Whole Exome Sequencing of Cell-Free DNA for Early Lung Cancer: A Pilot Study to Differentiate Benign From Malignant CT-Detected Pulmonary Lesions

Introduction: Indeterminate pulmonary lesions (IPL) detected by CT pose a significant clinical challenge, frequently necessitating long-term surveillance or biopsy for diagnosis. In this pilot investigation, we performed whole exome sequencing (WES) of plasma cell free (cfDNA) and matched germline DNA in patients with CT-detected pulmonary lesions to determine the feasibility of somatic cfDNA mutations to differentiate benign from malignant pulmonary nodules.Methods: 33 patients with a CT-detected pulmonary lesions were retrospectively enrolled (n = 16 with a benign nodule, n = 17 with a malignant nodule). Following isolation and amplification of plasma cfDNA and matched peripheral blood mononuclear cells (PBMC) from patient blood samples, WES of cfDNA and PBMC DNA was performed. After genomic alignment and filtering, we looked for lung-cancer associated driver mutations and next identified high-confidence somatic variants in both groups.Results: Somatic cfDNA mutations were observed in both groups, with the cancer group demonstrating more variants than the benign group (1083 ± 476 versus 553 ± 519, p < 0.0046). By selecting variants present in >2 cancer patients and not the benign group, we accurately identified 82% (14/17) of cancer patients.Conclusions: This study suggests a potential role for cfDNA for the early identification of lung cancer in patients with CT-detected pulmonary lesions. Importantly, a substantial number of somatic variants in healthy patients with benign pulmonary nodules were also found. Such “benign” variants, while largely unexplored to date, have widespread relevance to all liquid biopsies if cfDNA is to be used accurately for cancer detection

A Bright Submillimeter Source in the Bullet Cluster (1E0657--56) Field Detected with BLAST

We present the 250, 350, and 500 micron detection of bright submillimeter emission in the direction of the Bullet Cluster measured by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). The 500 micron centroid is coincident with an AzTEC 1.1 mm point-source detection at a position close to the peak lensing magnification produced by the cluster. However, the 250 micron and 350 micron centroids are elongated and shifted toward the south with a differential shift between bands that cannot be explained by pointing uncertainties. We therefore conclude that the BLAST detection is likely contaminated by emission from foreground galaxies associated with the Bullet Cluster. The submillimeter redshift estimate based on 250-1100 micron photometry at the position of the AzTEC source is z_phot = 2.9 (+0.6 -0.3), consistent with the infrared color redshift estimation of the most likely IRAC counterpart. These flux densities indicate an apparent far-infrared luminosity of L_FIR = 2E13 Lsun. When the amplification due to the gravitational lensing of the cluster is removed, the intrinsic far-infrared luminosity of the source is found to be L_FIR <= 10^12 Lsun, consistent with typical luminous infrared galaxies.Comment: Accepted for publication in the Astrophysical Journal. Maps are available at http://blastexperiment.info

The BLAST View of the Star Forming Region in Aquila (ell=45deg,b=0deg)

We have carried out the first general submillimeter analysis of the field towards GRSMC 45.46+0.05, a massive star forming region in Aquila. The deconvolved 6 deg^2 (3\degree X 2\degree) maps provided by BLAST in 2005 at 250, 350, and 500 micron were used to perform a preliminary characterization of the clump population previously investigated in the infrared, radio, and molecular maps. Interferometric CORNISH data at 4.8 GHz have also been used to characterize the Ultracompact HII regions (UCHIIRs) within the main clumps. By means of the BLAST maps we have produced an initial census of the submillimeter structures that will be observed by Herschel, several of which are known Infrared Dark Clouds (IRDCs). Our spectral energy distributions of the main clumps in the field, located at ~7 kpc, reveal an active population with temperatures of T~35-40 K and masses of ~10^3 Msun for a dust emissivity index beta=1.5. The clump evolutionary stages range from evolved sources, with extended HII regions and prominent IR stellar population, to massive young stellar objects, prior to the formation of an UCHIIR.The CORNISH data have revealed the details of the stellar content and structure of the UCHIIRs. In most cases, the ionizing stars corresponding to the brightest radio detections are capable of accounting for the clump bolometric luminosity, in most cases powered by embedded OB stellar clusters

Substance use disorders and risk of suicide in a general US population: a case control study

