The diagnosis and medical management of tuberculous meningitis in adults

Tuberculous meningitis (TBM) is a medical emergency for which tuberculosis (TB) treatment should be initiated as soon as possible after diagnosis. Owing to the low diagnostic yields of confirmatory tests, TBM is often diagnosed based on suggestive clinical and cerebrospinal fluid findings, evidence for TB outside the central nervous system (CNS), typical brain imaging features and exclusion of other causes of meningitis. TB drug regimens used in TBM may be suboptimal as they are informed by studies of TB outside the CNS, rather than being based on randomised controlled trials in TBM. TBM has a high mortality and the management of HIV-co-infected patients is further complicated by neurological TB-immune reconstitution inflammatory syndrome (IRIS), which frequently occurs after starting antiretroviral therapy (ART) during TBM treatment and contributes to the poor outcome in HIV-associated TBM. HIV-infected TBM patients due to start ART should be counselled about the risk of developing neurological TB-IRIS, typical symptoms that could be expected and need to return to hospital should any of these develop. Currently, the only evidence-based treatment for TB-IRIS is with corticosteroids, which should be considered in all cases of neurological TB-IRIS

Air Pollution and Climate Forcing of the Charcoal Industry in Africa

The demand for charcoal in Africa is growing rapidly, driven by urbanization and lack of access to electricity. Charcoal production and use, including plastic burning to initiate combustion, release large quantities of trace gases and particles that impact air quality and climate. Here, we develop an inventory of current (2014) and future (2030) emissions from the charcoal supply chain in Africa that we implement in the GEOS-Chem model to quantify the contribution of charcoal to surface concentrations of PM2.5 and ozone and direct radiative forcing due to aerosols and ozone. We estimate that the charcoal industry in 2014 required 140–460 Tg of biomass and 260 tonnes of plastic and that industry emissions could double by 2030, so that methane emissions from the charcoal industry could outcompete those from open fires by 2025. In 2014, the largest enhancements in PM2.5 (0.5–1.4 μg m–3) and ozone (0.4–0.7 ppbv) occur around the densely populated cities in East and West Africa. Cooling due to aerosols (−100 to −300 mW m–2) is concentrated over dense cities, whereas warming due to ozone is widespread, peaking at 4.2 mW m–2 over the Atlantic Ocean. These effects will worsen with ongoing dependence on this energy source, spurred by rapid urbanization and absence of viable cleaner alternatives

Short communications: The first documented record of Western Reef Heron Egretta (gularis) schistacea for Tanzania

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Natural variation in abiotic stress responsive gene expression and local adaptation to climate in Arabidopsis thaliana.

Gene expression varies widely in natural populations, yet the proximate and ultimate causes of this variation are poorly known. Understanding how variation in gene expression affects abiotic stress tolerance, fitness, and adaptation is central to the field of evolutionary genetics. We tested the hypothesis that genes with natural genetic variation in their expression responses to abiotic stress are likely to be involved in local adaptation to climate in Arabidopsis thaliana. Specifically, we compared genes with consistent expression responses to environmental stress (expression stress responsive, "eSR") to genes with genetically variable responses to abiotic stress (expression genotype-by-environment interaction, "eGEI"). We found that on average genes that exhibited eGEI in response to drought or cold had greater polymorphism in promoter regions and stronger associations with climate than those of eSR genes or genomic controls. We also found that transcription factor binding sites known to respond to environmental stressors, especially abscisic acid responsive elements, showed significantly higher polymorphism in drought eGEI genes in comparison to eSR genes. By contrast, eSR genes tended to exhibit relatively greater pairwise haplotype sharing, lower promoter diversity, and fewer nonsynonymous polymorphisms, suggesting purifying selection or selective sweeps. Our results indicate that cis-regulatory evolution and genetic variation in stress responsive gene expression may be important mechanisms of local adaptation to climatic selective gradients

Critical Values for Yen’s Q3: Identification of Local Dependence in the Rasch model using Residual Correlations

The assumption of local independence is central to all IRT models. Violations can lead to inflated estimates of reliability and problems with construct validity. For the most widely used fit statistic Q3 there are currently no well-documented suggestions of the critical values which should be used to indicate local dependence, and for this reason a variety of arbitrary rules of thumb are used. In this study, we used an empirical data example and Monte Carlo simulation to investigate the different factors that can influence the null distribution of residual correlations, with the objective of proposing guidelines that researchers and practitioners can follow when making decisions about local dependence during scale development and validation. We propose that a parametric bootstrapping procedure should be implemented in each separate situation in order to obtain the critical value of local dependence applicable to the data set, and provide example critical values for a number of data structure situations. The results show that for the Q3 fit statistic no single critical value is appropriate for all situations, as the percentiles in the empirical null distribution are influenced by the number of items, the sample size, and the number of response categories. Furthermore, our results show that local dependence should be considered relative to the average observed residual correlation, rather than to a uniform value, as this results in more stable percentiles for the null distribution of an adjusted fit statistic

Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting

Ensuring the Involvement of Children in the Evaluation of New Tuberculosis Treatment Regimens

William Burman and colleagues review the barriers to involving children in studies of new tuberculosis treatments and recommend strategies for overcoming these barriers