Cancers of unknown primary diagnosed during hospitalization: a population-based study

Background: Cancers of Unknown Primary (CUP) are the 3-4th most common causes of cancer death and recent clinical guidelines recommend that patients should be directed to a team dedicated to their care. Our aim was to inform the care of patients diagnosed with CUP during hospital admission. Methods: Descriptive study using hospital admissions (Scottish Morbidity Record 01) linked to cancer registrations (ICD-10 C77-80) and death records from 1998 to 2011 in West of Scotland, UK (population 2.4 m). Cox proportional hazards models were used to assess effects of baseline variables on survival. Results: Seven thousand five hundred ninety nine patients were diagnosed with CUP over the study period, 54.4% female, 67.4% aged ≥ 70 years, 36.7% from the most deprived socio-economic quintile. 71% of all diagnoses were made during a hospital admission, among which 88.6% were emergency presentations and the majority (56.3%) were admitted to general medicine. Median length of stay was 15 days and median survival after admission 33 days. Non-specific morphology, emergency admission, age over 60 years, male sex and admission to geriatric medicine were all associated with poorer survival in adjusted analysis. Conclusions: Patients with a diagnosis of CUP are usually diagnosed during unplanned hospital admissions and have very poor survival. To ensure that patients with CUP are quickly identified and directed to optimal care, increased surveillance and rapid referral pathways will be required

Landsat 9 Micrometeoroid and Orbital Debris (MMOD) Mission Success Approach

No abstract availabl

Compensation of x-ray mirror distortion by cooling temperature control

Synchrotron radiation is emitted from a bending magnet source in a wide ray fan which is collected by the first optical element in a beamline. In order to maximize angular acceptance, and hence flux, it is beneficial to increase the length of this mirror and optical design requirements may necessitate that the optical surface be over 1 m in length. Such mirrors also require cooling as they may be subject to high heat loads from the incident radiation. Two beamlines, B07 and B24, at Diamond Light Source, UK, use 1.4 m long toroidal mirrors which utilize a similar side-clamped cooling manifold design. While this scheme has been successful in providing effective cooling of the mirror, it has also been discovered that it introduces deformation of the radius of curvature which is sufficient to alter the focusing characteristics of the mirror. At both beamlines, the horizontal focus of the beam was found to differ by up to several meter from the design position at the exit slit which resulted in poor flux throughput, reduced energy resolution and other side effects. A pencil beam scan method has been used to diagnose this issue and infer the position of the focus and mirror shape. Through the use of a standalone chiller to alter the temperature of the water within the cooling loop, it has been possible to correct the distortion of the radius and restore the focus to its nominal position

Evaluating the potential impact of selection for the A2 milk allele on inbreeding and performance in Australian Holstein cattle

Selection decisions are generally based on estimated breeding values (EBV) for a combination of traits that are polygenic (e.g. milk production). However, in some cases, there is additional intense selection for a single allele, or SNP, for a perceived benefit, such as selection for polled or A2 milk. Using a dataset where the A2 mutation was imputed using a reference population with whole genome sequence, we tested the hypothesis that intense selection in Australian Holstein cattle for the A2 allele in the β-casein gene may have resulted in increased inbreeding. We also estimated the average difference in performance between animals homozygous for the A1 or A2 allele for a range of traits. Using high-density genotypes we compared differences in genome-wide and regional inbreeding between Holstein cows homozygous for either the A1 or A2 β-casein alleles i.e. A1/A1 or A2/A2. This study shows that between the years 2000 to 2017, the frequency of the A2/A2 genotype increased by 20% in Holstein cows (from 32% to 52%). Our results suggest that selection for homozygosity at the β-casein A2 allele has increased inbreeding both across the genome and on chromosome 6 in A2/A2 Holstein cows. Animals that were A2/A2 were twice as likely to have a run of homozygosity of at least 1Mb long across the β-casein locus compared to animals that were A1/A1. Cows that are homozygous for the A2 allele had an average protein yield EBV advantage of 0.24 genetic standard deviations (SD) compared to A1/A1 homozygous cows. In contrast, A2/A2 homozygous animals were on average 0.2 genetic SD inferior on fertility EBV. As a result, the difference in the overall economic index (that includes traits contributing to profitability) there was only a small advantage of 0.05 SD for A2/A2 cows compared to A1/A1 cows. However, strong selection for the A2 allele has likely led to a higher level of regional and overall inbreeding which in the long term could harm genetic progress for some or all economic traits. Therefore, applying approaches that mitigate rapid inbreeding while selecting for preferred alleles and quantitative traits may be desirable

