Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: a systematic review and meta-analysis

alexandrossfakianakis shared this article with you from Inoreader Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: a systematic review and meta-analysis via Clinical Infectious Diseases Advance Access Abstract Background Optimal doses of first line drugs for drug-susceptible tuberculosis (DS-TB) treatment in children and young adolescents remain uncertain. We aimed to determine if children treated using WHO-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic exposures. Methods Titles, abstracts, and full-text articles were screened. We searched Pubmed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children <18 years, being treated for DS-TB with rifampicin, pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO, CRD42021274222. Results Of 304 studies identified, 46 studies were eligible for full-text review and 12 and 18 articles were included for the efficacy and pharmacokinetic analysis, respectively. Of 1,830 children in cluded in the efficacy analysis, 82% had favourable outcomes (range 25%-95%). At WHO-recommended doses, exposures to rifampicin, pyrazinamide, and ethambutol were lower in children as compared to adults. Children ≤6 years have 35% lower AUC than older children (14.4 (9.9-18.8) vs 22.0 (13.8-30.1) μg.h/mL) and children with HIV (CWHIV) had 35% lower rifampicin AUC than HIV negative children (17.3 (11.4-23.2) vs 26.5 (21.3-31.7) μg.h/mL). Heterogeneity and small sample sizes were major limitations. Conclusion There is large variability in outcomes with an average 82% favourable outcomes. Drug exposures are lower in children than in adults. Younger children and CWHIV are underexposed to rifampicin. Standardization of pharmacokinetic paediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing. View on Web

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Editorial perspective: Leaving the baby in the bathwater in neurodevelopmental research

alexandrossfakianakis shared this article with you from Inoreader Editorial perspective: Leaving the baby in the bathwater in neurodevelopmental research via Journal of Child Psychology and Psychiatry Neurodevelopmental conditions are characterised by differences in the way children interact with the people and environments around them. Despite extensive investigation, attempts to uncover the brain mechanisms that underpin neurodevelopmental conditions have yet to yield any translatable insights. We contend that one key reason is that psychologists and cognitive neuroscientists study brain function by taking children away from their environment, into a controlled lab setting. Here, we discuss recent research that has aimed to take a different approach, moving away from experimental control through isolation and stimulus manipulation, and towards approaches that embrace the measurement and targeted interrogation of naturalistic, user-defined and complex, multivariate datasets. We review three worked examples (of stress processing, early activity level in ADHD and social brain development in autism) to illustrate how these new approaches might lead t o new conceptual and translatable insights into neurodevelopment. View on Web

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Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma

alexandrossfakianakis shared this article with you from Inoreader Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma via Neuro-Oncology Advance Access Abstract Background Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. Materials and Methods We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. Results VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR=0.70, 95% Confidence Interval 0.54-0.90, p=0.006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR=0.76, 0.66-0.88, p=0.0003). Antibody seropositivity to EBV was separately associated with improved survival (HR=0.71, 0.53-0.96, p=0.028). Antibody positivity to two other common viruses (CMV, HSV) was not associated with altered survival. Conclusions Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings. View on Web

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Contribution of genotypes in Prothrombin and Factor V Leiden to COVID‐19 and disease severity in patients at high risk for hereditary thrombophilia

alexandrossfakianakis shared this article with you from Inoreader Contribution of genotypes in Prothrombin and Factor V Leiden to COVID‐19 and disease severity in patients at high risk for hereditary thrombophilia via Journal of Medical Virology abstract Aim Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. Methods This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a subset of cases (n=4092). This subgroup was age and gender matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. Results The ratio of males (31.08%; 27.01%) and the mean age (36.85 ±15.20; 33.89±14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p<0.05). FVL prevalence, CT positivity rate, history of thrombosis, and Pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p<0.05). Disease severity was mainly affected by Factor V Leiden and not related to genotypes at the Prothrombin mutations. Conclusion Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients. This article is protected by copyright. All rights reserved. View on Web

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Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID‐19 severity

alexandrossfakianakis shared this article with you from Inoreader Title: Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID‐19 severity via Journal of Medical Virology Abstract Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1,469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are seve ral cyclins (CCNs), cell division cycles (CDCs), cyclin-dependent kinases (CDKs), and mini-chromosome maintenance (MCMs) proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and NK cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention. This article is protected by copyright. All rights reserved. View on Web

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Birth weight, gestational age and risk of cardiovascular disease in early adulthood: Influence of familial factors

alexandrossfakianakis shared this article with you from Inoreader Birth weight, gestational age and risk of cardiovascular disease in early adulthood: Influence of familial factors via American Journal of Epidemiology - Advance Access Abstract The association between intrauterine growth restriction (IUGR) and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a bi-national register-based cohort study to assess associations of birthweight for gestational age (GA), a proxy for IUGR, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live non-malformed singleton births in Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up of 10 years from age 18 onwards, 29,742 individuals developed incident CVD (hypertensive, ischemic heart, and cerebrovascular diseases). Compared with individuals born with appropriate birthweight for GA (AGA, 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA, <3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD [HRs (95% CIs): 1.38 (1.32-1.45) and 1 .31 (1.25-1.38), respectively]. The association was attenuated when comparing individuals born SGA with their AGA siblings (1.11, 0.99-1.25), but remained robust when comparing individuals born preterm with their term siblings (1.21, 1.07-1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA. View on Web

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