BACKGROUND: Prior research suggests that substance use disorders (SUDs) are associated with risk of suicide mortality, but most previous work has been conducted among Veterans Health Administration patients. Few studies have examined the relationship between SUDs and suicide mortality in general populations. Our study estimates the association of SUDs with suicide mortality in a general US population of men and women who receive care across eight integrated health systems. METHODS: We conducted a case-control study using electronic health records and claims data from eight integrated health systems of the Mental Health Research Network. Participants were 2674 men and women who died by suicide between 2000-2013 and 267,400 matched controls. The main outcome was suicide mortality, assessed using data from the health systems and confirmed by state death data systems. Demographic and diagnostic data on substance use disorders and other health conditions were obtained from each health system. First, we compared descriptive statistics for cases and controls, including age, gender, income, and education. Next, we compared the rate of each substance use disorder category for cases and controls. Finally, we used conditional logistic regression models to estimate unadjusted and adjusted odds of suicide associated with each substance use disorder category. RESULTS: All categories of substance use disorders were associated with increased risk of suicide mortality. Adjusted odds ratios ranged from 2.0 (CI 1.7, 2.3) for patients with tobacco use disorder only to 11.2 (CI 8.0, 15.6) for patients with multiple alcohol, drug, and tobacco use disorders. Substance use disorders were associated with increased relative risk of suicide for both women and men across all categories, but the relative risk was more pronounced in women. CONCLUSIONS: Substance use disorders are associated with significant risk of suicide mortality, especially for women, even after controlling for other important risk factors. Experiencing multiple substance use disorders is particularly risky. These findings suggest increased suicide risk screening and prevention efforts for individuals with substance use disorders are needed

BLAST05: Power Spectra of Bright Galactic Cirrus at Submillimeter Wavelengths

We report multi-wavelength power spectra of diffuse Galactic dust emission from BLAST observations at 250, 350, and 500 microns in Galactic Plane fields in Cygnus X and Aquila. These submillimeter power spectra statistically quantify the self-similar structure observable over a broad range of scales and can be used to assess the cirrus noise which limits the detection of faint point sources. The advent of submillimeter surveys with the Herschel Space Observatory makes the wavelength dependence a matter of interest. We show that the observed relative amplitudes of the power spectra can be related through a spectral energy distribution (SED). Fitting a simple modified black body to this SED, we find the dust temperature in Cygnus X to be 19.9 +/- 1.3 K and in the Aquila region 16.9 +/- 0.7 K. Our empirical estimates provide important new insight into the substantial cirrus noise that will be encountered in forthcoming observations.Comment: Submitted to the Astrophysical Journal. Maps and other data are available at http://blastexperiment.info

Submillimeter Number Counts From Statistical Analysis of BLAST Maps

We describe the application of a statistical method to estimate submillimeter galaxy number counts from confusion limited observations by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). Our method is based on a maximum likelihood fit to the pixel histogram, sometimes called 'P(D)', an approach which has been used before to probe faint counts, the difference being that here we advocate its use even for sources with relatively high signal-to-noise ratios. This method has an advantage over standard techniques of source extraction in providing an unbiased estimate of the counts from the bright end down to flux densities well below the confusion limit. We specifically analyse BLAST observations of a roughly 10 sq. deg. map centered on the Great Observatories Origins Deep Survey South (GOODS-S) field. We provide estimates of number counts at the three BLAST wavelengths, 250, 350, and 500 microns; instead of counting sources in flux bins we estimate the counts at several flux density nodes connected with power-laws. We observe a generally very steep slope for the counts of about -3.7 at 250 microns and -4.5 at 350 and 500 microns, over the range ~0.02-0.5 Jy, breaking to a shallower slope below about 0.015 Jy at all three wavelengths. We also describe how to estimate the uncertainties and correlations in this method so that the results can be used for model-fitting. This method should be well-suited for analysis of data from the Herschel satellite.Comment: Accepted for publication in the Astrophysical Journal; see associated data and other papers at http://blastexperiment.info

The BLAST Survey of the Vela Molecular Cloud: Physical Properties of the Dense Cores in Vela-D

The Balloon-borne Large-Aperture Submillimeter Telescope (BLAST) carried out a 250, 350 and 500 micron survey of the galactic plane encompassing the Vela Molecular Ridge, with the primary goal of identifying the coldest dense cores possibly associated with the earliest stages of star formation. Here we present the results from observations of the Vela-D region, covering about 4 square degrees, in which we find 141 BLAST cores. We exploit existing data taken with the Spitzer MIPS, IRAC and SEST-SIMBA instruments to constrain their (single-temperature) spectral energy distributions, assuming a dust emissivity index beta = 2.0. This combination of data allows us to determine the temperature, luminosity and mass of each BLAST core, and also enables us to separate starless from proto-stellar sources. We also analyze the effects that the uncertainties on the derived physical parameters of the individual sources have on the overall physical properties of starless and proto-stellar cores, and we find that there appear to be a smooth transition from the pre- to the proto-stellar phase. In particular, for proto-stellar cores we find a correlation between the MIPS24 flux, associated with the central protostar, and the temperature of the dust envelope. We also find that the core mass function of the Vela-D cores has a slope consistent with other similar (sub)millimeter surveys.Comment: Accepted for publication in the Astrophysical Journal. Data and maps are available at http://blastexperiment.info

