HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

WHAT'S KNOWN ON THIS SUBJECT: Curtailed sleep in children has been found to be associated with increased cardiovascular disease risk factors, including obesity. Few existing studies have examined measures of adiposity beyond BMI or have examined the effects of being chronically sleep curtailed. WHAT THIS STUDY ADDS:In this cohort of children who had research-level measures of sleep, BMI, total fat mass, and fat mass distribution, we found that chronic sleep curtailment from infancy to age 7 years was associated with higher overall and central adiposity in mid-childhood. abstract OBJECTIVES: To examine the extent to which chronic sleep curtailment from infancy to mid-childhood is associated with total and central adiposity. METHODS:We studied 1046 children participating in a prospective cohort study. At age 6 months and yearly from age 1 to 7 years, mothers reported their children' s sleep duration in a usual 24-hour period. The main exposure was a sleep curtailment score from age 6 months to 7 years. The range of the total score was 0 to 13, where 0 indicated the maximal sleep curtailment and 13 indicated never having curtailed sleep. Outcomes in mid-childhood were BMI z score, dual X-ray absorptiometry total and trunk fat mass index (kg/m 2 ), and waist and hip circumferences (cm). RESULTS:The mean (SD) sleep score was 10.2 (2.7); 4.4% scored a 0 to 4, indicating multiple exposures to sleep curtailment between age 6 months to 7 years, 12.3% scored 5 to 7, 14.1% scored 8 to 9, 28.8% scored 10 to 11, and 40.3% scored 12 to 13. In multivariable models, children who had a sleep score of 0 to 4 had a BMI z score that was 0.48 U (95% confidence interval, 0.13 to 0.83) higher than those who had a sleep score of 12 to 13. We observed similar associations of higher total and trunk fat mass index and waist and hip circumferences, and higher odds of obesity (odds ratio, 2.62; 95% confidence interval, 0.99 to 6.97) among children who had a score of 0 to 4 vs 12 to 13. CONCLUSIONS:Chronic sleep curtailment from infancy to school age was associated with higher overall and central adiposity in midchildhood. Dr Taveras conceptualized and designed the study, obtained funding, and drafted the initial manuscript; Dr Gillman assisted with the conceptualization and design of the study, helped obtain funding, and reviewed and revised the manuscript; Dr Redline assisted with the conceptualization and design of the study, helped obtain funding, and reviewed and revised the manuscript; Ms Peña assisted with the conceptualization of the study exposure definitions and reviewed and revised the manuscript; Ms Shiman carried out the initial analyses and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.www.pediatrics.org/cgi

Chronic sleep curtailment from infancy to mid-childhood was more prevalent among black, Hispanic, and Asian children. These differences were partially but not entirely explained by socio-contextual variables. Independently, children from lower socioeconomic status and those with greater exposures to TV also had greater sleep curtailment.

ObjectiveTo examine associations of chronic insufficient sleep with mid-childhood cardio-metabolic health.Design and methodsAt 6 months and yearly from 1–7 years, mothers participating in the Project Viva cohort reported children’s 24-hour sleep duration. The main exposure was a sleep curtailment score, ranging from 0 (maximal curtailment) to 13 (never having curtailed sleep). The main outcome was a mid-childhood metabolic risk score, derived as the mean of 5 sex- and cohort-specific z-scores for waist circumference, systolic blood pressure, HDL cholesterol (scaled inversely), and log-transformed triglycerides and HOMA-IR; higher scores indicate higher risk.ResultsThe mean (standard deviation [SD]) sleep score was 10.0 (2.8); 5.1% scored 0–4, 13.9% scored 5–7, 14.1% scored 8–9, 28.7% scored 10–11, and 38.3% scored 12–13. Mean (SD, range) metabolic risk score was −0.03 (0.6, −1.8 to 2.6). In multivariable models, the metabolic risk score difference for children with most versus least curtailed sleep was 0.29 units (95% Confidence Interval [CI]: 0.02, 0.57). Further adjustment for mid-childhood BMI-z score attenuated this difference to 0.08 units (95% CI: −0.14, 0.30).ConclusionsChronic insufficient sleep from infancy to school-age was associated with higher mid-childhood metabolic risk. This association was explained by sleep duration’s influence on mid-childhood adiposity.