| 2941. |
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| 2942. |
- Thomas, B., et al.
(författare)
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Global Cardiovascular and Renal Outcomes of Reduced GFR
- 2017
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 28:7, s. 2167-2179
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Tidskriftsartikel (refereegranskat)abstract
- The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.
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| 2943. |
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| 2944. |
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| 2945. |
- Thrift, Aaron P., et al.
(författare)
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Mendelian randomization study of height and risk of colorectal cancer
- 2015
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 44:2, s. 662-672
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Tidskriftsartikel (refereegranskat)abstract
- Background: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk. Methods: To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10 226 CRC cases and 10 286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC. Results: Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02-1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05-1.26), but not men (OR = 0.98, 95% CI = 0.92-1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01-1.14) and for women (OR = 1.09, 95% CI = 1.01-1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96-1.15). Conclusion: We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.
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| 2946. |
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| 2947. |
- Tian, Ruiyi, et al.
(författare)
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Clonal Hematopoiesis and Risk of Incident Lung Cancer
- 2023
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 41:7, s. 1423-1433
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer. METHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung v breast cancer: 1.61; 95% CI, 1.03 to 2.53). CONCLUSION: Independent of known risk factors, CH is associated with increased risk of lung cancer.
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| 2948. |
- Tobin, J. J., et al.
(författare)
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A triple protostar system formed via fragmentation of a gravitationally unstable disk
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 538:7626, s. 483-
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Tidskriftsartikel (refereegranskat)abstract
- Binary and multiple star systems are a frequent outcome of the star formation process(1,2) and as a result almost half of all stars with masses similar to that of the Sun have at least one companion star(3). Theoretical studies indicate that there are two main pathways that can operate concurrently to form binary/multiple star systems: large-scale fragmentation of turbulent gas cores and filaments(4,5) or smaller-scale fragmentation of a massive protostellar disk due to gravitational instability(6,7). Observational evidence for turbulent fragmentation on scales of more than 1,000 astronomical units has recently emerged(8,9). Previous evidence for disk fragmentation was limited to inferences based on the separations of more-evolved pre-main sequence and protostellar multiple systems(10-13). The triple protostar system L1448 IRS3B is an ideal system with which to search for evidence of disk fragmentation as it is in an early phase of the star formation process, it is likely to be less than 150,000 years old(14) and all of the protostars in the system are separated by less than 200 astronomical units. Here we report observations of dust and molecular gas emission that reveal a disk with a spiral structure surrounding the three protostars. Two protostars near the centre of the disk are separated by 61 astronomical units and a tertiary protostar is coincident with a spiral arm in the outer disk at a separation of 183 astronomical units(13). The inferred mass of the central pair of protostellar objects is approximately one solar mass, while the disk surrounding the three protostars has a total mass of around 0.30 solar masses. The tertiary protostar itself has a minimum mass of about 0.085 solar masses. We demonstrate that the disk around L1448 IRS3B appears susceptible to disk fragmentation at radii between 150 and 320 astronomical units, overlapping with the location of the tertiary protostar. This is consistent with models for a protostellar disk that has recently undergone gravitational instability, spawning one or two companion stars.
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| 2949. |
- Tokarew, JM, et al.
(författare)
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Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites
- 2021
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 725-754
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.
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| 2950. |
- Toledo-Redondo, S., et al.
(författare)
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Kinetic Interaction of Cold and Hot Protons With an Oblique EMIC Wave Near the Dayside Reconnecting Magnetopause
- 2021
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 48:8
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Tidskriftsartikel (refereegranskat)abstract
- We report observations of the ion dynamics inside an Alfven branch wave that propagates near the reconnecting dayside magnetopause. The measured frequency, wave normal angle and polarization are consistent with the predictions of a dispersion solver. The magnetospheric plasma contains hot protons (keV), cold protons (eV), plus some heavy ions. While the cold protons follow the magnetic field fluctuations and remain frozen-in, the hot protons are at the limit of magnetization. The cold protons exchange energy back and forth, adiabatically, with the wave fields. The cold proton velocity fluctuations contribute to balance the Hall term fluctuations in Ohm's law, and the wave E field has small ellipticity and right-handed polarization. The dispersion solver indicates that increasing the cold proton density facilitates propagation and amplification of these waves at oblique angles, as for the observed wave. Plain Language Summary The Earth's magnetosphere is a very dilute cloud of charged particles that are trapped in the Earth's magnetic field. This cloud is surrounded by the solar wind, another very dilute gas that flows supersonically throughout the solar system. These two plasmas can couple to each other via magnetic reconnection, a fundamental plasma process that occurs at the dayside region of the interface between the two plasmas. When reconnection occurs, large amounts of energy and particles enter the magnetosphere, driving the near Earth space dynamics and generating, for instance, aurorae. The magnetospheric plasma sources are the solar wind and the Earth's ionosphere. Multiple plasma populations can be found inside the Earth's magnetosphere, depending on the plasma origin and its time history, as well as the magnetospheric forcing of the solar wind. In this study, we show how the presence of multiple particle populations at the interface between the solar wind and the magnetosphere modifies the properties of the waves that propagate there. Waves are known to play a fundamental role in converting energy and heating these very dilute charged gas clouds.
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