomnia in children with NDDs. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy, effectiveness, and safety of the currently prescribed pediatric sleep medicines in children with NDDs.

Specialized proresolving mediators (SPMs) decrease NF-κB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-κB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A₄ (15-epi-LXA₄), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-κB regulators A20 and single Ig IL-1R-related molecule (SIGIRR). Of interest, 15-epi-LXA₄ induced A20 and SIGIRR in an lipoxin A₄ receptor/formyl peptide receptor 2 (ALX/FPR2) receptor-dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-κB-induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA₄ also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-κB activity and to establish mechanisms for NF-κB regulation by SPMs for pneumonia resolution.

The experience of traumatizing events and resulting posttraumatic stress disorder (PTSD) symptomology relates to a range of impulsive behaviors. While both PTSD and impulsivity are heterogeneous and multidimensional constructs, no research has used person-centered approaches to examine subgroups of individuals based on these response endorsements. Hence, our study examined PTSD-impulsivity typologies and their construct validity in two samples: university students (n = 412) and community participants recruited through Amazon's MTurk (n = 346). Measures included the Stressful Life Events Screening Questionnaire (PTEs), PTSD Checklist for DSM-5 (PTSD severity), UPPS Impulsive Behavior Scale (negative urgency, lack of premeditation, lack of perseverance, sensation seeking). Dimensions of Anger Reaction Scale (anger), and the Patient Health Questionnaire-9 (depression). For both samples, results of latent profile analyses indicated a best-fitting 3-class solution: High, Moderate, and Low PTSD-Negative Urgency. Negative urgency was the most distinguishing impulsivity facet. Anger and depression severity significantly predicted membership in the more severe symptomatology classes. Thus, individuals can be meaningfully categorized into three subgroups based on PTSD and impulsivity item endorsements. We provide some preliminary evidence for a negative urgency subtype of PTSD characterized by greater depression and anger regulation difficulties; and underscore addressing emotional regulation skills for these subgroup members.

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OBJECTIVE:Adverse cross-cultural interactions are a persistent problem within medicine impacting minority patients' use of services and health outcomes. To test whether 1) enhancing the evidence-based Physician Asthma Care Education (PACE), a continuing medical education program, with cross cultural communication training (PACE Plus) would improve the asthma outcomes of African American and Latino/Hispanic children; and 2) whether PACE is effective in diverse groups of children. METHODS:A three-arm randomized control trial was used to compare PACE Plus, PACE, and usual care. Participants were primary care physicians (n = 112) and their African American or Latino/Hispanic pediatric patients with persistent asthma (n = 867). The primary outcome of interest included changes in emergency department visits for asthma overtime, measured at baseline, and 9 and 21 months following the intervention. Other outcomes included hospitalizations, asthma symptom experience, caregiver asthma-related quality of life, and patient-provider communication measures. RESULTS:Over the long term, PACE Plus physicians reported significant improvements in confidence and use of patient-centered communication and counseling techniques (p < 0.01) compared to PACE physicians. No other significant benefit in primary and secondary outcomes was observed in this trial. CONCLUSION/CONCLUSIONS:PACE Plus did not show significant benefit in asthma-specific clinical outcomes. More trials and multi-component strategies continue to be needed to address complex risk factors and reduce disparities in asthma care. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov: NCT01251523 December 1, 2010.

Complementing long-standing traditions centered on histology, fMRI approaches are rapidly maturing in delineating brain areal organization at the macroscale. The non-human primate (NHP) provides the opportunity to overcome critical barriers in translational research. Here, we establish the data requirements for achieving reproducible and internally valid parcellations in individuals. We demonstrate that functional boundaries serve as a functional fingerprint of the individual animals and can be achieved under anesthesia or awake conditions (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher-order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHPs, provide insights into the impact of scan state, and motivate efforts toward harmonizing protocols.

Background:The declining transition rate to psychotic disorder and the increasing rate of nonpsychotic poor outcomes among subjects at clinical high risk (CHR) for psychosis have increased the need for biomarkers to predict remission regardless of transition. This study investigated whether mismatch negativity (MMN) predicts the prognosis of CHR individuals during a 6-year follow-up period. Methods:A total of 47 healthy control (HC) subjects and 48 subjects at CHR for psychosis participated in the MMN assessment. The clinical statuses of the CHR subjects were examined at baseline and regularly for up to 6 years. The CHR subjects were divided into remitter and nonremitter groups, and the baseline MMN amplitudes and latencies were compared across the remitter, nonremitter, and HC groups. Regression analyses were performed to identify the predictive factors of remission, the improvement of attenuated positive symptoms, and functional recovery. Results:CHR nonremitters showed reduced MMN amplitudes at baseline compared to CHR remitters and HC subjects. A logistic regression analysis revealed that the baseline MMN amplitude at the frontal electrode site was the only significant predictor of remission. In a multiple regression analysis, the MMN amplitude, antipsychotic use, and years of education predicted an improvement in attenuated positive symptoms. The MMN amplitude at baseline predicted functional recovery. Conclusions:These results suggest that MMN is a putative predictor of prognosis regardless of the transition to psychotic disorder in subjects at CHR. Early prognosis prediction and the provision of appropriate interventions based on the initial CHR status might be aided using MMN.