Impact of three ampicillin dosage regimens on selection of ampicillin resistance in Enterobacteriaceae and excretion of blaTEM genes in swine feces

The aim of this study was to assess the impact of three ampicillin dosage regimens on ampicillin resistance among Enterobacteriaceae recovered from swine feces using phenotypic and genotypic approaches. Phenotypically, ampicillin resistance was determined from the percentage of resistant Enterobacteriaceae and MICs of E. coli isolates. The pool of ampicillin resistance genes was also monitored by quantification of blaTEM genes, which code for the most frequently produced β-lactamases in Gram-negative bacteria, using a newly-developed real-time PCR assay. Ampicillin was administered intramuscularly and by oral route to fed or fasted pigs for 7 days at 20 mg/kg. The average percentage of resistant Enterobacteriaceae before treatment was between 2.5% and 12% and blaTEM genes quantities were below 107 copies/g of feces. By days four and seven, the percentage of resistant Enterobacteriaceae exceeded 50% in all treated groups, with some highly resistant strains (MIC>256µg/mL). In the control group, blaTEM genes quantities fluctuated between 104 - 106 copies/g of feces, whereas they fluctuated between 106-108 and 107-109 copies/g of feces for intramuscular and oral routes, respectively. Whereas phenotypic evaluations did not discriminate between the three ampicillin dosage regimens, blaTEM genes quantification was able to differentiate between the effects of two routes of ampicillin administration. Our results suggest that fecal blaTEM genes quantification provides a sensitive tool to evaluate the impact of ampicillin administration on the selection of ampicillin resistance in the digestive microflora and its dissemination in the environment

Fuel for the Work Required: A Theoretical Framework for Carbohydrate Periodization and the Glycogen Threshold Hypothesis.

Deliberately training with reduced carbohydrate (CHO) availability to enhance endurance-training-induced metabolic adaptations of skeletal muscle (i.e. the 'train low, compete high' paradigm) is a hot topic within sport nutrition. Train-low studies involve periodically training (e.g., 30-50% of training sessions) with reduced CHO availability, where train-low models include twice per day training, fasted training, post-exercise CHO restriction and 'sleep low, train low'. When compared with high CHO availability, data suggest that augmented cell signalling (73% of 11 studies), gene expression (75% of 12 studies) and training-induced increases in oxidative enzyme activity/protein content (78% of 9 studies) associated with 'train low' are especially apparent when training sessions are commenced within a specific range of muscle glycogen concentrations. Nonetheless, such muscle adaptations do not always translate to improved exercise performance (e.g. 37 and 63% of 11 studies show improvements or no change, respectively). Herein, we present our rationale for the glycogen threshold hypothesis, a window of muscle glycogen concentrations that simultaneously permits completion of required training workloads and activation of the molecular machinery regulating training adaptations. We also present the 'fuel for the work required' paradigm (representative of an amalgamation of train-low models) whereby CHO availability is adjusted in accordance with the demands of the upcoming training session(s). In order to strategically implement train-low sessions, our challenge now is to quantify the glycogen cost of habitual training sessions (so as to inform the attainment of any potential threshold) and ensure absolute training intensity is not compromised, while also creating a metabolic milieu conducive to facilitating the endurance phenotype

Type IIA orientifold compactification on SU(2)-structure manifolds

We investigate the effective theory of type IIA string theory on six-dimensional orientifold backgrounds with SU(2)-structure. We focus on the case of orientifolds with O6-planes, for which we compute the bosonic effective action in the supergravity approximation. For a generic SU(2)-structure background, we find that the low-energy effective theory is a gauged N=2 supergravity where moduli in both vector and hypermultiplets are charged. Since all these supergravities descend from a corresponding N=4 background, their scalar target space is always a quotient of a SU(1,1)/U(1) x SO(6,n)/SO(6)xSO(n) coset, and is therefore also very constrained.Comment: 31 pages; v2: local report number adde

The effect of early versus late treatment initiation after diagnosis on the outcomes of patients treated for multidrug-resistant tuberculosis: a systematic review.

