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Children who spend their early lives in institutions experience profound psychosocial deprivation that is associated with altered stress response system development. Here, we used data from a longitudinal randomized controlled trial of foster care for institutionally reared children to examine whether caregiving quality and stressful life events (SLEs) in early adolescence (age 12) influence patterns of hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity. Controlling for the effect of institutional care, higher caregiving quality at age 12 was associated with heightened cortisol and SNS reactivity. However, moderation analysis revealed that the latter effect was only observed among never-institutionalized children, whereas ever-institutionalized children demonstrated a persistently blunted SNS response regardless of recent caregiving quality. Among institutionally reared children, SLEs interacted with prior random assignment to foster care, such that those placed in foster care early in development had a SNS response that approximated never-institutionalized children when SLEs at age 12 were low. In contrast, SNS reactivity was persistently blunted among those with prolonged deprivation, regardless of recent SLEs. Early-life deprivation is associated with persistent blunting of stress response systems, but normalization may be achievable if SLEs are limited following placement into enriched family-based care.
Early adversity has been shown to sensitize individuals to the effects of later stress and enhance risk of psychopathology. Using a longitudinal randomized trial of foster care as an alternative to institutional care, we extend the stress sensitization hypothesis to examine whether early institutional rearing sensitizes individuals to stressful events in adolescence engendering chronic low-grade inflammation. At baseline, institutionalized children in Romania (ages 6–31 months) were randomly assigned to foster care or to remain in usual care within institutions. A group of never-institutionalized children was recruited as an in-country comparison sample. At ages 12 and 16, participants reported stressful events. At age 16, Interleukin-6 (IL-6) and C-reactive protein (CRP) were derived from blood spots. Among children assigned to care as usual, more stressful events at age 12, but not age 16, were associated with higher IL-6. In the same group, stressful events at age 16 were associated with higher CRP, though these effects attenuated after adjusting for covariates. These associations were not observed in the foster care or never-institutionalized groups. The findings suggest that heightened inflammation following stress exposure is one pathway through which early neglect could compromise physical health. In contrast, early family care might buffer against these risks.
Adverse developmental outcomes for some children following institutional care are well established. Removal from institutional care and placement into families can promote recovery. However, little is known about how positive outcomes are sustained across adolescence among children with histories of severe deprivation. The present study examined the caregiving conditions that are associated with attaining and maintaining competent functioning (i.e., outcomes within typical levels) from middle childhood to adolescence following exposure to early institutional care. The participants included children with and without a history of institutional care who had competence assessed at ages 8, 12, and 16 years across seven domains: family relationships, peer relationships, academic performance, physical health, mental health, substance use (ages 12 and 16 years only), and risk-taking behavior. The participants were grouped based on whether they were always versus not always competent and never versus ever competent at ages 8 through 16 years. Adolescents with a history of institutional care were less likely to be consistently competent than those who were family reared. Among those who were exposed to early institutional rearing, maintaining competent functioning from 8 to 16 years was associated with spending less time in institutions and receiving higher-quality caregiving early in life. Ensuring high quality early caregiving may promote competent functioning following early deprivation.
Children reared in institutions experience profound deprivation that is associated with both heightened levels of psychopathology and deficits in executive functioning (EF). It is unclear whether deficits in EF among institutionally-reared children serve as a vulnerability factor that increases risk for later psychopathology. It is also unclear whether this putative association between EF and psychopathology is transdiagnostic (i.e. cuts across domains of psychopathology), or specific to a given syndrome. Thus, we examined whether global deficits in EF mediate the association between severe childhood neglect and general v. specific psychopathology in adolescence.
The sample consisted of 188 children from the Bucharest Early Intervention Project, a longitudinal study examining the brain and behavioral development of children reared in Romanian institutions and a comparison group of never-institutionalized children. EF was assessed at age 8, 12, and 16 using a well-validated measure of neuropsychological functioning. Psychopathology was measured as general (P) and specific internalizing (INT) and externalizing (EXT) factors at age 12 and 16.
Institutionally-reared children had lower global EF and higher general psychopathology (P) at all ages compared to never-institutionalized children. Longitudinal path analysis revealed that the effect of institutionalization on P at age 16 operated indirectly through poorer EF from ages 8 to 12. No indirect effects involving EF were observed for INT or EXT at age 16.
We conclude that stable, global deficits in EF serve as a cognitive endophenotype that increases transdiagnostic vulnerability to psychopathology in adolescence among those who have experienced profound early neglect.
OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.