The large administrative databases of health plans contain information on drug-related medical adverse events (AE) and constitute an increasingly powerful tool for the assessment of drug safety. We ...conducted a retrospective observational study using an administrative managed care claims database covering 9 million members from diverse regions of the United States. Patients aged ≥18 years who received ≥2 prescriptions for lipid-lowering drugs between July 1, 2000 and December 1, 2004 were included in the study. Hospitalizations with diagnosis codes (
International Classification of Diseases, 9th Revision, Clinical Modification ICD-9) related to muscle, kidney, and liver were determined for patients exposed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibrates, extended-release niacin, cholesterol absorption inhibitors, or statin combination therapy. A total of 473,343 patients contributed 490,988 person-years of monotherapy and 11,624 person-years of combination dyslipidemia therapy. Rates of hospitalization due to AEs in patients on monotherapy with currently available statins were similar, whereas the incidence of hospitalization for muscle disorders increased 6.7-fold with cerivastatin therapy. Patients who received a lipid-lowering medication with a concomitant cytochrome P450 3A4 (CYP3A4) inhibitor had a 6-fold increased rate of muscle disorders, including rhabdomyolysis. Hypertension was associated with a 5-fold increase in both muscle and renal events, whereas patients with diabetes mellitus had a 2.5-fold increased risk of renal events. No hospitalized cases of the index AEs were observed in study subjects during the 6-month period before initiation of the lipid-lowering drug. Statin monotherapy as currently prescribed is generally well tolerated and safe.
Background. Neutrophils from patients with chronic kidney disease (CKD) are dysfunctional and thus a contributing factor to the risk of infections. The mechanisms for leucocyte dysfunction in CKD are ...not fully understood. It is known that lipopolysaccharide (LPS) activates transcription of several genes encoding proinflammatory cytokines. We therefore aimed to study the effect of LPS on neutrophil expression of genes related to the inflammatory response to address the hypothesis that LPS-induced gene transcriptions are altered in CKD patients.
Methods. We analysed gene expression of LPS-stimulated neutrophils from 30 patients with CKD and 15 healthy controls. Superoxide dismutase-2 (SOD2), IL1A, IL-1R1, IL-1R2 and IL8RA gene expression from both neutrophils and differentiated HL60 cells were measured by quantitative polymerase chain reaction. Differentiated HL60 cells were stimulated with phorbol-12-myristate-7-acetate (PMA) after inhibition of SOD2 by small interfering RNA followed by respiratory burst assessment using flow cytometry.
Results. LPS stimulation induced a significant mobilization of CD11b on neutrophils from CKD and healthy controls. Upregulation of SOD2, IL1A, IL-1R1 and IL-1R2 gene expression in neutrophils from healthy controls after LPS stimulation was contrasted by no change in gene transcription (IL-1R1 and IL-1R2) or even a downregulation in patients with CKD (SOD2 and IL1A). Inhibition of SOD2 reduced the PMA-induced respiratory burst and IL1A, IL-1R1, IL-1R2 and IL8RA gene expression in neutrophil-differentiated HL60 cells.
Conclusions. Because of the critical role of SOD2 in the generation of hydrogen peroxide during phagocytosis, downregulation of SOD2 gene expression after LPS stimulation in neutrophils from patients with CKD indicates a potential mechanism for neutrophil dysfunction and cytokine dysregulation in these patients.
In this phase 3 study involving patients with HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis, treatment with 12 weeks of sofosbuvir and velpatasvir resulted in a ...sustained virologic response in 99% of patients.
The hepatitis C virus (HCV), a single-stranded RNA virus of the family Flaviviridae with six major genotypes, infects up to 150 million people worldwide.
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Chronic HCV infection causes progressive liver fibrosis, which can lead to cirrhosis, hepatic decompensation, and hepatocellular carcinoma.
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As many as half a million people die annually from liver disease associated with chronic HCV infection.
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In recent years, the development of drugs that directly interfere with HCV replication has revolutionized HCV treatment. There are now effective combinations of direct-acting antiviral agents for most patients, but in choosing an appropriate regimen, clinicians must take into account . . .
