Randomized clinical trials to identify optimal antibiotic treatment duration

Background Antibiotic resistance is a major barrier to the continued success of antibiotic treatment. Such resistance is often generated by overly long durations of antibiotic treatment. A barrier to identifying the shortest effective treatment duration is the cost of the sequence of clinical trials needed to determine shortest optimal duration. We propose a new method to identify the optimal treatment duration of an antibiotic treatment regimen. Methods Subjects are randomized to varying treatment durations and the cure proportions of these durations are linked using a logistic regression model, making effective use of information across all treatment duration groups. In this paper, Monte Carlo simulation is used to evaluate performance of such a model. Results Using a hypothetical dataset, the logistic regression model is seen to provide increased precision in defining the point estimate and confidence interval (CI) of the cure proportion at each treatment duration. When applied to the determination of non-inferiority, the regression model allows identification of the shortest duration meeting the predefined non-inferiority margin. Conclusions This analytic strategy represents a practical way to develop shortened regimens for tuberculosis and other infectious diseases. Application of this strategy to clinical trials of antibiotic therapy could facilitate decreased antibiotic usage, reduce cost, minimize toxicity, and decrease the emergence of antibiotic resistance

Identification of flavin-containing monooxygenase 5 (FMO5) as a regulator of glucose homeostasis and a potential sensor of gut bacteria

We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5−/− mice). In comparison with wild-type (WT) counterparts, Fmo5−/− mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals. When fed a high-fat diet, they are protected against weight gain and reduction of insulin sensitivity. The phenotype of Fmo5−/− mice is independent of diet and the gut microbiome and is determined solely by the host genotype. Fmo5−/− mice have metabolic characteristics similar to those of germ-free mice, indicating that FMO5 plays a role in sensing or responding to gut bacteria. In WT mice, FMO5 is present in the mucosal epithelium of the gastrointestinal tract where it is induced in response to a high-fat diet. In comparison with WT mice, Fmo5−/− mice have fewer colonic goblet cells, and they differ in the production of the colonic hormone resistin-like molecule β. Fmo5−/− mice have lower concentrations of tumor necrosis factor α in plasma and of complement component 3 in epididymal white adipose tissue, indicative of improved inflammatory tone. Our results implicate FMO5 as a regulator of body weight and of glucose disposal and insulin sensitivity and, thus, identify FMO5 as a potential novel therapeutic target for obesity and insulin resistance

On the type Ia supernovae 2007on and 2011iv: Evidence for Chandrasekhar-mass explosions at the faint end of the luminosity-width relationship

Radiative transfer models of two transitional type Ia supernovae (SNe Ia) have been produced using the abundance stratification technique. These two objects - designated SN 2007on and SN 2011iv - both exploded in the same galaxy, NGC1404, which allows for a direct comparison. SN 2007on synthesized 0.25M⊙of56Ni and was less luminous than SN 2011iv, which produced 0.31M⊙of56Ni. SN2007on had a lower central density (ρc) and higher explosion energy (Ekin~1.3 ± 0.3 × 1051erg) than SN 2011iv, and it produced less nuclear statistical equilibrium (NSE) elements (0.06M⊙). Whereas, SN2011iv had a larger ρc, which increased the electron capture rate in the lowest velocity regions, and produced 0.35M⊙of stable NSE elements. SN 2011iv had an explosion energy of ~Ekin~0.9 ± 0.2 × 1051erg. Both objects had an ejecta mass consistent with the Chandrasekhar mass (Ch-mass), and their observational properties are well described by predictions from delayed-detonation explosion models. Within this framework, comparison to the sub-luminous SN 1986G indicates SN 2011iv and SN 1986G have different transition densities (ρtr) but similar ρc. Whereas SN 1986G and SN 2007on had a similar ρtrbut different ρc. Finally, we examine the colour-stretch parameter sBVversus Lmaxrelation and determine that the bulk of SNe Ia (including the sub-luminous ones) are consistent with Ch-mass delayed-detonation explosions, where the main parameter driving the diversity is ρtr. We also find ρcto be driving the second-order scatter observed at the faint end of the luminosity-width relationship. © 2018 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society

Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo

Whether neurons can restore their original connectivity patterns during circuit repair is unclear. Taking advantage of the regenerative capacity of zebrafish retina, we show here the remarkable specificity by which surviving neurons reassemble their connectivity upon regeneration of their major input. H3 horizontal cells (HCs) normally avoid red and green cones, and prefer ultraviolet over blue cones. Upon ablation of the major (ultraviolet) input, H3 HCs do not immediately increase connectivity with other cone types. Instead, H3 dendrites retract and re-extend to contact new ultraviolet cones. But, if regeneration is delayed or absent, blue-cone synaptogenesis increases and ectopic synapses are made with red and green cones. Thus, cues directing synapse specificity can be maintained following input loss, but only within a limited time period. Further, we postulate that signals from the major input that shape the H3 HC's wiring pattern during development persist to restrict miswiring after damage

A comprehensive review of the proline mimic azetidine-2-carboxylic acid (A2C).

