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IntroductionWe aimed to integrate all available epidemiological evidence to characterise an exposure–response model of ambient fine particulate matter (PM2.5) and the risk of chronic kidney disease (CKD) across the spectrum of PM2.5 concentrations experienced by humans. We then estimated the global and national burden of CKD attributable to PM2.5.MethodsWe collected data from prior studies on the association of PM2.5 with CKD and used an integrative meta-regression approach to build non-linear exposure–response models of the risk of CKD associated with PM2.5 exposure. We then estimated the 2017 global and national incidence, prevalence, disability-adjusted life-years (DALYs) and deaths due to CKD attributable to PM2.5 in 194 countries and territories. Burden estimates were generated by linkage of risk estimates to Global Burden of Disease study datasets.ResultsThe exposure–response function exhibited evidence of an increase in risk with increasing PM2.5 concentrations, where the rate of risk increase gradually attenuated at higher PM2.5 concentrations. Globally, in 2017, there were 3 284 358.2 (95% UI 2 800 710.5 to 3 747 046.1) incident and 122 409 460.2 (108 142 312.2 to 136 424 137.9) prevalent cases of CKD attributable to PM2.5, and 6 593 134.6 (5 705 180.4 to 7 479 818.4) DALYs and 211 019.2 (184 292.5 to 236 520.4) deaths due to CKD attributable to PM2.5. The burden was disproportionately borne by low income and lower middle income countries and exhibited substantial geographic variability, even among countries with similar levels of sociodemographic development. Globally, 72.8% of prevalent cases of CKD attributable to PM2.5 and 74.2% of DALYs due to CKD attributable to PM2.5 were due to concentrations above 10 µg/m3, the WHO air quality guidelines.ConclusionThe global burden of CKD attributable to PM2.5 is substantial, varies by geography and is disproportionally borne by disadvantaged countries. Most of the burden is associated with PM2.5 levels above the WHO guidelines, suggesting that achieving those targets may yield reduction in CKD burden.

Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.

Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)–based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir–ritonavir (LPV–rtv) ARV– or non-nucleoside reverse transcriptase inhibitor nevirapine ARV–treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV–rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV–rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. Autism Res 2016, 9: 513-535. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Background. In 2007, Malawi replaced sulfadoxine-pyrimethamine (SP) with an artemisinin-based combination therapy as the first-line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy. Here we estimate the effect of reduced SP pressure on the prevalence of SP-resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci. Methods. Samples obtained from individuals with clinical malaria during a period of high SP use (1999–2001), a transitional period (2007–2008), and a period of low SP use (2012) were genotyped for resistance markers at pfdhfr-ts codons 51, 59, and 108 and pfdhps codons 437, 540, and 581. Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr-ts and pfdhps. Results. An increase in the prevalence of the resistance haplotypes DHFR 51I/59R/108N and DHPS 437G/540E occurred under sustained drug pressure, with no change in haplotype prevalence 5 years after reduction in SP pressure. The DHPS 437G/540E/581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure. Changes to the sweep characteristics flanking pfdhfr-ts and pfdhps were minimal. Conclusions. In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future.

Background Persistence of sulfadoxine–pyrimethamine (SP) resistance has been described in an urban setting in Malawi where malaria transmission is relatively low. Higher malaria transmission is associated with greater genetic diversity and more frequent genetic recombination, which could lead to a more rapid re-emergence of SP-sensitive parasites, as well as more rapid degradation of selective sweeps. In this study, the impact of local variation in malaria transmission on the prevalence of SP-resistant haplotypes and selective sweep characteristics was investigated at an urban site with low parasite prevalence and two rural sites with moderate and high parasite prevalence. Methods Samples from three sites with different parasite prevalence were genotyped for resistance markers within pfdhfr-ts and pfdhps and at microsatellites flanking these genes. Expected heterozygosity (He) was estimated to evaluate genetic diversity. Results No difference in the prevalence of highly resistant DHFR 51I/59R/108N and DHPS 437G/540E was found between sites. Small differences in He flanking pfdhfr-ts and pfdhps were seen between rural-moderate and the other sites, as well as some shared haplotypes between the rural-high and urban-low sites. Conclusions The results do not show an effect of local variation in malaria transmission, as inferred from parasite prevalence, on SP-resistant haplotype prevalence. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0860-7) contains supplementary material, which is available to authorized users.