Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Development and Disease: How Susceptibility to an Emerging Pathogen Changes through Anuran Development

Ranaviruses have caused die-offs of amphibians across the globe. In North America, these pathogens cause more amphibian mortality events than any other pathogen. Field observations suggest that ranavirus epizootics in amphibian communities are common during metamorphosis, presumably due to changes in immune function. However, few controlled studies have compared the relative susceptibility of amphibians to ranaviruses across life stages. Our objectives were to measure differences in mortality and infection prevalence following exposure to ranavirus at four developmental stages and determine whether the differences were consistent among seven anuran species. Based on previous studies, we hypothesized that susceptibility to ranavirus would be greatest at metamorphosis. Our results did not support this hypothesis, as four of the species were most susceptible to ranavirus during the larval or hatchling stages. The embryo stage had the lowest susceptibility among species probably due to the protective membranous layers of the egg. Our results indicate that generalizations should be made cautiously about patterns of susceptibility to ranaviruses among amphibian developmental stages and species. Further, if early developmental stages of amphibians are susceptible to ranaviruses, the impact of ranavirus epizootic events may be greater than realized due to the greater difficulty of detecting morbid hatchlings and larvae compared to metamorphs

Local Gene Silencing of Monocyte Chemoattractant Protein-1 Prevents Vulnerable Plaque Disruption in Apolipoprotein E-Knockout Mice

Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been demonstrated to play important roles in atherosclerosis and becoming an important therapeutic target for atherosclerosis. The present study was undertaken to test the hypothesis that local RNAi of MCP-1 by site-specific delivery of adenovirus-mediated small hairpin RNA (shRNA) may enhance plaque stability and prevent plaque disruption in ApoE−/− mice. We designed an adenovirus-mediated shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout (ApoE−/−) mice (n = 120) were fed a high-fat diet and vulnerable plaques were induced by perivascular placement of constrictive collars around the carotid artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two weeks after treatment, plaque disruption rates were significantly lower in the Ad-MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local MCP-1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by immunostaining, qRT-PCR and western blot (P<0.001). Compared with the Ad-EGFP group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen and smooth muscle cells, and decreased levels of lipid and macrophages. The expression of inflammatory cytokines and activities of matrix metalloproteinases (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more stable plaque phenotype and prevented plaque disruption. A marked suppression of the local inflammatory cytokine expression may be the central mechanism involved

Methylation Markers of Early-Stage Non-Small Cell Lung Cancer

Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers.We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis.We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups.We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility

Dark energy survey year 1 results: Redshift distributions of the weak-lensing source galaxies

We describe the derivation and validation of redshift distribution estimates and their uncertainties for the populations of galaxies used as weak-lensing sources in the Dark Energy Survey (DES) Year 1 cosmological analyses. The Bayesian Photometric Redshift (BPZ) code is used to assign galaxies to four redshift bins between z ≈ 0.2 and ≈1.3, and to produce initial estimates of the lensing-weighted redshift distributions nPZi(z) ∝ dni/dz for members of bin i. Accurate determination of cosmological parameters depends critically on knowledge of ni, but is insensitive to bin assignments or redshift errors for individual galaxies. The cosmological analyses allow for shifts ni (z) = nPZi(z - Δzi) to correct themean redshift of ni(z) for biases in nPZi. The Δzi are constrained by comparison of independently estimated 30-band photometric redshifts of galaxies in the Cosmic Evolution Survey (COSMOS) field to BPZ estimates made from the DES griz fluxes, for a sample matched in fluxes, pre-seeing size, and lensing weight to the DES weak-lensing sources. In companion papers, the Δzi of the three lowest redshift bins are further constrained by the angular clustering of the source galaxies around red galaxies with secure photometric redshifts at 0.15 &lt; z &lt; 0.9. This paper details the BPZ and COSMOS procedures, and demonstrates that the cosmological inference is insensitive to details of the ni(z) beyond the choice of Δzi. The clustering and COSMOS validation methods produce consistent estimates of Δzi in the bins where both can be applied, with combined uncertainties of σΔzi = 0.015, 0.013, 0.011, and 0.022 in the four bins. Repeating the photo-z procedure instead using the Directional Neighbourhood Fitting algorithm, or using the ni(z) estimated from the matched sample in COSMOS, yields no discernible difference in cosmological inferences

Dark energy survey year 1 results: weak lensing shape catalogues

We present two galaxy shape catalogues from the Dark Energy Survey Year 1 data set, covering 1500 deg2 with a median redshift of 0.59. The catalogues cover two main fields: Stripe 82, and an area overlapping the South Pole Telescope survey region. We describe our data analysis process and in particular our shape measurement using two independent shear measurement pipelines, METACALIBRATION and IM3SHAPE. The METACALIBRATION catalogue uses a Gaussian model with an innovative internal calibration scheme, and was applied to riz bands, yielding 34.8M objects. The IM3SHAPE catalogue uses amaximum-likelihood bulge/disc model calibrated using simulations, and was applied to r-band data, yielding 21.9M objects. Both catalogues pass a suite of null tests that demonstrate their fitness for use in weak lensing science. We estimate the 1σ uncertainties in multiplicative shear calibration to be 0.013 and 0.025 for the METACALIBRATION and IM3SHAPE catalogues, respectively

