Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis

Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed that mice fed a high-fat diet have shorter mammary cancer latency, increased tumor growth and more pulmonary metastases than mice fed a standard diet. Subsequent genetic analysis identified several modifiers of metastatic mammary cancer along with widespread interactions between cancer modifiers and dietary fat. To elucidate diet-dependent genetic modifiers of mammary cancer and metastasis risk, global gene expression profiles and copy number alterations from mammary cancers were measured and expression quantitative trait loci (eQTL) identified. Functional candidate genes that colocalized with previously detected metastasis modifiers were identified. Additional analyses, such as eQTL by dietary fat interaction analysis, causality and database evaluations, helped to further refine the candidate loci to produce an enriched list of genes potentially involved in the pathogenesis of metastatic mammary cancer

First-in-human clinical trial of ultrasonic propulsion of kidney stones

PURPOSE: Ultrasonic propulsion is a new technology using focused ultrasound energy applied transcutaneously to reposition kidney stones. We report what are to our knowledge the findings from the first human investigational trial of ultrasonic propulsion toward the applications of expelling small stones and dislodging large obstructing stones. MATERIALS AND METHODS: Subjects underwent ultrasonic propulsion while awake without sedation in clinic, or during ureteroscopy while anesthetized. Ultrasound and a pain questionnaire were completed before, during and after propulsion. The primary outcome was to reposition stones in the collecting system. Secondary outcomes included safety, controllable movement of stones and movement of stones less than 5 mm and 5 mm or greater. Adverse events were assessed weekly for 3 weeks. RESULTS: Kidney stones were repositioned in 14 of 15 subjects. Of the 43 targets 28 (65%) showed some level of movement while 13 (30%) were displaced greater than 3 mm to a new location. Discomfort during the procedure was rare, mild, brief and self-limited. Stones were moved in a controlled direction with more than 30 fragments passed by 4 of the 6 subjects who had previously undergone a lithotripsy procedure. The largest stone moved was 10 mm. One patient experienced pain relief during treatment of a large stone at the ureteropelvic junction. In 4 subjects a seemingly large stone was determined to be a cluster of small passable stones after they were moved. CONCLUSIONS: Ultrasonic propulsion was able to successfully reposition stones and facilitate the passage of fragments in humans. No adverse events were associated with the investigational procedure

A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: The COVID-SED study

BACKGROUND: Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. STUDY DESIGN AND METHODS: Dual-center, retrospective cohort study conducted over 6 months (March-August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 h were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of - 3 to - 5 or Riker Sedation-Agitation Scale of 1-3. To examine impact of early sedation depth on hospital mortality (primary outcome), we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days. RESULTS: 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation (p \u3c 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65-7.17; p \u3c 0.01). These results were stable in the subgroup of patients with COVID-19. CONCLUSIONS: The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach

The Resolved Structure and Dynamics of an Isolated Dwarf Galaxy: A VLT and Keck Spectroscopic Survey of WLM

We present spectroscopic data for 180 red giant branch stars in the isolated dwarf irregular galaxy WLM. Observations of the Calcium II triplet lines in spectra of RGB stars covering the entire galaxy were obtained with FORS2 at the VLT and DEIMOS on Keck II allowing us to derive velocities, metallicities, and ages for the stars. With accompanying photometric and radio data we have measured the structural parameters of the stellar and gaseous populations over the full galaxy. The stellar populations show an intrinsically thick configuration with $0.39 \leq q_{0} \leq 0.57$. The stellar rotation in WLM is measured to be $17 \pm 1$ km s$^{-1}$, however the ratio of rotation to pressure support for the stars is $V/\sigma \sim 1$, in contrast to the gas whose ratio is seven times larger. This, along with the structural data and alignment of the kinematic and photometric axes, suggests we are viewing WLM as a highly inclined oblate spheroid. Stellar rotation curves, corrected for asymmetric drift, are used to compute a dynamical mass of $4.3\pm 0.3\times10^{8}$M$_{\odot}$ at the half light radius ($r_{h} = 1656 \pm 49$ pc). The stellar velocity dispersion increases with stellar age in a manner consistent with giant molecular cloud and substructure interactions producing the heating in WLM. Coupled with WLM's isolation, this suggests that the extended vertical structure of its stellar and gaseous components and increase in stellar velocity dispersion with age are due to internal feedback, rather than tidally driven evolution. These represent some of the first observational results from an isolated Local Group dwarf galaxy which can offer important constraints on how strongly internal feedback and secular processes modulate SF and dynamical evolution in low mass isolated objects.Comment: 14 Pages, 17 figures, 3 tables. Accepted for publication in Ap

Spectrum and Morphology of the Two Brightest Milagro Sources in the Cygnus Region: MGRO J2019+37 and MGRO J2031+41