The element abundance ratios of four low-mass stars with extremely low metallicities (abundances of elements heavier than helium) indicate that the gas out of which the stars formed was enriched in ...each case by at most a few--and potentially only one--low-energy supernova. Such supernovae yield large quantities of light elements such as carbon but very little iron. The dominance of low-energy supernovae seems surprising, because it had been expected that the first stars were extremely massive, and that they disintegrated in pair-instability explosions that would rapidly enrich galaxies in iron. What has remained unclear is the yield of iron from the first supernovae, because hitherto no star has been unambiguously interpreted as encapsulating the yield of a single supernova. Here we report the optical spectrum of SMSS J031300.36-670839.3, which shows no evidence of iron (with an upper limit of 10(-7.1) times solar abundance). Based on a comparison of its abundance pattern with those of models, we conclude that the star was seeded with material from a single supernova with an original mass about 60 times that of the Sun (and that the supernova left behind a black hole). Taken together with the four previously mentioned low-metallicity stars, we conclude that low-energy supernovae were common in the early Universe, and that such supernovae yielded light-element enrichment with insignificant iron. Reduced stellar feedback both chemically and mechanically from low-energy supernovae would have enabled first-generation stars to form over an extended period. We speculate that such stars may perhaps have had an important role in the epoch of cosmic reionization and the chemical evolution of early galaxies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lunar and terrestrial planet formation in the Grand Tack scenario Jacobson, S. A.; Morbidelli, A.
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
09/2014, Letnik:
372, Številka:
2024
Journal Article
Recenzirano
Odprti dostop
We present conclusions from a large number of N-body simulations of the giant impact phase of terrestrial planet formation. We focus on new results obtained from the recently proposed Grand Tack ...model, which couples the gas-driven migration of giant planets to the accretion of the terrestrial planets. The giant impact phase follows the oligarchic growth phase, which builds a bi-modal mass distribution within the disc of embryos and planetesimals. By varying the ratio of the total mass in the embryo population to the total mass in the planetesimal population and the mass of the individual embryos, we explore how different disc conditions control the final planets. The total mass ratio of embryos to planetesimals controls the timing of the last giant (Moon-forming) impact and its violence. The initial embryo mass sets the size of the lunar impactor and the growth rate of Mars. After comparing our simulated outcomes with the actual orbits of the terrestrial planets (angular momentum deficit, mass concentration) and taking into account independent geochemical constraints on the mass accreted by the Earth after the Moon-forming event and on the time scale for the growth of Mars, we conclude that the protoplanetary disc at the beginning of the giant impact phase must have had most of its mass in Mars-sized embryos and only a small fraction of the total disc mass in the planetesimal population. From this, we infer that the Moon-forming event occurred between approximately 60 and approximately 130 Myr after the formation of the first solids and was caused most likely by an object with a mass similar to that of Mars.
•We combine N-body accretion and core–mantle differentiation models.•We model the chemical evolution of the mantles and cores of the terrestrial planets.•Tight constraints are placed on the ...compositions of Solar System primitive bodies.•Oxidation occurred in the early Solar System through the inward migration of ice.•Water that accretes to the planets originates in bodies that formed beyond 6–7AU.
In order to test accretion simulations as well as planetary differentiation scenarios, we have integrated a multistage core–mantle differentiation model with N-body accretion simulations. Impacts between embryos and planetesimals are considered to result in magma ocean formation and episodes of core formation. The core formation model combines rigorous chemical mass balance with metal–silicate element partitioning data and requires that the bulk compositions of all starting embryos and planetesimals are defined as a function of their heliocentric distances of origin. To do this, we assume that non-volatile elements are present in Solar System (CI) relative abundances in all bodies and that oxygen and H2O contents are the main compositional variables. The primary constraint on the combined model is the composition of the Earth’s primitive mantle. In addition, we aim to reproduce the composition of the martian mantle and the mass fractions of the metallic cores of Earth and Mars. The model is refined by least squares minimization with up to five fitting parameters that consist of the metal–silicate equilibration pressure and 1–4 parameters that define the starting compositions of primitive bodies. This integrated model has been applied to six Grand Tack N-body accretion simulations. Investigations of a broad parameter space indicate that: (1) accretion of Earth was heterogeneous, (2) metal–silicate equilibration pressures increase as accretion progresses and are, on average, 60–70% of core–mantle boundary pressures at the time of each impact, and (3) a large fraction (70–100%) of the metal of impactor cores equilibrates with a small fraction of the silicate mantles of proto-planets during each core formation event. Results are highly sensitive to the compositional model for the primitive starting bodies and several accretion/core-formation models can thus be excluded. Acceptable fits to the Earth’s mantle composition are obtained only when bodies that originated close to the Sun, at <0.9–1.2AU, are highly reduced and those from beyond this distance are increasingly oxidized. Reasonable concentrations of H2O in Earth’s mantle are obtained when bodies originating from beyond 6–7AU contain 20wt% water ice (icy bodies that originated between the snow line and this distance did not contribute to Earth’s accretion because they were swept up by Jupiter and Saturn). In the six models examined, water is added to the Earth mainly after 60–80% of its final mass has accreted. The compositional evolution of the mantles of Venus and Mars are also constrained by the model. The FeO content of the martian mantle depends critically on the heliocentric distance at which the Mars-forming embryo originated. Finally, the Earth’s core is predicted to contain 8–9wt% silicon, 2–4wt% oxygen and 10–60ppm hydrogen, whereas the martian core is predicted to contain low concentrations (<1wt%) of Si and O.
