RATIONALE:Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known.
OBJECTIVE:To ...determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis.
METHODS AND RESULTS:We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis.
CONCLUSIONS:Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
VISUAL OVERVIEW:An online visual overview is available for this article.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths. Patients with advanced HCC are treated with sorafenib. A recent randomized controlled trial demonstrated a ...survival benefit for regorafenib treatment in patients with advanced HCC who had progressed on sorafenib. We aimed to evaluate the cost-effectiveness of this approach.
To evaluate the cost effectiveness of regorafenib, we used a Markov model that incorporates health outcomes, measured by life-years and quality-adjusted life-years (QALYs). Drug costs were based on 2017 discounted prices. Model robustness was validated by probabilistic sensitivity analyses using Monte Carlo simulations.
The use of regorafenib results in a gain of 19.76 weeks of life (0.38 Life Years) as compared to placebo. When adjusted for quality of life, using regorafenib produced a gain of 0.25 quality adjusted life years (QALYs). The incremental cost-effectiveness ratio for regorafenib compared with best supportive care was between $201,797 and $268,506 per QALY.
The modest incremental benefit at a relatively high incremental cost of regorafenib treatment suggests that it is not cost-effective at commonly accepted willingness to pay thresholds.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There are two classes of viable progenitors for normal Type Ia supernovae (SNe Ia): systems in which a white dwarf explodes at the Chandrasekhar mass ( ), and systems in which a white dwarf explodes ...below the Chandrasekhar mass (sub- ). It is not clear which of these channels is dominant; observations and light-curve modeling have provided evidence for both. Here we use an extensive grid of 4500 time-dependent, multiwavelength radiation transport simulations to show that the sub- model can reproduce the entirety of the width-luminosity relation, while the model can only produce the brighter events , implying that fast-declining SNe Ia come from sub- explosions. We do not assume a particular theoretical paradigm for the progenitor or explosion mechanism, but instead construct parameterized models that vary the mass, kinetic energy, and compositional structure of the ejecta, thereby realizing a broad range of possible outcomes of white dwarf explosions. We provide fitting functions based on our large grid of detailed simulations that map observable properties of SNe Ia, such as peak brightness and light-curve width, to physical parameters such as and total ejected mass. These can be used to estimate the physical properties of observed SNe Ia.
ABSTRACT Type Ia supernovae (SNe Ia) that are multiply imaged by gravitational lensing can extend the SN Ia Hubble diagram to very high redshifts (z 2), probe potential SN Ia evolution, and deliver ...high-precision constraints on H0, w, and m via time delays. However, only one, iPTF16geu, has been found to date, and many more are needed to achieve these goals. To increase the multiply imaged SN Ia discovery rate, we present a simple algorithm for identifying gravitationally lensed SN Ia candidates in cadenced, wide-field optical imaging surveys. The technique is to look for supernovae that appear to be hosted by elliptical galaxies, but that have absolute magnitudes implied by the apparent hosts' photometric redshifts that are far brighter than the absolute magnitudes of normal SNe Ia (the brightest type of supernovae found in elliptical galaxies). Importantly, this purely photometric method does not require the ability to resolve the lensed images for discovery. Active galactic nuclei, the primary sources of contamination that affect the method, can be controlled using catalog cross-matches and color cuts. Highly magnified core-collapse SNe will also be discovered as a byproduct of the method. Using a Monte Carlo simulation, we forecast that the Large Synoptic Survey Telescope can discover up to 500 multiply imaged SNe Ia using this technique in a 10 year z-band search, more than an order of magnitude improvement over previous estimates. We also predict that the Zwicky Transient Facility should find up to 10 multiply imaged SNe Ia using this technique in a 3 year R-band search-despite the fact that this survey will not resolve a single system.
We present results from a search for a radio transient associated with the LIGO/Virgo source S190814bv, a likely neutron star-black hole (NSBH) merger, with the Australian Square Kilometre Array ...Pathfinder. We imaged a 30 deg2 field at ΔT = 2, 9, and 33 days post-merger at a frequency of 944 MHz, comparing them to reference images from the Rapid ASKAP Continuum Survey observed 110 days prior to the event. Each epoch of our observations covers 89% of the LIGO/Virgo localization region. We conducted an untargeted search for radio transients in this field, resulting in 21 candidates. For one of these, AT2019osy, we performed multiwavelength follow-up and ultimately ruled out the association with S190814bv. All other candidates are likely unrelated variables, but we cannot conclusively rule them out. We discuss our results in the context of model predictions for radio emission from NSBH mergers and place constrains on the circum-merger density and inclination angle of the merger. This survey is simultaneously the first large-scale radio follow-up of an NSBH merger, and the most sensitive widefield radio transients search to-date.