Deconvolution of Images from BLAST 2005: Insight into the K3-50 and IC 5146 Star-Forming Regions

We present an implementation of the iterative flux-conserving Lucy-Richardson (L-R) deconvolution method of image restoration for maps produced by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). We have analyzed its performance and convergence extensively through simulations and cross-correlations of the deconvolved images with available highresolution maps. We present new science results from two BLAST surveys, in the Galactic regions K3-50 and IC 5146, further demonstrating the benefits of performing this deconvolution. We have resolved three clumps within a radius of 4.'5 inside the star-forming molecular cloud containing K3-50. Combining the well-resolved dust emission map with available multi-wavelength data, we have constrained the Spectral Energy Distributions (SEDs) of five clumps to obtain masses (M), bolometric luminosities (L), and dust temperatures (T). The L-M diagram has been used as a diagnostic tool to estimate the evolutionary stages of the clumps. There are close relationships between dust continuum emission and both 21-cm radio continuum and 12CO molecular line emission. The restored extended large scale structures in the Northern Streamer of IC 5146 have a strong spatial correlation with both SCUBA and high resolution extinction images. A dust temperature of 12 K has been obtained for the central filament. We report physical properties of ten compact sources, including six associated protostars, by fitting SEDs to multi-wavelength data. All of these compact sources are still quite cold (typical temperature below ~ 16 K) and are above the critical Bonner-Ebert mass. They have associated low-power Young Stellar Objects (YSOs). Further evidence for starless clumps has also been found in the IC 5146 region.Comment: 13 pages, 12 Figures, 3 Table

The Balloon-Borne Large Aperture Submillimeter Telescope (BLAST) 2005: A 10 deg^2 Survey of Star Formation in Cygnus X

We present Cygnus X in a new multi-wavelength perspective based on an unbiased BLAST survey at 250, 350, and 500 micron, combined with rich datasets for this well-studied region. Our primary goal is to investigate the early stages of high mass star formation. We have detected 184 compact sources in various stages of evolution across all three BLAST bands. From their well-constrained spectral energy distributions, we obtain the physical properties mass, surface density, bolometric luminosity, and dust temperature. Some of the bright sources reaching 40 K contain well-known compact H II regions. We relate these to other sources at earlier stages of evolution via the energetics as deduced from their position in the luminosity-mass (L-M) diagram. The BLAST spectral coverage, near the peak of the spectral energy distribution of the dust, reveals fainter sources too cool (~ 10 K) to be seen by earlier shorter-wavelength surveys like IRAS. We detect thermal emission from infrared dark clouds and investigate the phenomenon of cold ``starless cores" more generally. Spitzer images of these cold sources often show stellar nurseries, but these potential sites for massive star formation are ``starless" in the sense that to date there is no massive protostar in a vigorous accretion phase. We discuss evolution in the context of the L-M diagram. Theory raises some interesting possibilities: some cold massive compact sources might never form a cluster containing massive stars; and clusters with massive stars might not have an identifiable compact cold massive precursor.Comment: 42 pages, 31 Figures, 6 table

The Impossibility of a Perfectly Competitive Labor Market

Using the institutional theory of transaction cost, I demonstrate that the assumptions of the competitive labor market model are internally contradictory and lead to the conclusion that on purely theoretical grounds a perfectly competitive labor market is a logical impossibility. By extension, the familiar diagram of wage determination by supply and demand is also a logical impossibility and the neoclassical labor demand curve is not a well-defined construct. The reason is that the perfectly competitive market model presumes zero transaction cost and with zero transaction cost all labor is hired as independent contractors, implying multi-person firms, the employment relationship, and labor market disappear. With positive transaction cost, on the other hand, employment contracts are incomplete and the labor supply curve to the firm is upward sloping, again causing the labor demand curve to be ill-defined. As a result, theory suggests that wage rates are always and everywhere an amalgam of an administered and bargained price. Working Paper 06-0