Restrictive antibiotic stewardship associated with reduced hospital mortality in gram-negative infection

Introduction: Antimicrobial stewardship has an important role in the control of Clostridium difficile infection (CDI) and antibiotic resistance. An important component of UK stewardship interventions is the restriction of broad-spectrum beta-lactam antibiotics and promotion of agents associated with a lower risk of CDI such as gentamicin. Whilst the introduction of restrictive antibiotic guidance has been associated with improvements in CDI and antimicrobial resistance evidence of the effect on outcome following severe infection is lacking. Methods: In 2008, Glasgow hospitals introduced a restrictive antibiotic guideline. A retrospective before/after study assessed outcome following gram-negative bacteraemia in the 2-year period around implementation. Results: Introduction of restrictive antibiotic guidelines was associated with a reduction in utilisation of ceftriaxone and co-amoxiclav and an increase in amoxicillin and gentamicin. 1593 episodes of bacteraemia were included in the study. The mortality over 1 year following gram-negative bacteraemia was lower in the period following guideline implementation (RR 0.852, P = 0.045). There was no evidence of a difference in secondary outcomes including ITU admission, length of stay, readmission, recurrence of bacteraemia and need for renal replacement therapy. There was a fall in CDI (RR 0.571, P = 0.014) and a reduction in bacterial resistance to ceftriaxone and co-amoxiclav but no evidence of an increase in gentamicin resistance after guideline implementation. Conclusion: Restrictive antibiotic guidelines were associated with a reduction in CDI and bacterial resistance but no evidence of adverse outcomes following gram-negative bacteraemia. There was a small reduction in one year mortality

The quick and the dead: when reaction beats intention

Everyday behaviour involves a trade-off between planned actions and reaction to environmental events.Evidence from neurophysiology, neurology and functional brain imaging suggests different neural bases for the control of different movement types. Here we develop a behavioural paradigm to test movement dynamics for intentional versus reaction movements and provide evidence for a ‘reactive advantage’ in movement execution, whereby the same action is executed faster in reaction to an opponent. We placed pairs of participants in competition with each other to make a series of button presses. Within subject analysis of movement times revealed a 10 per cent benefit for reactive actions. This was maintained when opponents performed dissimilar actions, and when participants competed against a computer, suggesting that the effect is not related to facilitation produced by action observation. Rather, faster ballistic movements may be a general property of reactive motor control, potentially providing a useful means of promoting survival

Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise

This is the final version of the article. Available from Springer via the DOI in this record.In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t (1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.Wellcome TrustNational Institute for Health Researc

Characterisation of the dynamic nature of lipids throughout the lifespan of genetically identical female and male Daphnia magna

Lipids play a significant role in regulation of health and disease. To enhance our understanding of the role of lipids in regulation of lifespan and healthspan additional studies are required. Here, UHPLC-MS/MS lipidomics was used to measure dynamic changes in lipid composition as a function of age and gender in genetically identical male and female Daphnia magna with different average lifespans. We demonstrate statistically significant age-related changes in triglycerides (TG), diglycerides (DG), phosphatidylcholine, phosphatidylethanolamine, ceramide and sphingomyelin lipid groups, for example, in males, 17.04% of TG lipid species decline with age whilst 37.86% increase in relative intensity with age. In females, 23.16% decrease and 25.31% increase in relative intensity with age. Most interestingly, the rate and direction of change can differ between genetically identical female and male Daphnia magna, which could be the cause and/or the consequence of the different average lifespans between the two genetically identical genders. This study provides a benchmark dataset to understand how lipids alter as a function of age in genetically identical female and male species with different average lifespan and ageing rate.Peer reviewe

Structure-based virtual screening, synthesis and biological evaluation of potential FAK-FAT domain inhibitors for treatment of metastatic cancer

Focal adhesion kinase (FAK) is a tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. In cancer cells, FAK promotes the progression and metastasis of tumours. In this study, we used structure-based virtual screening to filter a library of more than 210K compounds against the focal adhesion targeting FAK-focal adhesion targeting (FAT) domain to identify 25 virtual hit compounds which were screened in the invasive breast cancer line (MDA-MB-231). Most notably, compound I showed low micromolar antiproliferative activity, as well as antimigratory activity. Moreover, examination in a model of triple negative breast cancer (TNBC), revealed that, despite not effecting FAK phosphorylation, compound I significantly impairs proliferation whilst impairing focal adhesion growth and turnover leading to reduced migration. Further optimisation and synthesis of analogues of the lead compound I using a four-step synthetic procedure was performed, and analogues were assessed for their antiproliferative activity against three breast cancer (MDA-MB-231, T47D, BT474) cell lines and one pancreatic cancer (MIAPaCa2) cell line. Compound 5f was identified as a promising lead compound with IC50 values in the range of 4.59–5.28 μM in MDA-MB-231, T47D, BT474, and MIAPaCa2. Molecular modelling and pharmacokinetic studies provided more insight into the therapeutic features of this new series

