Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin's anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin. Endometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed. In women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response. Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin

Mobilising knowledge in complex health systems: A call to action

Worldwide, policymakers, health system managers, practitioners and researchers struggle to use evidence to improve policy and practice. There is growing recognition that this challenge relates to the complex systems in which we work. The corresponding increase in complexity-related discourse remains primarily at a theoretical level. This paper moves the discussion to a practical level, proposing actions that can be taken to implement evidence successfully in complex systems. Key to success is working with, rather than trying to simplify or control, complexity. The integrated actions relate to co-producing knowledge, establishing shared goals and measures, enabling leadership, ensuring adequate resourcing, contributing to the science of knowledge-to-action, and communicating strategically. This is the final version of the article. It first appeared from Policy Press via http://dx.doi.org/10.1332/174426416X1471255375031

Object Detection Through Exploration With A Foveated Visual Field

We present a foveated object detector (FOD) as a biologically-inspired alternative to the sliding window (SW) approach which is the dominant method of search in computer vision object detection. Similar to the human visual system, the FOD has higher resolution at the fovea and lower resolution at the visual periphery. Consequently, more computational resources are allocated at the fovea and relatively fewer at the periphery. The FOD processes the entire scene, uses retino-specific object detection classifiers to guide eye movements, aligns its fovea with regions of interest in the input image and integrates observations across multiple fixations. Our approach combines modern object detectors from computer vision with a recent model of peripheral pooling regions found at the V1 layer of the human visual system. We assessed various eye movement strategies on the PASCAL VOC 2007 dataset and show that the FOD performs on par with the SW detector while bringing significant computational cost savings.Comment: An extended version of this manuscript was published in PLOS Computational Biology (October 2017) at https://doi.org/10.1371/journal.pcbi.100574

Enhanced seasonal forecast skill following stratospheric sudden warmings

Advances in seasonal forecasting have brought widespread socio-economic benefits. However, seasonal forecast skill in the extratropics is relatively modest, prompting the seasonal forecasting community to search for additional sources of predictability. For over a decade it has been suggested that knowledge of the state of the stratosphere can act as a source of enhanced seasonal predictability; long-lived circulation anomalies in the lower stratosphere that follow stratospheric sudden warmings are associated with circulation anomalies in the troposphere that can last up to two months. Here, we show by performing retrospective ensemble model forecasts that such enhanced predictability can be realized in a dynamical seasonal forecast system with a good representation of the stratosphere. When initialized at the onset date of stratospheric sudden warmings, the model forecasts faithfully reproduce the observed mean tropospheric conditions in the months following the stratospheric sudden warmings. Compared with an equivalent set of forecasts that are not initialized during stratospheric sudden warmings, we document enhanced forecast skill for atmospheric circulation patterns, surface temperatures over northern Russia and eastern Canada and North Atlantic precipitation. We suggest that seasonal forecast systems initialized during stratospheric sudden warmings are likely to yield significantly greater forecast skill in some regions

The LSST DESC data challenge 1: Generation and analysis of synthetic images for next-generation surveys

Data Challenge 1 (DC1) is the first synthetic data set produced by the Rubin Observatory Legacy Survey of Space and Time (LSST) Dark Energy Science Collaboration (DESC). DC1 is designed to develop and validate data reduction and analysis and to study the impact of systematic effects that will affect the LSST data set. DC1 is comprised of r-band observations of 40 deg2 to 10 yr LSST depth. We present each stage of the simulation and analysis process: (a) generation, by synthesizing sources from cosmological N-body simulations in individual sensor-visit images with different observing conditions; (b) reduction using a development version of the LSST Science Pipelines; and (c) matching to the input cosmological catalogue for validation and testing. We verify that testable LSST requirements pass within the fidelity of DC1. We establish a selection procedure that produces a sufficiently clean extragalactic sample for clustering analyses and we discuss residual sample contamination, including contributions from inefficiency in star-galaxy separation and imperfect deblending. We compute the galaxy power spectrum on the simulated field and conclude that: (i) survey properties have an impact of 50 per cent of the statistical uncertainty for the scales and models used in DC1; (ii) a selection to eliminate artefacts in the catalogues is necessary to avoid biases in the measured clustering; and (iii) the presence of bright objects has a significant impact (2-6) in the estimated power spectra at small scales (> 1200), highlighting the impact of blending in studies at small angular scales in LSST

A comparison of hospital readmission rates between two general physicians with different outpatient review practices