A Planetary Microlensing Event with an Unusually Red Source Star: MOA-2011-BLG-291

We present the analysis of planetary microlensing event MOA-2011-BLG-291, which has a mass ratio of $q=(3.8\pm0.7)\times10^{-4}$ and a source star that is redder (or brighter) than the bulge main sequence. This event is located at a low Galactic latitude in the survey area that is currently planned for NASA's WFIRST exoplanet microlensing survey. This unusual color for a microlensed source star implies that we cannot assume that the source star is in the Galactic bulge. The favored interpretation is that the source star is a lower main sequence star at a distance of $D_S=4.9\pm1.3\,$kpc in the Galactic disk. However, the source could also be a turn-off star on the far side of the bulge or a sub-giant in the far side of the Galactic disk if it experiences significantly more reddening than the bulge red clump stars. However, these possibilities have only a small effect on our mass estimates for the host star and planet. We find host star and planet masses of $M_{\rm host} =0.15^{+0.27}_{-0.10}M_\odot$ and $m_p=18^{+34}_{-12}M_\oplus$ from a Bayesian analysis with a standard Galactic model under the assumption that the planet hosting probability does not depend on the host mass or distance. However, if we attempt to measure the host and planet masses with host star brightness measurements from high angular resolution follow-up imaging, the implied masses will be sensitive to the host star distance. The WFIRST exoplanet microlensing survey is expected to use this method to determine the masses for many of the planetary systems that it discovers, so this issue has important design implications for the WFIRST exoplanet microlensing survey

A CD8 + NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution. Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy. Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome. NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression. We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics

A CD8 + NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution. Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy. Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome. NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression. We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS

OGLE-2018-BLG-0022: First Prediction of an Astrometric Microlensing Signal from a Photometric Microlensing Event

In this work, we present the analysis of the binary microlensing event OGLE-2018-BLG-0022 that is detected toward the Galactic bulge field. The dense and continuous coverage with the high-quality photometry data from ground-based observations combined with the space-based {\it Spitzer} observations of this long time-scale event enables us to uniquely determine the masses $M_1=0.40 \pm 0.05~M_\odot$ and $M_2=0.13\pm 0.01~M_\odot$ of the individual lens components. Because the lens-source relative parallax and the vector lens-source relative proper motion are unambiguously determined, we can likewise unambiguously predict the astrometric offset between the light centroid of the magnified images (as observed by the {\it Gaia} satellite) and the true position of the source. This prediction can be tested when the individual-epoch {\it Gaia} astrometric measurements are released.Comment: 10 pages, 10 figures, 4 table

SpitzerSpitzer Parallax of OGLE-2018-BLG-0596: A Low-mass-ratio Planet around an M-dwarf

We report the discovery of a $Spitzer$ microlensing planet OGLE-2018-BLG-0596Lb, with preferred planet-host mass ratio $q \sim 2\times10^{-4}$. The planetary signal, which is characterized by a short $(\sim 1~{\rm day})$ "bump" on the rising side of the lensing light curve, was densely covered by ground-based surveys. We find that the signal can be explained by a bright source that fully envelops the planetary caustic, i.e., a "Hollywood" geometry. Combined with the source proper motion measured from $Gaia$, the $Spitzer$ satellite parallax measurement makes it possible to precisely constrain the lens physical parameters. The preferred solution, in which the planet perturbs the minor image due to lensing by the host, yields a Uranus-mass planet with a mass of $M_{\rm p} = 13.9\pm1.6~M_{\oplus}$ orbiting a mid M-dwarf with a mass of $M_{\rm h} = 0.23\pm0.03~M_{\odot}$. There is also a second possible solution that is substantially disfavored but cannot be ruled out, for which the planet perturbs the major image. The latter solution yields $M_{\rm p} = 1.2\pm0.2~M_{\oplus}$ and $M_{\rm h} = 0.15\pm0.02~M_{\odot}$. By combining the microlensing and $Gaia$ data together with a Galactic model, we find in either case that the lens lies on the near side of the Galactic bulge at a distance $D_{\rm L} \sim 6\pm1~{\rm kpc}$. Future adaptive optics observations may decisively resolve the major image/minor image degeneracy.Comment: 34 pages, 8 figures, Submitted to AAS journa