Nitrate pharmacokinetics: taking note of the difference

Copyright © 2015 Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Nitric Oxide: Biology and Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Nitric Oxide: Biology and Chemistry (2015), DOI: 10.1016/j.niox.2015.04.006It is now recognised that administration of oral nitrate (NO3(-)), in its various forms, increases the level of nitric oxide (NO) metabolites in the circulation of humans. Its application to modulate physiology and alleviate cardiovascular dysfunction in some patients is now recorded and shows particular promise in hypertension, in modifying platelet activation/aggregation, and in conditions where tissue ischemia prevails. The potential of oral NO3(-) to modify exercise/performance via elevation of plasma nitrite concentration ([NO2(-)]) has been applied across a range of human test systems. Herein we discuss how the choice of NO3(-) source, route of administration and resulting pharmacokinetics might influence the outcome of physiological measures and potentially contribute to discrepancies in performance trials. There are but a few examples of detailed pharmacokinetic data on which the majority of researchers base their test protocols in different cohorts/settings. We compare and contrast the results of key publications with the aim of highlighting a consensus of our current understanding and critical considerations for those entering the field

Effect of Strength on Velocity and Power During Back Squat Exercise in Resistance-Trained Men and Women

The purpose was to examine load-velocity and load-power relationships of back squat in resistance-trained men (n = 20, 21.3 ± 1.4 years, 183.0 ± 8.0 cm, 82.6 ± 8.0 kg, 11.5 ± 5.0% total body fat) and women (n = 18; 20.0 ± 1.0 years; 166.5 ± 6.9 cm; 63.9 ± 7.9 kg, 20.3 ± 5.0% body fat). Body composition testing was performed followed by determination of back squat 1 repetition maximum (1RM). After at least 72 hours of recovery, subjects returned to the laboratory and completed 2 repetitions at each of 7 separate loads (30, 40, 50, 60, 70, 80, and 90% 1RM) in a random order. During each repetition, peak and average velocity and power were quantified using a commercially available linear position transducer. Men produced higher absolute peak and average power and velocity at all loads. When power output was normalized for body mass, significant differences remained. However, when normalizing for strength, no significant differences were observed between sexes. Furthermore, when subjects were subdivided into strong and weak groups, those above the median 1RM produced higher peak power, but only at loads greater than 60% 1RM. It was concluded that differences between men and women may be a result of strength rather than biological sex. Furthermore, training for maximal strength may be an appropriate method to augment maximal power output in those athletes who exhibit low levels of strength

The Statistical Approach to Quantifying Galaxy Evolution

Studies of the distribution and evolution of galaxies are of fundamental importance to modern cosmology; these studies, however, are hampered by the complexity of the competing effects of spectral and density evolution. Constructing a spectroscopic sample that is able to unambiguously disentangle these processes is currently excessively prohibitive due to the observational requirements. This paper extends and applies an alternative approach that relies on statistical estimates for both distance (z) and spectral type to a deep multi-band dataset that was obtained for this exact purpose. These statistical estimates are extracted directly from the photometric data by capitalizing on the inherent relationships between flux, redshift, and spectral type. These relationships are encapsulated in the empirical photometric redshift relation which we extend to z ~ 1.2, with an intrinsic dispersion of dz = 0.06. We also develop realistic estimates for the photometric redshift error for individual objects, and introduce the utilization of the galaxy ensemble as a tool for quantifying both a cosmological parameter and its measured error. We present deep, multi-band, optical number counts as a demonstration of the integrity of our sample. Using the photometric redshift and the corresponding redshift error, we can divide our data into different redshift intervals and spectral types. As an example application, we present the number redshift distribution as a function of spectral type.Comment: 40 pages (LaTex), 21 Figures, requires aasms4.sty; Accepted by the Astrophysical Journa

Imaging Fourier transform spectrometers for environmental sensing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77073/1/AIAA-1998-291-523.pd