BACKGROUND: There has been a relentless increase in emergency medical admissions in the UK over recent years. Many of these patients suffer with chronic conditions requiring continuing medical attention. We wished to determine whether conventional outpatient clinic follow up after discharge has any impact on the rate of readmission to hospital. METHODS: Two consultant general physicians with the same patient case-mix but markedly different outpatient follow-up practice were chosen. Of 1203 patients discharged, one consultant saw twice as many patients in the follow-up clinic than the other (Dr A 9.8% v Dr B 19.6%). The readmission rate in the twelve months following discharge was compared in a retrospective analysis of hospital activity data. Due to the specialisation of the admitting system, patients mainly had cardiovascular or cerebrovascular disease or had taken an overdose. Few had respiratory or infectious diseases. Outpatient follow-up was focussed on patients with cardiac disease. RESULTS: Risk of readmission increased significantly with age and length of stay of the original episode and was less for digestive system and musculo-skeletal disorders. 28.7% of patients discharged by Dr A and 31.5 % of those discharged by Dr B were readmitted at least once. Relative readmission risk was not significantly different between the consultants and there was no difference in the length of stay of readmissions. CONCLUSIONS: Increasing the proportion of patients with this age- and case-mix who are followed up in a hospital general medical outpatient clinic is unlikely to reduce the demand for acute hospital beds

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

Extending methane profiles from aircraft into the stratosphere for satellite total column validation: A comparative analysis of different data sources

Airborne observations of greenhouse gases are a very useful reference for validation of satellite-based column averaged dry air mole fraction data. However, since the aircraft data are available only up to about 9-13 km altitude, these profiles do not fully represent the depth of the atmosphere observed by satellites and therefore need to be extended synthetically into the stratosphere. In the near future, observations of CO₂ and CH₄ made from passenger aircraft are expected to be available through the In-Service Aircraft for a Global Observing System (IAGOS) project. In this study, we analyse three different data sources that are available for the stratospheric extension of aircraft profiles by comparing the error introduced by each of them into the total column and provide recommendations regarding the best approach. First, we analyse CH₄ fields from two different models of atmospheric composition - the European Centre for Medium-Range Weather Forecasts (ECMWF) Integrated Forecasting System for Composition (C-IFS) and the TOMCAT/SLIMCAT 3-D 20 chemical transport model. Secondly, we consider scenarios that simulate the effect of using CH₄ climatologies such as those based on balloons or satellite limb soundings. Thirdly, we assess the impact of using a-priori profiles used in the satellite retrievals for the stratospheric part of the total column. We find that the models considered in this study have a better estimation of the stratospheric CH₄ as compared to the climatology-based data and the satellite a-priori profiles. Both the C-IFS and TOMCAT models have a bias of about -9 ppb at the locations where tropospheric vertical profiles will be measured 25 by IAGOS. The C-IFS model, however, has a lower random error (6.5 ppb) than TOMCAT (12.8 ppb). These values are well within the minimum desired accuracy and precision of satellite total column XCH₄ retrievals (10 ppb and 34 ppb, respectively). In comparison, the a-priori profile from the University of Leicester Greenhouse Gases Observing Satellite (GOSAT) Proxy XCH₄ retrieval and climatology-based data introduce larger random errors in the total column, being limited in spatial coverage and temporal variability. Furthermore, we find that the bias in the models varies with latitude and season. Therefore, applying appropriate bias correction to the model fields before using them for profile extension is expected to further decrease the error contributed by the stratospheric part of the profile to the total column

A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode

<p>Abstract</p> <p>Background</p> <p>Interleukin-8 (IL-8) is a potent chemo-attractant cytokine responsible for neutrophil infiltration in lungs with idiopathic pulmonary fibrosis (IPF). The IL-8 protein and mRNA expression are increased in the lung with IPF. We evaluated the effect of single nucleotide polymorphisms (SNPs) of the IL-8 gene on the risk of IPF.</p> <p>Methods</p> <p>One promoter (rs4073T>A) and two intronic SNPs (rs2227307T>G and rs2227306C>T) of the IL-8 genes were genotyped in 237 subjects with IPF and 456 normal controls. Logistic regression analysis was applied to evaluate the association of these SNPs with IPF. IL-8 in BAL fluids was measured using a quantitative sandwich enzyme immunoassay, and promoter activity was assessed using the luciferase reporter assay.</p> <p>Results</p> <p>The minor allele frequencies of rs4073T>A and rs2227307T>G were significantly lower in the 162 subjects with surgical biopsy-proven IPF and 75 subjects with clinical IPF compared with normal controls in the recessive model (OR = 0.46 and 0.48, <it>p </it>= 0.006 and 0.007, respectively). The IL-8 protein concentration in BAL fluids significantly increased in 24 subjects with IPF compared with 14 controls (<it>p </it>= 0.009). Nine IPF subjects homozygous for the rs4073 T>A common allele exhibited higher levels of the IL-8 protein compared with six subjects homozygous for the minor allele (<it>p </it>= 0.024). The luciferase activity of the rs4073T>A common allele was significantly higher than that of the rs4073T>A minor allele (<it>p </it>= 0.002).</p> <p>Conclusion</p> <p>The common allele of a promoter SNP, rs4073T>A, may increase susceptibility to the development of IPF via up-regulation of IL-8.</p