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- Furtado, R. H. M., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:21, s. 1581-1591
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and >= 160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17160 patients; mean age, 64.0 +/- 6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; F<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (P-interactions = 5 0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.
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- Whiffin, N, et al.
(författare)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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- Ergun, R. E., et al.
(författare)
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Observations of Particle Acceleration in Magnetic Reconnection-driven Turbulence
- 2020
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Ingår i: Astrophysical Journal. - : IOP PUBLISHING LTD. - 0004-637X .- 1538-4357. ; 898:2
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Tidskriftsartikel (refereegranskat)abstract
- The Magnetospheric Multiscale Mission observes, in detail, charged particle heating and substantial nonthermal acceleration in a region of strong turbulence (vertical bar delta B vertical bar/vertical bar B vertical bar similar to 1, where B is the magnetic field) that surrounds a magnetic reconnection X-line. Magnetic reconnection enables magnetic field annihilation in a volume that far exceeds that of the diffusion region. The formidable magnetic field annihilation breaks into strong, intermittent turbulence with magnetic field energy as the driver. The strong, intermittent turbulence appears to generate the necessary conditions for nonthermal acceleration. It creates intense, localized currents (J) and unusually large-amplitude electric fields (E). The combination of turbulence-generated E and J results in a significant net positive mean of J center dot E, which signifies particle energization. Ion and electron heating rates are such that they experience a fourfold increase from their initial temperature. Importantly, the strong turbulence also generates magnetic holes or depletions in vertical bar B vertical bar that can trap particles. Trapping considerably increases the dwell time of a subset of particles in the turbulent region, which results in significant nonthermal particle acceleration. The direct observation of strong turbulence that is enabled by magnetic reconnection with nonthermal particle acceleration has far-reaching implications, since turbulence in plasmas is pervasive and may occupy significant volumes of the interstellar medium and intergalactic space. For example, strong turbulence from magnetic field annihilation in the supernova nebulae may dominate large volumes. As such, this observed energization process could plausibly contribute to the supply and development of the cosmic-ray spectrum.
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- Zona, Donatella, et al.
(författare)
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Earlier snowmelt may lead to late season declines in plant productivity and carbon sequestration in Arctic tundra ecosystems
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO2 later in the season.
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- Hansel, P. J., et al.
(författare)
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Mapping MMS Observations of Solitary Waves in Earth's Magnetic Field
- 2021
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Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 126:12
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Tidskriftsartikel (refereegranskat)abstract
- Electrostatic solitary waves (ESWs) are a type of nonlinear time-domain plasma structure (TDS) generally defined by bipolar electric fields and propagation parallel to the local magnetic field. Formation mechanisms for TDSs in the magnetosphere have been studied extensively and are associated with plasma boundary layers and the braking of bursty bulk flows (BBFs). However, the rapid timescales over which these TDSs occur (<2 ms) make them infeasible to count by eye over large time periods. Furthermore, high-cadence data are not always available. The Solitary Wave Detector (SWD) on NASA's Magnetospheric Multiscale (MMS) mission quantifies the occurrence and amplitude of TDS throughout the constellation's orbit; analysis of burst (65 kS/s) parallel electric field data indicates that the SWD captures approximately 60% of all bipolar TDS encountered in the tail region, enabling large-scale examination of their occurrence. Maps of TDS occurrence rates during several years of the MMS mission were generated from SWD data, showing enhanced TDS density in the tail region between 6 and 9 Re; enhance occurrence in or near shocks; and an unexpected enhancement in the dawn side of the tail and in the radiation belt.
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