Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid ...metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross section is by far the largest of all low-energy neutrino couplings. This ...mode of interaction offers new opportunities to study neutrino properties and leads to a miniaturization of detector size, with potential technological applications. We observed this process at a 6.7σ̃ confidence level, using a low-background, 14.6-kilogram CsINa scintillator exposed to the neutrino emissions from the Spallation Neutron Source at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the standard model for this process, were observed in high signal-to-background conditions. Improved constraints on nonstandard neutrino interactions with quarks are derived from this initial data set.
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Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well‐known gene‐drug pairs. Published ...recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.
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Changes in diurnal temperature range (DTR) over global land areas are compared from a broad range of independent data sets. All data sets agree that global‐mean DTR has decreased significantly since ...1950, with most of that decrease occurring over 1960–1980. The since‐1979 trends are not significant, with inter‐data set disagreement even over the sign of global changes. Inter‐data set spread becomes greater regionally and in particular at the grid box level. Despite this, there is general agreement that DTR decreased in North America, Europe, and Australia since 1951, with this decrease being partially reversed over Australia and Europe since the early 1980s. There is substantive disagreement between data sets prior to the middle of the twentieth century, particularly over Europe, which precludes making any meaningful conclusions about DTR changes prior to 1950, either globally or regionally. Several variants that undertake a broad range of approaches to postprocessing steps of gridding and interpolation were analyzed for two of the data sets. These choices have a substantial influence in data sparse regions or periods. The potential of further insights is therefore inextricably linked with the efficacy of data rescue and digitization for maximum and minimum temperature series prior to 1950 everywhere and in data sparse regions throughout the period of record. Over North America, station selection and homogeneity assessment is the primary determinant. Over Europe, where the basic station data are similar, the postprocessing choices are dominant. We assess that globally averaged DTR has decreased since the middle twentieth century but that this decrease has not been linear.
Key Points
It is virtually certain globally diurnal temperature range declined since 1950
Large differences/method sensitivities preclude assessment of DTR before 1950
In some regions DTR has very likely increased in the last two to three decades
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Forming stars emit a substantial amount of radiation into their natal environment. We use ORION, an adaptive mesh refinement (AMR) three-dimensional gravito-radiation-hydrodyanics code, to simulate ...low-mass star formation in a turbulent molecular cloud. We compare the distributions of stellar masses, accretion rates, and temperatures in the cases with and without radiative transfer, and we demonstrate that radiative feedback has a profound effect on accretion, multiplicity, and mass by reducing the number of stars formed and the total rate at which gas turns into stars. We also show that once the star formation reaches a steady state, protostellar radiation is by far the dominant source of energy in the simulation, exceeding viscous dissipation and compressional heating by at least an order of magnitude. Calculations that omit radiative feedback from protstars significantly underestimate the gas temperature and the strength of this effect. Although heating from protostars is mainly confined to the protostellar cores, we find that it is sufficient to suppress disk fragmentation that would otherwise result in very low-mass companions or brown dwarfs. We demonstrate that the mean protostellar accretion rate increases with the final stellar mass so that the star formation time is only a weak function of mass.
Because retinal and cerebral arterioles share similar pathologic processes, retinal microvascular changes are expected to be markers of cerebral small vessel disease (SVD). To better understand the ...role of SVD in cognitive function, we investigated the relationship between retinal microvascular abnormalities and longitudinal changes in cognitive function in a community-based study.
A total of 803 participants underwent 4 cognitive assessments between 1990-1992 and 2004-2006, using the Word Fluency (WF) test, Digit Symbol Substitution (DSS), and Delayed Word Recall as well as retinal photography in 1993-1995. Covariate adjusted random effects linear models for repeated measures were used to determine the associations of cognitive change with specific retinal vascular abnormalities.
Individuals with retinopathy showed declines in executive function and psychomotor speed, with 1) an average decline in WF of -1.64 words per decade (95% confidence interval CI -3.3, -0.02) compared to no decline in those without retinopathy +0.06 (95% CI -0.6, 0.8) and 2) a higher frequency of rapid decliners on the DSS test.
Signs of retinal vascular changes, as markers of the cerebral microvasculature, are associated with declines in executive function and psychomotor speed, adding to the growing evidence for the role of microvascular disease in cognitive decline in the elderly.
We characterize the infall rate onto protostellar systems forming in self-gravitating radiation-hydrodynamics simulations. Using two dimensionless parameters to determine the disks' susceptibility to ...gravitational fragmentation, we infer limits on protostellar system multiplicity and the mechanism of binary formation. We show that these parameters give robust predictions even in the case of marginally resolved protostellar disks. We find that protostellar systems with radiation feedback predominately form binaries via turbulent fragmentation, not disk instability, and predict that turbulent fragmentation is the dominant channel for binary formation for low-mass stars. We clearly demonstrate that systems forming in simulations including radiative feedback have fundamentally different parameters than those in purely hydrodynamics simulations.
Formation of Massive Star Systems by Accretion Krumholz, Mark R; Klein, Richard I; McKee, Christopher F ...
Science (American Association for the Advancement of Science),
02/2009, Volume:
323, Issue:
5915
Journal Article
Peer reviewed
Open access
Massive stars produce so much light that the radiation pressure they exert on the gas and dust around them is stronger than their gravitational attraction, a condition that has long been expected to ...prevent them from growing by accretion. We present three-dimensional radiation-hydrodynamic simulations of the collapse of a massive prestellar core and find that radiation pressure does not halt accretion. Instead, gravitational and Rayleigh-Taylor instabilities channel gas onto the star system through nonaxisymmetric disks and filaments that self-shield against radiation while allowing radiation to escape through optically thin bubbles. Gravitational instabilities cause the disk to fragment and form a massive companion to the primary star. Radiation pressure does not limit stellar masses, but the instabilities that allow accretion to continue lead to small multiple systems.
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Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh-Taylor instability is thought to produce structure at the interface ...between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh-Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants.
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant ...indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin‐related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
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