Longitudinal phase space (LPS) provides a critical information about electron beam dynamics for various scientific applications. For example, it can give insight into the high-brightness X-ray ...radiation from a free electron laser. Existing diagnostics are invasive, and often times cannot operate at the required resolution. In this work we present a machine learning-based Virtual Diagnostic (VD) tool to accurately predict the LPS for every shot using spectral information collected non-destructively from the radiation of relativistic electron beam. We demonstrate the tool's accuracy for three different case studies with experimental or simulated data. For each case, we introduce a method to increase the confidence in the VD tool. We anticipate that spectral VD would improve the setup and understanding of experimental configurations at DOE's user facilities as well as data sorting and analysis. The spectral VD can provide confident knowledge of the longitudinal bunch properties at the next generation of high-repetition rate linear accelerators while reducing the load on data storage, readout and streaming requirements.
Earth and the Moon are shown here to have indistinguishable oxygen isotope ratios, with a difference in Δ'¹⁷ O of −1 ± 5 parts per million (2 standard error). On the basis of these data and our new ...planet formation simulations that include a realistic model for primordial oxygen isotopic reservoirs, our results favor vigorous mixing during the giant impact and therefore a high-energy, high-angular-momentum impact. The results indicate that the late veneer impactors had an average Δ'¹⁷ O within approximately 1 per mil of the terrestrial value, limiting possible sources for this late addition of mass to the Earth-Moon system.
The Al/Si and Mg/Si ratios in non-carbonaceous chondrites are lower than the solar (i.e., CI-chondritic) values, in sharp contrast to the non-CI carbonaceous meteorites and the Earth, which are ...enriched in refractory elements and have Mg/Si ratios that are solar or larger. We show that the formation of a first generation of planetesimals during the condensation of refractory elements implies the subsequent formation of residual condensates with strongly sub-solar Al/Si and Mg/Si ratios. The mixing of residual condensates with different amounts of material with solar refractory/Si element ratios explains the Al/Si and Mg/Si values of non-carbonaceous chondrites. To match quantitatively the observed ratios, we find that the first-planetesimals should have accreted when the disk temperature was ∼1,330–1,400 K depending on pressure and assuming a solar C/O ratio of the disk. We discuss how this model relates to our current understanding of disk evolution, grain dynamics, and planetesimal formation. We also extend the discussion to moderately volatile elements (e.g., Na), explaining how it may be possible that the depletion of these elements in non-carbonaceous chondrites is correlated with the depletion of refractory elements (e.g., Al). Extending the analysis to Cr, we find evidence for a higher than solar C/O ratio in the protosolar disk's gas when/where condensation from a fractionated gas occurred. Finally, we discuss the possibility that the supra-solar Al/Si and Mg/Si ratios of the Earth are due to the accretion of ∼40% of the mass of our planet from the first-generation of refractory-rich planetesimals.
•We explain why the Earth has supra-CI Al/SI and Mg/Si ratios.•We explain why enstatite and ordinary chondrites have sub-CI Al/SI and Mg/Si ratios.•We explain the different chemical compositions of Earth and enstatite chondrites.
Regional air‐sea fluxes of anthropogenic CO2 are estimated using a Green's function inversion method that combines data‐based estimates of anthropogenic CO2 in the ocean with information about ocean ...transport and mixing from a suite of Ocean General Circulation Models (OGCMs). In order to quantify the uncertainty associated with the estimated fluxes owing to modeled transport and errors in the data, we employ 10 OGCMs and three scenarios representing biases in the data‐based anthropogenic CO2 estimates. On the basis of the prescribed anthropogenic CO2 storage, we find a global uptake of 2.2 ± 0.25 Pg C yr−1, scaled to 1995. This error estimate represents the standard deviation of the models weighted by a CFC‐based model skill score, which reduces the error range and emphasizes those models that have been shown to reproduce observed tracer concentrations most accurately. The greatest anthropogenic CO2 uptake occurs in the Southern Ocean and in the tropics. The flux estimates imply vigorous northward transport in the Southern Hemisphere, northward cross‐equatorial transport, and equatorward transport at high northern latitudes. Compared with forward simulations, we find substantially more uptake in the Southern Ocean, less uptake in the Pacific Ocean, and less global uptake. The large‐scale spatial pattern of the estimated flux is generally insensitive to possible biases in the data and the models employed. However, the global uptake scales approximately linearly with changes in the global anthropogenic CO2 inventory. Considerable uncertainties remain in some regions, particularly the Southern Ocean.
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