Dark Energy Survey Year 3 results: marginalization over redshift distribution uncertainties using ranking of discrete realizations

Cosmological information from weak lensing surveys is maximized by sorting source galaxies into tomographic redshift subsamples. Any uncertainties on these redshift distributions must be correctly propagated into the cosmological results. We present hyperrank, a new method for marginalizing over redshift distribution uncertainties, using discrete samples from the space of all possible redshift distributions, improving over simple parametrized models. In hyperrank, the set of proposed redshift distributions is ranked according to a small (between one and four) number of summary values, which are then sampled, along with other nuisance parameters and cosmological parameters in the Monte Carlo chain used for inference. This approach can be regarded as a general method for marginalizing over discrete realizations of data vector variation with nuisance parameters, which can consequently be sampled separately from the main parameters of interest, allowing for increased computational efficiency. We focus on the case of weak lensing cosmic shear analyses and demonstrate our method using simulations made for the Dark Energy Survey (DES). We show that the method can correctly and efficiently marginalize over a wide range of models for the redshift distribution uncertainty. Finally, we compare hyperrank to the common mean-shifting method of marginalizing over redshift uncertainty, validating that this simpler model is sufficient for use in the DES Year 3 cosmology results presented in companion papers

Dark Energy Survey Y3 results: Blending shear and redshift biases in image simulations

As the statistical power of galaxy weak lensing reaches per cent level precision, large, realistic, and robust simulations are required to calibrate observational systematics, especially given the increased importance of object blending as survey depths increase. To capture the coupled effects of blending in both shear and photometric redshift calibration, we define the effective redshift distribution for lensing, nγ(z), and describe how to estimate it using image simulations. We use an extensive suite of tailored image simulations to characterize the performance of the shear estimation pipeline applied to the Dark Energy Survey (DES) Year 3 data set. We describe the multiband, multi-epoch simulations, and demonstrate their high level of realism through comparisons to the real DES data. We isolate the effects that generate shear calibration biases by running variations on our fiducial simulation, and find that blending-related effects are the dominant contribution to the mean multiplicative bias of approximately $-2{{ rm per cent}}$. By generating simulations with input shear signals that vary with redshift, we calibrate biases in our estimation of the effective redshift distribution, and demonstrate the importance of this approach when blending is present. We provide corrected effective redshift distributions that incorporate statistical and systematic uncertainties, ready for use in DES Year 3 weak lensing analyses

Detection of the significant impact of source clustering on higher-order statistics with DES Year 3 weak gravitational lensing data

We measure the impact of source galaxy clustering on higher-order summary statistics of weak gravitational lensing data. By comparing simulated data with galaxies that either trace or do not trace the underlying density field, we show this effect can exceed measurement uncertainties for common higher-order statistics for certain analysis choices. We evaluate the impact on different weak lensing observables, finding that third moments and wavelet phase harmonics are more affected than peak count statistics. Using Dark Energy Survey Year 3 data we construct null tests for the source-clustering-free case, finding a p-value of p = 4 × 10−3 (2.6σ) using third-order map moments and p = 3 × 10−11 (6.5σ) using wavelet phase harmonics. The impact of source clustering on cosmological inference can be either be included in the model or minimized through ad-hoc procedures (e.g. scale cuts). We verify that the procedures adopted in existing DES Y3 cosmological analyses were sufficient to render this effect negligible. Failing to account for source clustering can significantly impact cosmological inference from higher-order gravitational lensing statistics, e.g. higher-order N-point functions, wavelet-moment observables, and deep learning or field level summary statistics of weak lensing maps

Dark Energy Survey Year 3 results: Galaxy-halo connection from galaxy-galaxy lensing

Galaxy-galaxy lensing is a powerful probe of the connection between galaxies and their host dark matter haloes, which is important both for galaxy evolution and cosmology. We extend the measurement and modelling of the galaxy-galaxy lensing signal in the recent Dark Energy Survey Year 3 cosmology analysis to the highly non-linear scales (100 kpc). This extension enables us to study the galaxy-halo connection via a Halo Occupation Distribution (HOD) framework for the two lens samples used in the cosmology analysis: a luminous red galaxy sample (redmagic) and a magnitude-limited galaxy sample (maglim). We find that redmagic (maglim) galaxies typically live in dark matter haloes of mass log10(Mh/M) ≈ 13.7 which is roughly constant over redshift (13.3-13.5 depending on redshift). We constrain these masses to 15 per cent, approximately 1.5 times improvement over the previous work. We also constrain the linear galaxy bias more than five times better than what is inferred by the cosmological scales only. We find the satellite fraction for redmagic (maglim) to be 0.1-0.2 (0.1-0.3) with no clear trend in redshift. Our constraints on these halo properties are broadly consistent with other available estimates from previous work, large-scale constraints, and simulations. The framework built in this paper will be used for future HOD studies with other galaxy samples and extensions for cosmological analyses