The fraction of the Universe going into primordial black holes (PBHs) with initial mass Mlow * approximate 5 x 10 super(14)g, such that they are evaporating at the present epoch, is strongly ...constrained by observations of both the extragalactic and Galactic gamma -ray backgrounds. However, while the dominant contribution to the extragalactic background comes from the time-integrated emission of PBHs with initial mass Mlow *, the Galactic background is dominated by the instantaneous emission of those with initial mass slightly larger than Mlow * and current mass below Mlow *. Also, the instantaneous emission of PBHs smaller than 0.4Mlow * mostly comprises secondary particles produced by the decay of directly emitted quark and gluon jets. These points were missed in the earlier analysis by Lehoucq et al. using EGRET data. For a monochromatic PBH mass function, with initial mass (1 + mu )Mlow * and mu <<1, the current mass is (3 mu ) super(1/3)Mlow *, and the Galactic background constrains the fraction of the Universe going into PBHs as a function of mu . However, the initial mass function cannot be precisely monochromatic, and even a tiny spread of mass around Mlow * would generate a current low-mass tail of PBHs below Mlow *. This tail would be the main contributor to the Galactic background, so we consider its form and the associated constraints for a variety of scenarios with both extended and nearly monochromatic initial mass functions. In particular, we consider a scenario in which the PBHs form from critical collapse and have a mass function which peaks well above Mlow *. In this case, the largest PBHs could provide the dark matter without the Mlow * ones exceeding the gamma -ray background limits.
The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 ...diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
Summary Background Total joint replacements for end-stage osteoarthritis of the hip and knee are cost-effective and demonstrate significant clinical improvement. However, robust population based ...lifetime-risk data for implant revision are not available to aid patient decision making, which is a particular problem in young patient groups deciding on best-timing for surgery. Methods We did implant survival analysis on all patients within the Clinical Practice Research Datalink who had undergone total hip replacement or total knee replacement. These data were adjusted for all-cause mortality with data from the Office for National Statistics and used to generate lifetime risks of revision surgery based on increasing age at the time of primary surgery. Findings We identified 63 158 patients who had undergone total hip replacement and 54 276 who had total knee replacement between Jan 1, 1991, and Aug 10, 2011, and followed up these patients to a maximum of 20 years. For total hip replacement, 10-year implant survival rate was 95·6% (95% CI 95·3–95·9) and 20-year rate was 85·0% (83·2–86·6). For total knee replacement, 10-year implant survival rate was 96·1% (95·8–96·4), and 20-year implant survival rate was 89·7% (87·5–91·5). The lifetime risk of requiring revision surgery in patients who had total hip replacement or total knee replacement over the age of 70 years was about 5% with no difference between sexes. For those who had surgery younger than 70 years, however, the lifetime risk of revision increased for younger patients, up to 35% (95% CI 30·9–39·1) for men in their early 50s, with large differences seen between male and female patients (15% lower for women in same age group). The median time to revision for patients who had surgery younger than age 60 was 4·4 years. Interpretation Our study used novel methodology to investigate and offer new insight into the importance of young age and risk of revision after total hip or knee replacement. Our evidence challenges the increasing trend for more total hip replacements and total knee replacements to be done in the younger patient group, and these data should be offered to patients as part of the shared decision making process.
Single-cell RNA sequencing technologies suffer from many sources of technical noise, including under-sampling of mRNA molecules, often termed “dropout,” which can severely obscure important gene-gene ...relationships. To address this, we developed MAGIC (Markov affinity-based graph imputation of cells), a method that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts. We validate MAGIC on several biological systems and find it effective at recovering gene-gene relationships and additional structures. Applied to the epithilial to mesenchymal transition, MAGIC reveals a phenotypic continuum, with the majority of cells residing in intermediate states that display stem-like signatures, and infers known and previously uncharacterized regulatory interactions, demonstrating that our approach can successfully uncover regulatory relations without perturbations.
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•MAGIC restores noisy and sparse single-cell data using diffusion geometry•Corrected data are amenable to myriad downstream analyses•MAGIC enables archetypal analysis and inference of gene interactions•Transcription factor targets can be predicted without perturbation after MAGIC
A new algorithm overcomes limitations of data loss in single-cell sequencing experiments.
This study presents the application of a cost-effective, unmanned aerial vehicle (UAV) to investigate calving dynamics at a major marine-terminating outlet glacier draining the western sector of the ...Greenland ice sheet. The UAV was flown over Store Glacier on three sorties during summer 2013 and acquired over 2000 overlapping, geotagged images of the calving front at an similar to 40 cm ground sampling distance. Stereo-photogrammetry applied to these images enabled the extraction of high-resolution digital elevation models (DEMs) with vertical accuracies of plus or minus 1.9 m which were used to quantify glaciological processes from early July to late August 2013. The central zone of the calving front advanced by similar to 500 m, whilst the lateral margins remained stable. The orientation of crevasses and the surface velocity field derived from feature tracking indicates that lateral drag is the primary resistive force and that ice flow varies across the calving front from 2.5 m d super(-1) at the margins to in excess of 16 m d super(-1) at the centreline. Ice flux through the calving front is 3.8 107 m3 d super(-1), equivalent to 13.9 Gt a super(-1) and comparable to flux-gate estimates of Store Glacier's annual discharge. Water-filled crevasses were present throughout the observation period but covered a limited area of between 0.025 and 0.24% of the terminus and did not appear to exert any significant control over fracture or calving. We conclude that the use of repeat UAV surveys coupled with the processing techniques outlined in this paper have great potential for elucidating the complex frontal dynamics that characterise large calving outlet glaciers.
A new semi-analytical solution to the advection–dispersion–reaction equation for modelling solute transport in layered porous media is derived using the Laplace transform. Our solution approach ...involves introducing unknown functions representing the dispersive flux at the interfaces between adjacent layers, allowing the multilayer problem to be solved separately on each layer in the Laplace domain before being numerically inverted back to the time domain. The derived solution is applicable to the most general form of linear advection–dispersion–reaction equation, a finite medium comprising an arbitrary number of layers, continuity of concentration and dispersive flux at the interfaces between adjacent layers and transient boundary conditions of arbitrary type at the inlet and outlet. The derived semi-analytical solution extends and addresses deficiencies of existing analytical solutions in a layered medium, which consider analogous processes such as diffusion or reaction–diffusion only and/or require the solution of complicated nonlinear transcendental equations to evaluate the solution expressions. Code implementing our semi-analytical solution is supplied and applied to a selection of test cases, with the reported results in excellent agreement with a standard numerical solution and other analytical results available in the literature.
Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac ...output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.
We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.
Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval CI, -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.
In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.
The usage of performance-vesting (p-v) equity awards to top executives in large U.S. companies has grown from 20 to 70 percent from 1998 to 2012. We measure the effects of p-v provisions on value, ...delta, and vega of equity-based compensation. We find large differences in the value of p-v awards reported in company disclosures versus economic value. We also find that equity-based grants continue to convey significant compensation convexity (vega) after ASC 718 (2005) and that, counter to recent claims in the literature, our analysis empirically reaffirms the presence of a causal relation between compensation convexity (vega) and firm risk.
Antarctic supraglacial lakes (SGLs) have been linked to ice shelf collapse and the subsequent acceleration of inland ice flow, but observations of SGLs remain relatively scarce and their interannual ...variability is largely unknown. This makes it difficult to assess whether some ice shelves are close to thresholds of stability under climate warming. Here, we present the first observations of SGLs across the entire East Antarctic Ice Sheet over multiple melt seasons (2014-2020). Interannual variability in SGL volume is >200% on some ice shelves, but patterns are highly asynchronous. More extensive, deeper SGLs correlate with higher summer (December-January-February) air temperatures, but comparisons with modelled melt and runoff are complex. However, we find that modelled January melt and the ratio of November firn air content to summer melt are important predictors of SGL volume on some potentially vulnerable ice shelves, suggesting large increases in SGLs should be expected under future atmospheric warming.
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