No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, ...international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.
Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at
ClinicalTrials.gov, number
NCT00075218.
312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27·3 weeks (95% CI 16·0–32·1) in patients receiving sunitinib and 6·4 weeks (4·4–10·0) in those on placebo (hazard ratio 0·33; p<0·0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.
We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.
Stereoscopic 3D (S3D) displays provide an additional sense of depth compared to non-stereoscopic displays by sending slightly different images to the two eyes. But conventional S3D displays do not ...reproduce all natural depth cues. In particular, focus cues are incorrect causing mismatches between accommodation and vergence: The eyes must accommodate to the display screen to create sharp retinal images even when binocular disparity drives the eyes to converge to other distances. This mismatch causes visual discomfort and reduces visual performance. We propose and assess two new techniques that are designed to reduce the vergence-accommodation conflict and thereby decrease discomfort and increase visual performance. These techniques are much simpler to implement than previous conflict-reducing techniques. The first proposed technique uses variable-focus lenses between the display and the viewer's eyes. The power of the lenses is yoked to the expected vergence distance thereby reducing the mismatch between vergence and accommodation. The second proposed technique uses a fixed lens in front of one eye and relies on the binocularly fused percept being determined by one eye and then the other, depending on simulated distance. We conducted performance tests and discomfort assessments with both techniques and compared the results to those of a conventional S3D display. The first proposed technique, but not the second, yielded clear improvements in performance and reductions in discomfort. This dynamic-lens technique therefore offers an easily implemented technique for reducing the vergence-accommodation conflict and thereby improving viewer experience.
The carbon gain in restored logged forest
There is currently great interest in the capacity of global forest to store carbon and hence contribute to the mitigation of climate change in the coming ...decades. In a study of Southeast Asian tropical forest, Philipson
et al.
show that active restoration of logged forests generates higher rates of carbon accumulation than naturally regenerating forest. To estimate the economic feasibility of restoration treatments, they modeled the carbon price required to offset the cost of restoration, finding that the highest prices seen in recent years would be needed to approach those that could offset restoration costs. These results are important for tropical forest policy, establishing the importance of restoration for the carbon recovery potential of tropical forests.
Science
, this issue p.
838
Restoration of logged tropical forests will be incentivized by carbon prices, consistent with the 2016 Paris climate agreement.
More than half of all tropical forests are degraded by human impacts, leaving them threatened with conversion to agricultural plantations and risking substantial biodiversity and carbon losses. Restoration could accelerate recovery of aboveground carbon density (ACD), but adoption of restoration is constrained by cost and uncertainties over effectiveness. We report a long-term comparison of ACD recovery rates between naturally regenerating and actively restored logged tropical forests. Restoration enhanced decadal ACD recovery by more than 50%, from 2.9 to 4.4 megagrams per hectare per year. This magnitude of response, coupled with modal values of restoration costs globally, would require higher carbon prices to justify investment in restoration. However, carbon prices required to fulfill the 2016 Paris climate agreement $40 to $80 (USD) per tonne carbon dioxide equivalent would provide an economic justification for tropical forest restoration.
The Keck Cosmic Web Imager Integral Field Spectrograph Morrissey, Patrick; Matuszewski, Matuesz; Martin, D. Christopher ...
Astrophysical journal/The Astrophysical journal,
09/2018, Letnik:
864, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We report on the design and performance of the Keck Cosmic Web Imager (KCWI), a general purpose optical integral field spectrograph that has been installed at the Nasmyth port of the 10 m Keck II ...telescope on Maunakea, Hawaii. The novel design provides blue-optimized seeing-limited imaging from 350-560 nm with configurable spectral resolution from 1000-20,000 in a field of view up to 20″ × 33″. Selectable volume phase holographic (VPH) gratings and high-performance dielectric, multilayer silver, and enhanced-aluminum coatings provide end-to-end peak efficiency in excess of 45% while accommodating the future addition of a red channel that will extend wavelength coverage to 1 micron. KCWI takes full advantage of the excellent seeing and dark sky above Maunakea with an available nod-and-shuffle observing mode. The instrument is optimized for observations of faint, diffuse objects such as the intergalactic medium or cosmic web. In this paper, a detailed description of the instrument design is provided with measured performance results from the laboratory test program and 10 nights of on-sky commissioning during the spring of 2017. The KCWI team is lead by Caltech and JPL (project management, design, and implementation) in partnership with the University of California at Santa Cruz (camera optical and mechanical design) and the W. M. Keck Observatory (observatory interfaces).
