100 research outputs found

    Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

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    Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis

    New Insights into White-Light Flare Emission from Radiative-Hydrodynamic Modeling of a Chromospheric Condensation

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    (abridged) The heating mechanism at high densities during M dwarf flares is poorly understood. Spectra of M dwarf flares in the optical and near-ultraviolet wavelength regimes have revealed three continuum components during the impulsive phase: 1) an energetically dominant blackbody component with a color temperature of T \sim 10,000 K in the blue-optical, 2) a smaller amount of Balmer continuum emission in the near-ultraviolet at lambda << 3646 Angstroms and 3) an apparent pseudo-continuum of blended high-order Balmer lines. These properties are not reproduced by models that employ a typical "solar-type" flare heating level in nonthermal electrons, and therefore our understanding of these spectra is limited to a phenomenological interpretation. We present a new 1D radiative-hydrodynamic model of an M dwarf flare from precipitating nonthermal electrons with a large energy flux of 101310^{13} erg cm2^{-2} s1^{-1}. The simulation produces bright continuum emission from a dense, hot chromospheric condensation. For the first time, the observed color temperature and Balmer jump ratio are produced self-consistently in a radiative-hydrodynamic flare model. We find that a T \sim 10,000 K blackbody-like continuum component and a small Balmer jump ratio result from optically thick Balmer and Paschen recombination radiation, and thus the properties of the flux spectrum are caused by blue light escaping over a larger physical depth range compared to red and near-ultraviolet light. To model the near-ultraviolet pseudo-continuum previously attributed to overlapping Balmer lines, we include the extra Balmer continuum opacity from Landau-Zener transitions that result from merged, high order energy levels of hydrogen in a dense, partially ionized atmosphere. This reveals a new diagnostic of ambient charge density in the densest regions of the atmosphere that are heated during dMe and solar flares.Comment: 50 pages, 2 tables, 13 figures. Accepted for publication in the Solar Physics Topical Issue, "Solar and Stellar Flares". Version 2 (June 22, 2015): updated to include comments by Guest Editor. The final publication is available at Springer via http://dx.doi.org/10.1007/s11207-015-0708-

    Development and Validation of The SMAP Enhanced Passive Soil Moisture Product

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    Since the beginning of its routine science operation in March 2015, the NASA SMAP observatory has been returning interference-mitigated brightness temperature observations at L-band (1.41 GHz) frequency from space. The resulting data enable frequent global mapping of soil moisture with a retrieval uncertainty below 0.040 cu m/cu m at a 36 km spatial scale. This paper describes the development and validation of an enhanced version of the current standard soil moisture product. Compared with the standard product that is posted on a 36 km grid, the new enhanced product is posted on a 9 km grid. Derived from the same time-ordered brightness temperature observations that feed the current standard passive soil moisture product, the enhanced passive soil moisture product leverages on the Backus-Gilbert optimal interpolation technique that more fully utilizes the additional information from the original radiometer observations to achieve global mapping of soil moisture with enhanced clarity. The resulting enhanced soil moisture product was assessed using long-term in situ soil moisture observations from core validation sites located in diverse biomes and was found to exhibit an average retrieval uncertainty below 0.040 cu m/cu m. As of December 2016, the enhanced soil moisture product has been made available to the public from the NASA Distributed Active Archive Center at the National Snow and Ice Data Center

    Satellite and in situ observations for advancing global Earth surface modelling: a review

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    In this paper, we review the use of satellite-based remote sensing in combination with in situ data to inform Earth surface modelling. This involves verification and optimization methods that can handle both random and systematic errors and result in effective model improvement for both surface monitoring and prediction applications. The reasons for diverse remote sensing data and products include (i) their complementary areal and temporal coverage, (ii) their diverse and covariant information content, and (iii) their ability to complement in situ observations, which are often sparse and only locally representative. To improve our understanding of the complex behavior of the Earth system at the surface and sub-surface, we need large volumes of data from high-resolution modelling and remote sensing, since the Earth surface exhibits a high degree of heterogeneity and discontinuities in space and time. The spatial and temporal variability of the biosphere, hydrosphere, cryosphere and anthroposphere calls for an increased use of Earth observation (EO) data attaining volumes previously considered prohibitive. We review data availability and discuss recent examples where satellite remote sensing is used to infer observable surface quantities directly or indirectly, with particular emphasis on key parameters necessary for weather and climate prediction. Coordinated high-resolution remote-sensing and modelling/assimilation capabilities for the Earth surface are required to support an international application-focused effort

    Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

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    Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied \u201ccountry-specific\u201d factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a \u201cone-size-fits-all\u201d approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions

    Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

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    notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations

    Short 4th toes in rett-syndrome - a biological indicator

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    Classic Rett syndrome is now well-known as a non-dysmorphic developmental disorder almost certainly of genetic origin. Short 4th toe (uni- or bi-lateral) is inherited as an autosomal dominant with 27 % penetrance and is found also in certain dysmorphic syndromes. Having observed the anomaly in several Rett cases, we examined a cohort of classic Rett people at advisory clinics and all the residents in an adult learning disabled hospital in order to determine the significance of the association. Among the Rett clinic group 28 of 137 showed the anomaly (20 %). Among the heterogeneous hospital group it was found in 19 of 526 people, 9 of 206 females (4 %) and 10 of 320 males (3 %). Rett syndrome was present in 7 % of all the women (14 of 206 women). Four of the Rett women showed the toe anomaly (28 % of the Rett cases). The anomaly was found in 4 men and 4 women with Down syndrome, representing 16 % (8 of 49). Diagnoses in other men with the anomaly included foetal alcohol syndrome, toxoplasmosis, 18/2 translocation and birth injury. The only other woman with the anomaly was profoundly disabled with short limbs. The strong positive association of the anomaly with Rett syndrome and Down syndrome throws new light on the developmental processes affected by these diseases

    Relations between Periodontal Disease and Systemic Disease

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67891/2/10.1177_00220345620410013701.pd
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