BACKGROUND: Globally it is estimated that 480 000 people developed multidrug-resistant tuberculosis (MDR-TB) in 2014 and 190 000 people died from the disease. Successful treatment outcomes are achieved in only 50 % of patients with MDR-TB, compared to 86 % for drug susceptible disease. It is widely held that delay in time to initiation of treatment for MDR-TB is an important predictor of treatment outcome. The objective of this review was to assess the existing evidence on the outcomes of multidrug- and extensively drug-resistant tuberculosis patients treated early (≤4 weeks) versus late (>4 weeks) after diagnosis of drug resistance. METHODS: Eight sources providing access to 17 globally representative electronic health care databases, indexes, sources of evidence-based reviews and grey literature were searched using terms incorporating time to treatment and MDR-TB. Two-stage sifting in duplicate was employed to assess studies against pre-specified inclusion and exclusion criteria. Only those articles reporting WHO-defined treatment outcomes were considered for inclusion. Articles reporting on fewer than 10 patients, published before 1990, or without a comparison of outcomes in patient groups experiencing different delays to treatment initiation were excluded. RESULTS: The initial search yielded 1978 references, of which 1475 unique references remained after removal of duplicates and 28 articles published pre-1990. After title and abstract sifting, 64 papers underwent full text review. None of these articles fulfilled the criteria for inclusion in the review. CONCLUSIONS: Whilst there is an inherent logic in the theory that treatment delay will lead to poorer treatment outcomes, no published evidence was identified in this systematic review to support this hypothesis. Reports of programmatic changes leading to reductions in treatment delay exist in the literature, but attribution of differences in outcomes specifically to treatment delay is confounded by other contemporaneous changes. Further primary research on this question is not considered a high priority use of limited resources, though where data are available, improved reporting of outcomes by time to treatment should be encouraged

A Comparison of Supersymmetry Breaking and Mediation Mechanisms

We give a unified treatment of different models of supersymmetry breaking and mediation from a four dimensional effective field theory standpoint. In particular a comparison between GMSB and various gravity mediated versions of SUSY breaking shows that, once the former is embedded within a SUGRA framework, there is no particular advantage to that mechanism from the point of view of FCNC suppression. We point out the difficulties of all these scenarios - in particular the cosmological modulus problem. We end with a discussion of possible string theory realizations.Comment: Added clarifications and references, 20 page

Explicit de Sitter Flux Vacua for Global String Models with Chiral Matter

We address the open question of performing an explicit stabilisation of all closed string moduli (including dilaton, complex structure and Kaehler moduli) in fluxed type IIB Calabi-Yau compactifications with chiral matter. Using toric geometry we construct Calabi-Yau manifolds with del Pezzo singularities. D-branes located at such singularities can support the Standard Model gauge group and matter content. In order to control complex structure moduli stabilisation we consider Calabi-Yau manifolds which exhibit a discrete symmetry that reduces the effective number of complex structure moduli. We calculate the corresponding periods in the symplectic basis of invariant three-cycles and find explicit flux vacua for concrete examples. We compute the values of the flux superpotential and the string coupling at these vacua. Starting from these explicit complex structure solutions, we obtain AdS and dS minima where the Kaehler moduli are stabilised by a mixture of D-terms, non-perturbative and perturbative alpha'-corrections as in the LARGE Volume Scenario. In the considered example the visible sector lives at a dP_6 singularity which can be higgsed to the phenomenologically interesting class of models at the dP_3 singularity.Comment: 49 pages, 5 figures; v2: references adde

Supersymmetric Vacua in N=2 Supergravity

We use the embedding tensor formalism to analyse maximally symmetric backgrounds of N=2 gauged supergravities which have the full N=2 supersymmetry. We state the condition for N=2 vacua and discuss some of their general properties. We show that if the gauged isometries leave the SU(2) R-symmetry invariant, then the N=2 vacuum must be Minkowski. This implies that there are no AdS backgrounds with eight unbroken supercharges in the effective N=2 supergravity of six-dimensional SU(3) x SU(3) structure compactifications of type II string theory and M-theory. Combined with previous results on N=1 vacua, we show that there exist N=2 supergravities with a given set of gauged Abelian isometries that have both N=2 and N=1 vacua. We also argue that an analogue of our analysis holds in five and six spacetime dimensions.Comment: 14 pages, v2: references added, statement on SU(3) x SU(3) structure compactifications clarified; v3: published version with statement on moduli space of N=2 AdS vacua correcte