The Cygnus region is a very bright and complex portion of the TeV sky, host to unidentified sources and a diffuse excess with respect to conventional cosmic-ray propagation models. Two of the brightest TeV sources, MGRO J2019+37 and MGRO J2031+41, are analyzed using Milagro data with a new technique, and their emission is tested under two different spectral assumptions: a power law and a power law with an exponential cutoff. The new analysis technique is based on an energy estimator that uses the fraction of photomultiplier tubes in the observatory that detect the extensive air shower. The photon spectrum is measured in the range 1 to 200 TeV using the last 3 years of Milagro data (2005-2008), with the detector in its final configuration. MGRO J2019+37 is detected with a significance of 12.3 standard deviations ($\sigma$), and is better fit by a power law with an exponential cutoff than by a simple power law, with a probability $>98$% (F-test). The best-fitting parameters for the power law with exponential cutoff model are a normalization at 10 TeV of $7^{+5}_{-2}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$, a spectral index of $2.0^{+0.5}_{-1.0}$ and a cutoff energy of $29^{+50}_{-16}$ TeV. MGRO J2031+41 is detected with a significance of 7.3$\sigma$, with no evidence of a cutoff. The best-fitting parameters for a power law are a normalization of $2.4^{+0.6}_{-0.5}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$ and a spectral index of $3.08^{+0.19}_{-0.17}$. The overall flux is subject to an $\sim$30% systematic uncertainty. The systematic uncertainty on the power law indices is $\sim$0.1. A comparison with previous results from TeV J2032+4130, MGRO J2031+41 and MGRO J2019+37 is also presented.Comment: 11 pages, 10 figure

A pair production telescope for medium-energy gamma-ray polarimetry

We describe the science motivation and development of a pair production telescope for medium-energy (∼5–200 MeV) gamma-ray polarimetry. Our instrument concept, the Advanced Energetic Pair Telescope (AdEPT), takes advantage of the Three-Dimensional Track Imager, a low-density gaseous time projection chamber, to achieve angular resolution within a factor of two of the pair production kinematics limit (∼0.6° at 70 MeV), continuum sensitivity comparable with the Fermi-LAT front detector (<3 × 10−6 MeV cm−2 s−1 at 70 MeV), and minimum detectable polarization less than 10% for a 10 mCrab source in 106 s.submittedVersionFil: Hunter, Stanley D. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Bloser, Peter F. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Depaola, Gerardo Osvaldo. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Dion, Michael P. Department of Energy. Office of Science. Pacific Northwest National Laboratory; Estados Unidos de América.Fil: DeNolfo, Georgia A. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Hanu, Andrei. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Iparraguirre, Lorenzo Marcos. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Legere, Jason. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Longo, Francesco. Università Degli Studi de Trieste. Dipartimento di fisica; Italia.Fil: McConnell, Mark L. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Nowicki, Suzanne F. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Nowicki, Suzanne F. University of Maryland, Baltimore County. Department of Physics; Estados Unidos de América.Fil: Ryan, James M. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Son, Seunghee. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Son, Seunghee. University of Maryland, Baltimore County. Department of Physics; Estados Unidos de América.Fil: Stecker, Floyd W. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Física de Partículas y Campo

Prevalence of bullying and aggressive behavior and their relationship to mental health problems among 12- to 15-year-old Norwegian adolescents

The aim of this study was to examine the relationships between being bullied and aggressive behavior and self-reported mental health problems among young adolescents. A representative population sample of 2,464 young Norwegian adolescents (50.8% girls) aged 12–15 years was assessed. Being bullied was measured using three items concerning teasing, exclusion, and physical assault. Self-esteem was assessed by Harter’s self-perception profile for adolescents. Emotional and behavioral problems were measured by the Moods and Feelings Questionnaire (MFQ) and the youth self-report (YSR). Aggressive behavior was measured by four items from the YSR. One-tenth of the adolescents reported being bullied, and 5% reported having been aggressive toward others during the past 6 months. More of the students being bullied and students being aggressive toward others reported parental divorce, and they showed higher scores on all YSR subscales and on the MFQ questions, and lower scores on the global self-worth subscale (Harter) than students not being bullied or aggressive. A few differences emerged between the two groups being bullied or being aggressive toward others: those who were aggressive showed higher total YSR scores, higher aggression and delinquency scores, and lower social problems scores, and reported higher scores on the social acceptance subscale (Harter) than bullied students. However, because social problems were demonstrated in both the involved groups, interventions designed to improve social competence and interaction skills should be integrated in antibullying programs

MEGA: A Medium-Energy Gamma-ray Astronomy mission concept

The Medium Energy Gamma-ray Astronomy (MEGA) telescope concept will soon be proposed as a MIDEX mission. This mission would enable a sensitive all-sky survey of the medium-energy gamma-ray sky (0.4 - 50 MeV) and bridge the huge sensitivity gap between the COMPTEL and OSSE experiments on the Compton Gamma Ray Observatory, the SPI and IBIS instruments on INTEGRAL, and the visionary Advanced Compton Telescope (ACT) mission. The scientific goals include, among other things, compiling a much larger catalog of sources in this energy range, performing far deeper searches for supernovae, better measuring the galactic continuum and line emissions, and identifying the components of the cosmic diffuse gamma-ray emission. MEGA will accomplish these goals using a tracker made of Si strip detector (SSD) planes surrounded by a dense high-Z calorimeter. At lower photon energies (below ∼ 30 MeV), the design is sensitive to Compton interactions, with the SSD system serving as a scattering medium that also detects and measures the Compton recoil energy deposit. If the energy of the recoil electron is sufficiently high (\u3e 2 MeV) its momentum vector can also be measured. At higher photon energies (above ∼10 MeV), the design is sensitive to pair production events, with the SSD system measuring the tracks of the electron and positron. A prototype instrument has been developed and calibrated in the laboratory and at a gamma-ray beam facility. We present calibration results from the prototype and describe the proposed satellite mission

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis