Objective To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood ...pressure, with cardiovascular disease events and mortality.Data sources Medline, Embase, Cinahl, and Web of Science, searched to 15 February 2016 for full text articles in English.Eligibility criteria for study selection Prospective cohort studies or clinical trials in adults, except those in patients receiving haemodialysis, where the condition may directly impact blood pressure variability. Standardised hazard ratios were extracted and, if there was little risk of confounding, combined using random effects meta-analysis in main analyses. Outcomes included all cause and cardiovascular disease mortality and cardiovascular disease events. Measures of variability included standard deviation, coefficient of variation, variation independent of mean, and average real variability, but not night dipping or day-night variation.Results 41 papers representing 19 observational cohort studies and 17 clinical trial cohorts, comprising 46 separate analyses were identified. Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively).Conclusions Long term variability in blood pressure is associated with cardiovascular and mortality outcomes, over and above the effect of mean blood pressure. Associations are similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short term variability showed similar associations. Future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date.Systematic review registration PROSPERO CRD42014015695.
We determine the slip rate and pattern of interseismic coupling on the Main Himalayan Thrust along the entire Himalayan arc based on a compilation of geodetic, interferometric synthetic aperture ...radar, and microseismicity data. We show that convergence is perpendicular to the arc and increases eastwards from 13.3 ± 1.7 mm/yr to 21.2 ± 2.0 mm/yr. These rates are comparable to geological and geomorphic estimates, indicating an essentially elastic geodetic surface strain. The interseismic uplift rate predicted from the coupling model closely mimics the topography, suggesting that a small percentage of the interseismic strain is permanent. We find that the fault is fully locked along its complete length over about 100 km width. We don't find any resolvable aseismic barrier that could affect the seismic segmentation of the arc and limit the along‐strike propagation of seismic ruptures. The moment deficit builds up at a rate of 15.1 ± 1 × 1019 N m/yr for the entire length of the Himalaya.
Key Points
The whole Himalayan arc is locked to roughly 100 km width, with no resolvable aseismic patches
GPS and geomorphic shortening rates are comparable, indicating an elastic geodetic surface strain
The moment deficit builds up at a rate of 15.1 ± 1 × 1019 Nm/yr for the entire arc
Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and ...residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34
cells, with no effect on healthy CD34
cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1-dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival. SIGNIFICANCE: Small-molecule-induced degradation of BCR-ABL1 in CML provides an advantage over inhibition and provides insights into CML stem cell biology. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/18/4744/F1.large.jpg.
A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's ...recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.
Stingray: A Modern Python Library for Spectral Timing Huppenkothen, Daniela; Bachetti, Matteo; Stevens, Abigail L. ...
Astrophysical journal/The Astrophysical journal,
08/2019, Letnik:
881, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This paper describes the design and implementation of stingray, a library in Python built to perform time series analysis and related tasks on astronomical light curves. Its core functionality ...comprises a range of Fourier analysis techniques commonly used in spectral-timing analysis, as well as extensions for analyzing pulsar data, simulating data sets, and statistical modeling. Its modular build allows for easy extensions and incorporation of its methods into data analysis workflows and pipelines. We aim for the library to be a platform for the implementation of future spectral-timing techniques. We describe the overall vision and framework, core functionality, extensions, and connections to high-level command-line and graphical interfaces. The code is well tested, with a test coverage of currently 95%, and is accompanied by extensive Application Program Interface (API) documentation and a set of step-by-step tutorials.
Genome-scale metabolic models have proven to be valuable for predicting organism phenotypes from genotypes. Yet efforts to develop new models are failing to keep pace with genome sequencing. To ...address this problem, we introduce the Model SEED, a web-based resource for high-throughput generation, optimization and analysis of genome-scale metabolic models. The Model SEED integrates existing methods and introduces techniques to automate nearly every step of this process, taking approximately 48 h to reconstruct a metabolic model from an assembled genome sequence. We apply this resource to generate 130 genome-scale metabolic models representing a taxonomically diverse set of bacteria. Twenty-two of the models were validated against available gene essentiality and Biolog data, with the average model accuracy determined to be 66% before optimization and 87% after optimization.
The prediction of a supersonic solar wind
was first confirmed by spacecraft near Earth
and later by spacecraft at heliocentric distances as small as 62 solar radii
. These missions showed that plasma ...accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy
. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams
. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii
, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second-considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age
.
Abstract
Neutron Star Interior Composition Explorer
has a comparatively low background rate, but it is highly variable, and its spectrum must be predicted using measurements unaffected by the science ...target. We describe an empirical, three-parameter model based on observations of seven pointing directions that are void of detectable sources. Two model parameters track different types of background events, while the third is used to predict a low-energy excess tied to observations conducted in sunlight. An examination of 3556 good time intervals (GTIs), averaging 570 s, yields a median rate (0.4–12 keV; 50 detectors) of 0.87 c s
−1
, but in 5% (1%) of cases, the rate exceeds 10 (300) c s
−1
. Model residuals persist at 20%–30% of the initial rate for the brightest GTIs, implying one or more missing model parameters. Filtering criteria are given to flag GTIs likely to have unsatisfactory background predictions. With such filtering, we estimate a detection limit, 1.20 c s
−1
(3
σ
, single GTI) at 0.4–12 keV, equivalent to 3.6 × 10
−12
erg cm
−2
s
−1
for a Crab-like spectrum. The corresponding limit for soft X-ray sources is 0.51 c s
−1
at 0.3–2.0 keV, or 4.3 × 10
−13
erg cm
−2
s
−1
for a 100 eV blackbody. These limits would be four times lower if exploratory GTIs accumulate 10 ks of data after filtering at the level prescribed for faint sources. Such filtering selects background GTIs 85% of the time. An application of the model to a 1 s timescale makes it possible to distinguish source flares from possible surges in the background.
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