Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

Background and Objective: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. // Methods: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure–safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. // Results: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure–safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. // Conclusions: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization

Activation of JNK Signaling Mediates Amyloid-ß-Dependent Cell Death

Alzheimer's disease (AD) is an age related progressive neurodegenerative disorder. One of the reasons for Alzheimer's neuropathology is the generation of large aggregates of Aß42 that are toxic in nature and induce oxidative stress, aberrant signaling and many other cellular alterations that trigger neuronal cell death. However, the exact mechanisms leading to cell death are not clearly understood.We employed a Drosophila eye model of AD to study how Aß42 causes cell death. Misexpression of higher levels of Aß42 in the differentiating photoreceptors of fly retina rapidly induced aberrant cellular phenotypes and cell death. We found that blocking caspase-dependent cell death initially blocked cell death but did not lead to a significant rescue in the adult eye. However, blocking the levels of c-Jun NH(2)-terminal kinase (JNK) signaling pathway significantly rescued the neurodegeneration phenotype of Aß42 misexpression both in eye imaginal disc as well as the adult eye. Misexpression of Aß42 induced transcriptional upregulation of puckered (puc), a downstream target and functional read out of JNK signaling. Moreover, a three-fold increase in phospho-Jun (activated Jun) protein levels was seen in Aß42 retina as compared to the wild-type retina. When we blocked both caspases and JNK signaling simultaneously in the fly retina, the rescue of the neurodegenerative phenotype is comparable to that caused by blocking JNK signaling pathway alone.Our data suggests that (i) accumulation of Aß42 plaques induces JNK signaling in neurons and (ii) induction of JNK contributes to Aß42 mediated cell death. Therefore, inappropriate JNK activation may indeed be relevant to the AD neuropathology, thus making JNK a key target for AD therapies

Giant Modulation of Refractive Index from Correlated Disorder

Correlated disorder has been shown to enhance and modulate magnetic, electrical, dipolar, electrochemical and mechanical properties of materials. However, the possibility of obtaining novel optical and opto-electronic properties from such correlated disorder remains an open question. Here, we show unambiguous evidence of correlated disorder in the form of anisotropic, sub-angstrom-scale atomic displacements modulating the refractive index tensor and resulting in the giant optical anisotropy observed in BaTiS3, a quasi-one-dimensional hexagonal chalcogenide. Single crystal X-ray diffraction studies reveal the presence of antipolar displacements of Ti atoms within adjacent TiS6 chains along the c-axis, and three-fold degenerate Ti displacements in the a-b plane. 47/49Ti solid-state NMR provides additional evidence for those Ti displacements in the form of a three-horned NMR lineshape resulting from low symmetry local environment around Ti atoms. We used scanning transmission electron microscopy to directly observe the globally disordered Ti a-b plane displacements and find them to be ordered locally over a few unit cells. First-principles calculations show that the Ti a-b plane displacements selectively reduce the refractive index along the ab-plane, while having minimal impact on the refractive index along the chain direction, thus resulting in a giant enhancement in the optical anisotropy. By showing a strong connection between correlated disorder and the optical response in BaTiS3, this study opens a pathway for designing optical materials with high refractive index and functionalities such as a large optical anisotropy and nonlinearity.Comment: 24 pages, 3 figure

Redox-Induced Src Kinase and Caveolin-1 Signaling in TGF-β1-Initiated SMAD2/3 Activation and PAI-1 Expression

Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-β1. Identification of molecular events underlying to PAI-1 induction in response to TGF-β1 may yield novel targets for the therapy of cardiovascular disease.Reactive oxygen species are generated within 5 minutes after addition of TGF-β1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60(c-src) activation and PAI-1 expression. TGF-β1-stimulated Src kinase signaling sustained the duration (but not the initiation) of SMAD3 phosphorylation in VSMC by reducing the levels of PPM1A, a recently identified C-terminal SMAD2/3 phosphatase, thereby maintaining SMAD2/3 in an active state with retention of PAI-1 transcription. The markedly increased PPM1A levels in triple Src kinase (c-Src, Yes, Fyn)-null fibroblasts are consistent with reductions in both SMAD3 phosphorylation and PAI-1 expression in response to TGF-β1 compared to wild-type cells. Activation of the Rho-ROCK pathway was mediated by Src kinases and required for PAI-1 induction in TGF-β1-stimulated VSMCs. Inhibition of Rho-ROCK signaling blocked the TGF-β1-mediated decrease in nuclear PPM1A content and effectively attenuated PAI-1 expression. TGF-β1-induced PAI-1 expression was undetectable in caveolin-1-null cells, correlating with the reduced Rho-GTP loading and SMAD2/3 phosphorylation evident in TGF-β1-treated caveolin-1-deficient cells relative to their wild-type counterparts. Src kinases, moreover, were critical upstream effectors of caveolin-1(Y14) phosphoryation and initiation of downstream signaling.TGF-β1-initiated Src-dependent caveolin-1(Y14) phosphorylation is a critical event in Rho-ROCK-mediated suppression of nuclear PPM1A levels maintaining, thereby, SMAD2/3-dependent transcription of the PAI-1 gene

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of Neonatal Nutrition Interventions on Neonatal Mortality and Child Health and Development Outcomes: A Systematic Review

Background The last two decades have seen a significant decrease in mortality for children \u3c 5 years of age in low and middle‐income countries (LMICs); however, neonatal (age, 0–28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs. Objectives To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period. Search Methods We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019. Selection Criteria We aimed to include randomized and quasi‐experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate. Data Collection and Analysis Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all‐cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta‐analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main Results Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low‐ and middle‐income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea‐Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all‐cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90–1.08; six studies with 126,548 participants, statistical heterogeneity I2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89–1.07; 12 studies with 154,940 participants, statistical heterogeneity I2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94–1.14; eight studies with 118,376 participants, statistical heterogeneity I2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12–2.09; six studies with 100,256 participants, statistical heterogeneity I2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty‐three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born \u3c 37 weeks gestation) and/or low birth weight (\u3c 2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all‐cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66–0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I2 0%, funnel plot symmetrical, GRADE quality high). Twenty‐nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35–0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I2 24%, funnel plot symmetrical, GRADE quality high). Twenty‐one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70–0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I2 23%, funnel plot symmetrical, GRADE quality high). Authors\u27 Conclusions Vitamin A supplementation during the neonatal period does not reduce all‐cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi‐experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all‐cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in‐home/community setting in LMICs

Health risk behaviours among adolescents in the English-speaking Caribbean: a review

<p>Abstract</p> <p>Background</p> <p>The aim of this paper was to review and summarize research on prevalence of health risk behaviours, their outcomes as well as risk and protective factors among adolescents in the English-speaking Caribbean.</p> <p>Methods</p> <p>Searching of online databases and the World Wide Web as well as hand searching of the <it>West Indian Medical Journal </it>were conducted. Papers on research done on adolescents aged 10 – 19 years old and published during the period 1980 – 2005 were included.</p> <p>Results</p> <p>Ninety-five relevant papers were located. Five papers were published in the 1980s, 47 in the 1990s, and from 2000–2005, 43 papers. Health risk behaviours and outcomes were divided into seven themes. Prevalence data obtained for these, included lifetime prevalence of <b>substance use</b>: cigarettes-24% and marijuana-17%; <b>high risk sexual behaviour</b>: initiation of sexual activity ≤ 10 years old-19% and those having more than six partners-19%; <b>teenage pregnancy</b>: teens account for 15–20% of all pregnancies and one-fifth of these teens were in their second pregnancy; <b>Sexually-Transmitted Infections (STIs)</b>: population prevalence of gonorrhoea and/or chlamydia in 18–21 year-olds was 26%; <b>mental health</b>: severe depression in the adolescent age group was 9%, and attempted suicide-12%; <b>violence and juvenile delinquency</b>: carrying a weapon to school in the last 30 days-10% and almost always wanting to kill or injure someone-5%; <b>eating disorders and obesity</b>: overweight-11%, and obesity-7%. Many of the risk behaviours in adolescents were shown to be related to the adolescent's family of origin, home environment and parent-child relationships. Also, the protective effects of family and school connectedness as well as increased religiosity noted in studies from the United States were also applicable in the Caribbean.</p> <p>Conclusion</p> <p>There is a substantial body of literature on Caribbean adolescents documenting prevalence and correlates of health risk behaviours. Future research should emphasize the designing and testing of interventions to alleviate this burden.</p