Predisposition to sporadic Alzheimer’s disease (SAD) involves interactions between a person’s unique combination of genetic variants and the environment. The molecular effect of these variants may be ...subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual’s risk of developing SAD.
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•hIPSC-derived neurons were made from six control individuals and seven SAD patients•Neurons have SAD risk (R) or protective (P) variants in the SORL1 gene•P variant neurons increase SORL1 expression and reduce Aβ after BDNF treatment•The reduction of Aβ in response to BDNF is dependent on SORL1 expression
Development of late-onset, sporadic Alzheimer’s disease (SAD) has been linked with a range of genetic loci, but determining how variants within these loci contribute to disease progression remains challenging. Using hIPSC-derived neurons from SAD patients and controls, Young et al. link risk and protective variants in the SORL1 gene, an SAD-associated locus, with BDNF-sensitive SORL1 expression, APP processing, and control of amyloid β production.
ABSTRACT
We investigate the effect of microlensing on the standardization of strongly lensed Type Ia supernovae (GLSNe Ia). We present predictions for the amount of scatter induced by microlensing ...across a range of plausible strong lens macromodels. We find that lensed images in regions of low convergence, shear and stellar density are standardizable, where the microlensing scatter is ≲ 0.15 mag, comparable to the intrinsic dispersion of a typical SN Ia. These standardizable configurations correspond to asymmetric lenses with an image located far outside the Einstein radius of the lens. Symmetric and small Einstein radius lenses (≲ 0.5 arcsec) are not standardizable. We apply our model to the recently discovered GLSN Ia iPTF16geu and find that the large discrepancy between the observed flux and the macromodel predictions from More et al. cannot be explained by microlensing alone. Using the mock GLSNe Ia catalogue of Goldstein et al., we predict that ∼22 per cent of GLSNe Ia discovered by Large Synoptic Survey Telescope (LSST) will be standardizable, with a median Einstein radius of 0.9 arcsec and a median time delay of 41 d. By breaking the mass-sheet degeneracy the full LSST GLSNe Ia sample will be able to detect systematics in H0 at the 0.5 per cent level.
Financial toxicity is now a well established and generally accepted toxicity related to cancer care. While policy makers and politicians continue to debate about system‐wide changes, physicians and ...patients can seek ways to decrease financial toxicity and to incorporate this issue into every decision‐making process.
See also pages 1453‐63.
Time delays between the multiple images of strongly gravitationally lensed Type Ia supernovae (glSNe Ia) have the potential to deliver precise cosmological constraints, but the effects of ...microlensing on time delay extraction have not been studied in detail. Here we quantify the effect of microlensing on the glSN Ia yield of the Large Synoptic Survey Telescope (LSST) and the effect of microlensing on the precision and accuracy of time delays that can be extracted from LSST glSNe Ia. Microlensing has a negligible effect on the LSST glSN Ia yield, but it can be increased by a factor of ∼2 over previous predictions to 930 systems using a novel photometric identification technique based on spectral template fitting. Crucially, the microlensing of glSNe Ia is achromatic until three rest-frame weeks after the explosion, making the early-time color curves microlensing-insensitive time delay indicators. By fitting simulated flux and color observations of microlensed glSNe Ia with their underlying, unlensed spectral templates, we forecast the distribution of absolute time delay error due to microlensing for LSST, which is unbiased at the sub-percent level and peaked at 1% for color curve observations in the achromatic phase, while for light-curve observations it is comparable to state-of-the-art mass modeling uncertainties (4%). About 70% of LSST glSN Ia images should be discovered during the achromatic phase, indicating that microlensing time delay uncertainties can be minimized if prompt multicolor follow-up observations are obtained. Accounting for microlensing, the 1-2 day time delay on the recently discovered glSN Ia iPTF16geu can be measured to 40% precision, limiting its cosmological utility.
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