The Palomar Cosmic Web Imager (PCWI), an integral field spectrograph designed to detect and map low surface brightness emission, has obtained imaging spectroscopic maps of Ly alpha from the ...circum-QSO medium (CQM) of QSO HS1549+19 at redshift z = 2.843. Extensive extended emission is detected from the CQM, consistent with fluorescent and pumped Ly alpha produced by the ionizing and Ly alpha continuum of the QSO. Many features present in PCWI spectral images match those detected in narrow-band images. Filamentary structures with narrow line profiles are detected in several cases as long as 250-400 kpc. One of these is centered at a velocity redshifted with respect to the systemic velocity, and displays a spatially collimated and kinematically cold line profile increasing in velocity width approaching the QSO. This suggests that the filament gas is infalling onto the QSO, perhaps in a cold accretion flow. Because of the strong ionizing flux, the neutral column density is low, typically N(H I) ~ 10 super(12)-10 super(15) cm super(-2), and the line center optical depth is also low (typically tau sub(0) < 10), insufficient to display well separated double peak emission characteristic of higher line optical depths. With a simple ionization and cloud model we can very roughly estimate the total gas mass (log M sub(gas) = 12.5 + or - 0.5) and the total (log M sub(tot) = 13.3 + or - 0.5). We can also calculate a kinematic mass from the total line profile (2 x 10 super(13) M sub(middot in circle)), which agrees with the mass estimated from the gas emission. The intensity-binned spectrum of the CQM shows a progression in kinematic properties consistent with heirarchical structure formation.
Objective
To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on ...cerebrovascular disease.
Methods
We used summary statistics from genome‐wide association studies for body mass index (BMI), waist‐to‐hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2‐sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.
Results
Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval CI = 44–113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29–91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59–457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01–0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one‐tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4–20%), but no evidence of mediation was found for average blood glucose.
Interpretation
Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516–524
Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely ...contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization.
Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up.
We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.
Several hypotheses have been proposed to explain recent, widespread increases in concentrations of dissolved organic carbon (DOC) in the surface waters of glaciated landscapes across eastern North ...America and northern and central Europe. Some invoke anthropogenic forcing through mechanisms related to climate change, nitrogen deposition or changes in land use, and by implication suggest that current concentrations and fluxes are without precedent. All of these hypotheses imply that DOC levels will continue to rise, with unpredictable consequences for the global carbon cycle. Alternatively, it has been proposed that DOC concentrations are returning toward pre-industrial levels as a result of a gradual decline in the sulphate content of atmospheric deposition. Here we show, through the assessment of time series data from 522 remote lakes and streams in North America and northern Europe, that rising trends in DOC between 1990 and 2004 can be concisely explained by a simple model based solely on changes in deposition chemistry and catchment acid-sensitivity. We demonstrate that DOC concentrations have increased in proportion to the rates at which atmospherically deposited anthropogenic sulphur and sea salt have declined. We conclude that acid deposition to these ecosystems has been partially buffered by changes in organic acidity and that the rise in DOC is integral to recovery from acidification. Over recent decades, deposition-driven increases in organic matter solubility may have increased the export of DOC to the oceans, a potentially important component of regional carbon balances. The increase in DOC concentrations in these regions appears unrelated to other climatic factors.
Solvent transport in membranes composed of stacked sheets of graphene oxide (GO) with molecular scale channels and a complex arrangement of hydrophobic and hydrophilic domains is not well understood. ...Here, we observe that the interlayer space between GO sheets expands in different solvents without disturbing the membrane integrity and is typically larger in aqueous media compared to nonaqueous media. However, the membranes have a tighter molecule sieving feature in aqueous media as demonstrated by lower permeance and higher solute rejection arising from interfacial water layers “sticking” to charged polar groups. As a result of this polar interaction, the permeance of polar solvents in GO membrane scales inversely to the polarity of the solvent, which is contrary to other polymeric and ceramic hydrophilic membranes and also scales inversely to the viscosity of solvents as per continuum expectations. We highlight the extended solvent-handling space of GO membranes, such as in polar protic, polar aprotic, and nonpolar solvents, demonstrating versatility over a commercial nanofiltration membrane, and we predict exciting new applications in advanced separation engineering.
We provide the analytical explanation of the interactions between precautionary saving and liquidity constraints. The effects of liquidity constraints and risks are similar because both stem from the ...same source: a concavification of the consumption function. Since a more concave consumption function exhibits heightened prudence, both constraints and risks strengthen the precautionary saving motive. In addition, we explain the apparently contradictory results that constraints and risks in some cases intensify, but in other cases weaken the precautionary saving motive. The central insight is that the effect of introducing an additional constraint or risk depends on whether it interacts with preexisting constraints or risks. If it does not interact with any preexisting constraints or risks, it intensifies the precautionary motive. If it does interact, it may reduce the precautionary motive in earlier periods at some levels of wealth.
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