A comparison of sensitivity-specificity imputation, direct imputation and fully Bayesian analysis to adjust for exposure misclassification when validation data are unavailable.

: Measurement error is an important source of bias in epidemiological studies. We illustrate three approaches to sensitivity analysis for the effect of measurement error: imputation of the 'true' exposure based on specifying the sensitivity and specificity of the measured exposure (SS); direct imputation (DI) using a regression model for the predictive values; and adjustment based on a fully Bayesian analysis. : We deliberately misclassify smoking status in data from a case-control study of lung cancer. We then implement the SS and DI methods using fixed-parameter (FBA) and probabilistic (PBA) bias analyses, and Bayesian analysis using the Markov-Chain Monte-Carlo program WinBUGS to show how well each recovers the original association. : The 'true' smoking-lung cancer odds ratio (OR), adjusted for sex in the original dataset, was OR = 8.18 [95% confidence limits (CL): 5.86, 11.43]; after misclassification, it decreased to OR = 3.08 (nominal 95% CL: 2.40, 3.96). The adjusted point estimates from all three approaches were always closer to the 'true' OR than the OR estimated from the unadjusted misclassified smoking data, and the adjusted interval estimates were always wider than the unadjusted interval estimate. When imputed misclassification parameters departed much from the actual misclassification, the 'true' OR was often omitted in the FBA intervals whereas it was always included in the PBA and Bayesian intervals. : These results illustrate how PBA and Bayesian analyses can be used to better account for uncertainty and bias due to measurement error.<br/

Self-stabilised fractality of sea-coasts through damped erosion

Erosion of rocky coasts spontaneously creates irregular seashores. But the geometrical irregularity, in turn, damps the sea-waves, decreasing the average wave amplitude. There may then exist a mutual self-stabilisation of the waves amplitude together with the irregular morphology of the coast. A simple model of such stabilisation is studied. It leads, through a complex dynamics of the earth-sea interface, to the appearance of a stationary fractal seacoast with dimension close to 4/3. Fractal geometry plays here the role of a morphological attractor directly related to percolation geometry.Comment: 4 pages, 5 figure

A Comparison of Methods for Poverty Estimation in Developing Countries

Small area estimation is a widely used indirect estimation technique for micro-level geographic profiling. Three unit level small area estimation techniques-the ELL or World Bank method, empirical best prediction (EBP) and M-quantile (MQ) - can estimate micro-level Foster, Greer, & Thorbecke (FGT) indicators: poverty incidence, gap and severity using both unit level survey and census data. However, they use different assumptions. The effects of using model-based unit level census data reconstructed from cross-tabulations and having no cluster level contextual variables for models are discussed, as are effects of small area and cluster level heterogeneity. A simulation-based comparison of ELL, EBP and MQ uses a model-based reconstruction of 2000/2001 data from Bangladesh and compares bias and mean square error. A three-level ELL method is applied for comparison with the standard two-level ELL that lacks a small area level component. An important finding is that the larger number of small areas for which ELL has been able to produce sufficiently accurate estimates in comparison with EBP and MQ has been driven more by the type of census data available or utilised than by the model per se

Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC(50)=12.2 μM; luteolin, EC(50)=14.6 μM; and wogonin, EC(50)=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.—Lucas, C. D., Allen, K. C., Dorward, D. A., Hoodless, L. J., Melrose, L. A., Marwick, J. A., Tucker, C. S., Haslett, C., Duffin, R., Rossi, A. G. Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. Trial registration number NCT01836692; Pre-result

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

Characterization of the effects of cross-linking of macrophage CD44 associated with increased phagocytosis of apoptotic PMN

Control of macrophage capacity for apoptotic cell clearance by soluble mediators such as cytokines, prostaglandins and lipoxins, serum proteins, and glucocorticoids may critically determine the rate at which inflammation resolves. Previous studies suggested that macrophage capacity for clearance of apoptotic neutrophils was profoundly altered following binding of CD44 antibodies. We have used a number of different approaches to further define the mechanism by which CD44 rapidly and specifically augment phagocytosis of apoptotic neutrophils. Use of Fab ’ fragments unequivocally demonstrated a requirement for cross-linking of macrophage surface CD44. The molecular mechanism of CD44-augmented phagocytosis was shown to be opsonin-independent and to be distinct from the Mer/protein S pathway induced by glucocorticoids and was not functional for clearance of apoptotic eosinophils. CD44-cross-linking also altered macrophage migration and induced cytoskeletal re-organisation together with phosphorylation of paxillin and activation of Rac2. Investigation of signal transduction pathways that might be critical for CD44 augmentation of phagocytosis revealed that Ca 2+ signalling, PI-3 kinase pathways and altered cAMP signalling were not involved, but did implicate a key role for tyrosine phosphorylation events. Finally, although CD44 antibodies were able to augment phagocytosis of apoptotic neutrophils by murine peritoneal and bone marrow-derived macrophages, we did not observe a difference in the clearance of neutrophils following induction of peritonitis with thioglycollate in CD44-deficient animals. Together, these data demonstrate that CD4

Contribution of peat compaction to relative sea-level rise within Holocene deltas

Modern and forecasted flooding of deltas is accelerated by subsidence of Holocene deposits. Subsidence caused by tectonics, isostasy, sediment compaction and anthropogenic processes, combined with eustatic sea-level rise, results in drowning and increased flood risk within densely populated deltas. Many deltaic sedimentary successions include substantial amounts of peat, which is highly compressible compared to clay, silt and sand. Peat compaction, therefore, may contribute considerably to total delta subsidence. Existing studies are inadequate for quantifying peat compaction across deltas. We present a numerical peat compaction model calibrated with an extensive field dataset. The model quantifies spatial and temporal trends in peat compaction within fluvial-dominated Holocene flood basin sequences of different compositions. Subsidence due to peat compaction is highly variable in time and space, with local rates of up to 15 mm/yr, depending on sedimentary sequence. This is extremely important information for developing sound delta management strategies. Artificial groundwater table lowering may cause substantial additional subsidence. Subsidence due to peat compaction might even exceed estimates of relative sea-level rise, and thus, may seriously increase the risk of delta drowning and human vulnerability to floodin