Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

© 2015, BMJ Publishing Group. All rights reserved. Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies ( < 5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy

Quantum-Liouville and Langevin Equations for Gravitational Radiation Damping

From a forward--backward path integral, we derive a master equation for the emission and absorption of gravitons by a massive quantum object in a heat bath of gravitons. Such an equation could describe collapse phenomena of dense stars. We also present a useful approximate Langevin equation for such a system.Comment: Author Information under http://www.physik.fu-berlin.de/~kleinert/institution.html . Latest update of paper (including all PS fonts) at http://www.physik.fu-berlin.de/~kleinert/31

High-Redshift Galaxies: Their Predicted Size and Surface Brightness Distributions and Their Gravitational Lensing Probability

Direct observations of the first generation of luminous objects will likely become feasible over the next decade. The advent of the Next Generation Space Telescope (NGST) will allow imaging of numerous galaxies and mini-quasars at redshifts z>5. We apply semi-analytic models of structure formation to estimate the rate of multiple imaging of these sources by intervening gravitational lenses. Popular CDM models for galaxy formation yield a lensing optical depth of about 1% for sources at redshift 10. The expected slope of the luminosity function of the early sources implies an additional magnification bias of about 5, bringing the fraction of lensed sources at z=10 to about 5%. We estimate the angular size distribution of high-redshift disk galaxies and find that most of them are more extended than the resolution limit of NGST, roughly 0.06 arcseconds. We also show that there is only a modest redshift evolution in the mean surface brightness of galaxies at z>2. The expected increase by 1-2 orders of magnitude in the number of resolved sources on the sky, due to observations with NGST, will dramatically improve upon the statistical significance of existing weak lensing measurements. We show that, despite this increase in the density of sources, confusion noise from z>2 galaxies is expected to be small for NGST observations.Comment: 27 pages, 8 PostScript figures (of which two are new), revised version accepted for Ap

Effects of Extreme Obliquity Variations on the Habitability of Exoplanets

We explore the impact of obliquity variations on planetary habitability in hypothetical systems with high mutual inclination. We show that large amplitude, high frequency obliquity oscillations on Earth-like exoplanets can suppress the ice-albedo feedback, increasing the outer edge of the habitable zone. We restrict our exploration to hypothetical systems consisting of a solar-mass star, an Earth-mass planet at 1 AU, and 1 or 2 larger planets. We verify that these systems are stable for $10^8$ years with N-body simulations, and calculate the obliquity variations induced by the orbital evolution of the Earth-mass planet and a torque from the host star. We run a simplified energy balance model on the terrestrial planet to assess surface temperature and ice coverage on the planet's surface, and we calculate differences in the outer edge of the habitable zone for planets with rapid obliquity variations. For each hypothetical system, we calculate the outer edge of habitability for two conditions: 1) the full evolution of the planetary spin and orbit, and 2) the eccentricity and obliquity fixed at their average values. We recover previous results that higher values of fixed obliquity and eccentricity expand the habitable zone, but also find that obliquity oscillations further expand habitable orbits in all cases. Terrestrial planets near the outer edge of the habitable zone may be more likely to support life in systems that induce rapid obliquity oscillations as opposed to fixed-spin planets. Such planets may be the easiest to directly characterize with space-borne telescopes.Comment: 46 pages, 12 Figures, 5 Table

Axiomatic approach to radiation reaction of scalar point particles in curved spacetime

Several different methods have recently been proposed for calculating the motion of a point particle coupled to a linearized gravitational field on a curved background. These proposals are motivated by the hope that the point particle system will accurately model certain astrophysical systems which are promising candidates for observation by the new generation of gravitational wave detectors. Because of its mathematical simplicity, the analogous system consisting of a point particle coupled to a scalar field provides a useful context in which to investigate these proposed methods. In this paper, we generalize the axiomatic approach of Quinn and Wald in order to produce a general expression for the self force on a point particle coupled to a scalar field following an arbitrary trajectory on a curved background. Our equation includes the leading order effects of the particle's own fields, commonly referred to as ``self force'' or ``radiation reaction'' effects. We then explore the equations of motion which follow from this expression in the absence of non-scalar forces.Comment: 17 pages, 1 figur

PATENTS, R&D AND LAG EFFECTS: EVIDENCE FROM FLEXIBLE METHODS FOR COUNT PANEL DATA ON MANUFACTURING FIRMS

Hausman, Hall and Griliches (1984) and Hall, Griliches and Hausman (1986) investigated whether there was a lag in the patent-R&D relationship for the U.S. manufacturing sector using 1970¿s data. They found that there was little evidence of anything but contemporaneous movement of patents and R&D. We reexamine this important issue employing new longitudinal patent data at the firm level for the U.S. manufacturing sector from 1982 to 1992. To address unique features of the data, we estimate various distributed lag and dynamic multiplicative panel count data models. The paper also develops a new class of count panel data models based on series expansion of the distribution of individual effects. The empirical analyses show that, although results are somewhat sensitive to different estimation methods, the contemporaneous relationship between patenting and R&D expenditures continues to be rather strong, accounting for over 60% of the total R&D elasticity. Regarding the lag structure of the patents-R&D relationship, we do find a significant lag in all empirical specifications. Moreover, the estimated lag effects are higher than have previously been found, suggesting that the contribution of R&D history to current patenting has increased from the 1970¿s to the 1980¿s.Innovative activity, Patents and R&D, Individual effects, count panel data methods.

Ejection of Supernova-Enriched Gas From Dwarf Disk Galaxies

We examine the efficiency with which supernova-enriched gas may be ejected from dwarf disk galaxies, using a methodology previously employed to study the self-enrichment efficiency of dwarf spheroidal systems. Unlike previous studies that focused on highly concentrated starbursts, in the current work we consider discrete supernova events spread throughout various fractions of the disk. We model disk systems having gas masses of 10^8 and 10^9 solar masses with supernova rates of 30, 300, and 3000 per Myr. The supernova events are confined to the midplane of the disk, but distributed over radii of 0, 30, and 80% of the disk radius, consistent with expectations for Type II supernovae. In agreement with earlier studies, we find that the enriched material from supernovae is largely lost when the supernovae are concentrated near the nucleus, as expected for a starburst event. In contrast, however, we find the loss of enriched material to be much less efficient when the supernovae occur over even a relatively small fraction of the disk. The difference is due to the ability of the system to relax following supernova events that occur over more extended regions. Larger physical separations also reduce the likelihood of supernovae going off within low-density "chimneys" swept out by previous supernovae. We also find that, for the most distributed systems, significant metal loss is more likely to be accompanied by significant mass loss. A comparison with theoretical predications indicates that, when undergoing self-regulated star formation, galaxies in the mass range considered shall efficiently retain the products of Type II supernovae.Comment: 16 pages, 14 figures, to appear in Astrophysical Journal; higher resolution figures available through Ap