The relative fitness of drug-resistant Mycobacterium tuberculosis: a modelling study of household transmission in Peru.

The relative fitness of drug-resistant versus susceptible bacteria in an environment dictates resistance prevalence. Estimates for the relative fitness of resistant Mycobacterium tuberculosis (Mtb) strains are highly heterogeneous and mostly derived from in vitro experiments. Measuring fitness in the field allows us to determine how the environment influences the spread of resistance. We designed a household structured, stochastic mathematical model to estimate the fitness costs associated with multidrug resistance (MDR) carriage in Mtb in Lima, Peru during 2010-2013. By fitting the model to data from a large prospective cohort study of TB disease in household contacts, we estimated the fitness, relative to susceptible strains with a fitness of 1, of MDR-Mtb to be 0.32 (95% credible interval: 0.15-0.62) or 0.38 (0.24-0.61), if only transmission or progression to disease, respectively, was affected. The relative fitness of MDR-Mtb increased to 0.56 (0.42-0.72) when the fitness cost influenced both transmission and progression to disease equally. We found the average relative fitness of MDR-Mtb circulating within households in Lima, Peru during 2010-2013 to be significantly lower than concurrent susceptible Mtb If these fitness levels do not change, then existing TB control programmes are likely to keep MDR-TB prevalence at current levels in Lima, Peru

Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome.

Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs

A systematic review of tuberculosis detection and prevention studies in prisons

Many studies have demonstrated that prisons are hotspots of tuberculosis disease and transmission. Despite this, it remains unclear which interventions are most effective at controlling tuberculosis in prisons. The objective was to determine the study designs used to investigate tuberculosis control in prisons, and the efficacy of interventions undertaken. This systematic review included published studies which had the aim of reducing TB incidence or prevalence, or increasing the number of people screened for active pulmonary tuberculosis in incarcerated populations. 2,429 records were identified, 178 full-text articles were screened, and 17 studies included. The majority of reports were before/after or prospective non-comparative studies. The median study duration was 23 months (range 5-144). The most common intervention was the introduction of active case finding (10/17 studies) but the timing and methods varied. Comparable pre- and post intervention outcome values were infrequently reported; therefore, it was not possible to quantify the efficacy of interventions. Data from studies of tuberculosis control in prisons is limited by a lack of: controlled interventions, reporting of pre-intervention methods, and comparable pre- and post-intervention outcomes. Prospective comparative trials of adequate duration to determine trends in incidence are necessary to understand which interventions are effective in prisons

On the total curvatures of a tame function

Given a definable function f, enough differentiable, we study the continuity of the total curvature function t --> K(t), total curvature of the level {f=t}, and the total absolute curvature function t-->|K| (t), total absolute curvature of the level {f=t}. We show they admits at most finitely many discontinuities

Characterization of non-aged and aged modern Prussian Blue pigments by Mössbauer spectroscopy, x-ray powder diffraction and x-ray absorption spectroscopy

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Developmental Fluoride Neurotoxicity: A Systematic Review and Meta-Analysis

Background: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children’s neurodevelopment. Objective: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development. Methods: We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, because many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using random-effects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg’s funnel plot, and Egger test to assess publication bias, and conducted meta-regressions to explore sources of variation in mean differences among the studies. Results: The standardized weighted mean difference in IQ score between exposed and reference populations was –0.45 (95% confidence interval: –0.56, –0.35) using a random-effects model. Thus, children in high-fluoride areas had significantly lower IQ scores than those who lived in low-fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease. Conclusions: The results support the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. Future research should include detailed individual-level information on prenatal exposure, neurobehavioral performance, and covariates for adjustment

Large K-exciton dynamics in GaN epilayers: the non-thermal and thermal regime

We present a detailed investigation concerning the exciton dynamics in GaN epilayers grown on c-plane sapphire substrates, focussing on the exciton formation and the transition from the nonthermal to the thermal regime. The time-resolved kinetics of LO-phonon replicas is used to address the energy relaxation in the excitonic band. From ps time-resolved spectra we bring evidence for a long lasting non-thermal excitonic distribution which accounts for the rst 50 ps. Such a behavior is con rmed in di erent experimental conditions, both when non-resonant and resonant excitation are used. At low excitation power density the exciton formation and their subsequent thermalization is dominated by impurity scattering rather than by acoustic phonon scattering. The estimate of the average energy of the excitons as a function of delay after the excitation pulse provides information on the relaxation time, which describes the evolution of the exciton population to the thermal regime.Comment: 9 pages,8 figure

Critical impact of Ehrlich-Schwöbel barrier on GaN surface morphology during homoepitaxial growth

We discuss the impact of kinetics, and in particular the effect of the Ehrlich-Schwöbel barrier (ESB), on the growth and surface morphology of homoepitaxial GaN layers. The presence of an ESB can lead to various self-assembled surface features, which strongly affect the surface roughness. We present an in-depth study of this phenomenon on GaN homoepitaxial layers grown by metal organic vapor phase epitaxy and molecular beam epitaxy. We show how a proper tuning of the growth parameters allows for the control of the surface morphology, independent of the growth technique