The imino acid azetidine-2-carboxylic acid (A2C), a proline homologue, was first identified in liliaceous plants in 1955. Its ability to exchange for proline in protein synthesis is responsible for its teratogenic effects and has made it a very useful tool for generating non-native proteins to study proteotoxic stress and ER stress. The tRNA synthetases from some A2C-producing plants can discriminate between proline and A2C, but for most plants and for mammalian cells, A2C is mistakenly used in protein synthesis in place of proline and can avoid cell proof-reading mechanisms. Human exposure to A2C would be very limited had it not been for the development of sugar beets as an alternative source of dietary sucrose to sugar cane, and the widespread use of the plentiful byproducts as livestock fodder. Fodder beets, a very high yielding forage crop, are also used as livestock fodder particularly for lactating cows. It is therefore possible for A2C to enter the human food chain and impact human health. It was hypothesised that its ability to replace proline in protein synthesis generates immunogenic neo-epitopes in myelin basic protein and could therefore be a causative factor for multiple sclerosis. In this review we discuss the distribution of A2C in nature, what is known about its toxicity, and the impact of the proline to A2C exchange on protein structure and function and in particular the proteins collagen and myelin basic protein. We summarise analytical approaches that can be used to quantify A2C in complex biological samples and the adaptations made by some organisms to avoid its toxic effects. We summarise the evidence for human exposure to A2C and the geographical and temporal links to higher incidences of MS. Finally, we highlight gaps in our knowledge that require addressing before we can determine if this non-protein amino acid is a threat to human health

Sex hormones and cause-specific mortality in the male veterans: the Vietnam Experience Study

Aim: To examine the association of testosterone, follicular stimulating hormone, luteinizing hormone with mortality. Design: Prospective cohort analysis. Methods: Participants were 4255 Vietnam-era US army veterans with a mean age of 38.3 years. From military service files, telephone interviews and a medical examination, socio-demographic and health data were collected. Contemporary morning fasted hormone concentrations were determined. All-cause, cardiovascular, cancer, external and 'other' cause mortality was ascertained over the subsequent 15 years. Hazard ratios were calculated, first with adjustment for age and then, additionally, for a range of confounders. Results: Individuals within the highest tertiles of follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were at increased risk of all-cause mortality following adjustment for a range of risk factors. However, with mutual adjustment, neither FSH nor LH significantly predicted mortality. Testosterone levels did not show an association with all-cause mortality, and none of the hormones were significantly associated with CVD, cancer, 'other' or external-cause mortality in fully adjusted models. Conclusions: Greater FSH and LH levels are associated with all-cause mortality, but not independently of one another

'Word from the street' : when non-electoral representative claims meet electoral representation in the United Kingdom

Taking the specific case of street protests in the UK – the ‘word from the street’– this article examines recent (re)conceptualizations of political representation, most particularly Saward’s notion of ‘representative claim’. The specific example of nonelectoral claims articulated by protestors and demonstrators in the UK is used to illustrate: the processes of making, constituting, evaluating and accepting claims for and by constituencies and audiences; and the continuing distinctiveness of claims based upon electoral representation. Two basic questions structure the analysis: first, why would the political representative claims of elected representatives trump the nonelectoral claims of mass demonstrators and, second, in what ways does the ‘perceived legitimacy’ of the former differ from the latter

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

On the Generalizability of Experimental Results

The age-old question of the generalizability of the results of experiments that are conducted in artificial laboratory settings to more realistic inferential and decision making situations is considered in this paper. Conservatism in probability revision provides an example of a result that 1) has received wide attention, including attention in terms of implications for real-world decision making, on the basis of experiments conducted in artificial settings and 2) is now apparently thought by many to be highly situational and not at all a ubiquitous phenomenon, in which case its implications for real-world decision making are not as extensive as originally claimed. In this paper we consider the questions of generalizations from the laboratory to the real world in some detail, both within the context of the experiments regarding conservatism and within a more general context. In addition, we discuss some of the difficulties inherent in experimentation in realistic settings, suggest possible procedures for avoiding or at least alleviating such difficulties, and make a plea for more realistic experiments