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

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

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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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

Investigating the role of TCR signalling during T cell development

MD (res)The thymus generates multiple T cell populations from an early common CD4(-) CD8(-) double negative (DN) progenitor. Conventional αβ T cells, such as CD4(+) and CD8(+) T cells undergo thymic positive selection on partial agonist interactions with self-peptide/MHC, whereas unconventional TCRαβ(+)CD8αα(+) intraepithelial lymphocytes (IELs) and regulatory T cells (Tregs), are thought to require full agonist interactions. By contrast, very little is known about how γδ T cells undergo selection. While it has been suggested that IL-17A-secreting γδ T cells rely on strong TCR signals resulting from potential interactions with a ligand, several studies have led to opposite conclusions. This thesis investigates the role of TCR signal strength during the early stages of thymocyte development, and how this dictates subsequent T cell fate. We show that FVB/n mice have relatively few unconventional TCRαβ(+)CD8αα(+) IELs in comparison to C57Bl/6 animals. This depleted IEL compartment correlated with reduced thymic IEL progenitors, an inefficient preTCR-driven DN-to-DP transition, and a relatively increased expression of full length pTαa transcripts in CD44(-)CD25(+) DN3 cells. Transgenic over-expression of pTαa in the absence of pTαb transcripts mimicked the phenotype of FVB/n animals. CD5 levels on DN3 cells from pTαa transgenic mice indicate that preTCR signalling was weaker than in C57Bl/6 mice, suggesting that signal strength at the β-selection checkpoint may influence subsequent selection of mature T cell populations. Consistent with this, we show that OT-II mice, which express a transgenic TCRαβ from an early DN stage of thymocyte 6 development, and which have high levels of CD5 on DN3 cells, have a relatively increased unconventional TCRαβ(+)CD8αα(+)IEL compartment. For γδ T cell development, we also show that weakening signal strength impairs the development of IL-17A-secreting γδ T cells. However, increasing signal strength, through the use of a cross-linking antibody, does not favour their development as predicted. These seemingly paradoxical observations are explored further. Taken together, these data suggest that the quality or quantity of TCR-mediated signals early in T cell development have fundamental consequences for subsequent T cell selection events that differentially generate distinct T cell subsets

Descriptive Complexity of Deterministic Polylogarithmic Time and Space

We propose logical characterizations of problems solvable in deterministic polylogarithmic time (PolylogTime) and polylogarithmic space (PolylogSpace). We introduce a novel two-sorted logic that separates the elements of the input domain from the bit positions needed to address these elements. We prove that the inflationary and partial fixed point vartiants of this logic capture PolylogTime and PolylogSpace, respectively. In the course of proving that our logic indeed captures PolylogTime on finite ordered structures, we introduce a variant of random-access Turing machines that can access the relations and functions of a structure directly. We investigate whether an explicit predicate for the ordering of the domain is needed in our PolylogTime logic. Finally, we present the open problem of finding an exact characterization of order-invariant queries in PolylogTime.Comment: Submitted to the Journal of Computer and System Science