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3. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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4. |
- Aragam, KG, et al.
(författare)
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Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
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5. |
- Chu, Audrey Y, et al.
(författare)
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Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:1, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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- Holguín-Veras, J., et al.
(författare)
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The New York city off-hour delivery program: A business and community-friendly sustainability program
- 2018
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Ingår i: Interfaces. - : Institute for Operations Research and the Management Sciences (INFORMS). - 0092-2102 .- 1526-551X. ; 48:1, s. 70-86
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Tidskriftsartikel (refereegranskat)abstract
- The New York City Off-Hour Delivery (NYC OHD) program is the work of a private-public-academic partnership - A collaborative effort of leading private-sector groups and companies, public-sector agencies led by the New York City Department of Transportation, and research partners led by Rensselaer Polytechnic Institute. The efforts of this partnership have induced more than 400 commercial establishments in NYC to accept OHD without supervision. The economic benefits are considerable: The carriers have reduced operational costs and parking fines by 45 percent; the receivers enjoy more reliable deliveries, enabling them to reduce inventory levels; the truck drivers have less stress, shorter work hours, and easier deliveries and parking; the delivery trucks produce 55-67 percent less emissions than they would during regular-hour deliveries, for a net reduction of 2.5 million tons of CO2 per year; and citizens' quality of life increases as a result of reduced conflicts between delivery trucks, cars, bicycles, and pedestrians, and through the use of low-noise delivery practices and technologies that minimize the impacts of noise. The total economic benefits exceed $20 million per year. The success of the OHD program is due largely to the policy design at its core, made possible with the behavioral microsimulation. This unique optimization-simulation system incorporates the research conducted into an operations research/management science tool that assesses the effectiveness of alternative policy designs. This enabled the successful implementation of the project within the most complex urban environment in the United States.
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7. |
- Li, Man, et al.
(författare)
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SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function
- 2017
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Ingår i: Journal of the American Society of Nephrology: JASN. - 1533-3450. ; 28:3, s. 981-994
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
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- Osborne, H. L.M., et al.
(författare)
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TOI-544 b: a potential water-world inside the radius valley in a two-planet system
- 2024
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Ingår i: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:4, s. 11138-11157
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Tidskriftsartikel (refereegranskat)abstract
- We report on the precise radial velocity follow-up of TOI-544 (HD 290498),ã bright K star ( V = 10.8), which hostsã small transiting planet recently disco v ered by the Trãnsiting Exoplanet Survey Satellite (TESS) . We collected 122 high-resolution High Accuracy Radial velocity Planet Searcher (HARPS)ãnd HARPS-N spectra to spectroscopically confirm the transiting planetãnd measure its mass. The nearly 3-yr baseline of our follow-upãllowed us to unveil the presence ofãnãdditional, non-transiting, longer-period companion planet. We derivedã radiusãnd mass for the inner planet, TOI-544 b, of 2.018 ±0.076 R⊙and 2.89 ±0.48 M⊙, respectively, which givesã bulk density of 1 . 93 + 0 . 30 -0 . 25 g cm -3 . TOI-544 c hasã minimum mass of 21.5 ±2.0 M⊙and orbital period of 50.1 ±0.2 d. The low density of planet-b implies that it has eitherãn Earth-like rocky core withã hydrogenãtmosphere, orã composition which harboursã significant fraction of water. The composition interpretation is degenerate depending on the specific choice of planet interior models used. Additionally, TOI-544 b hasãn orbital period of 1.55 dãnd equilibrium temperature of 999 ±14 K, placing it within the predicted location of the radius valley, where few planetsãre expected. TOI-544 b isã top target for futureãtmospheric observations, for example with JWST , which would enable better constraints of the planet composition.
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10. |
- Szatmari, Peter, et al.
(författare)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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11. |
- Weeks, Andrew R., et al.
(författare)
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Assessing the benefits and risks of translocations in changing environments : a genetic perspective
- 2011
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Ingår i: Evolutionary Applications. - : Wiley. - 1752-4571. ; 4:6, s. 709-725
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Tidskriftsartikel (refereegranskat)abstract
- Translocations are being increasingly proposed as a way of conserving biodiversity, particularly in the management of threatened and keystone species, with the aims of maintaining biodiversity and ecosystem function under the combined pressures of habitat fragmentation and climate change. Evolutionary genetic considerations should be an important part of translocation strategies, but there is often confusion about concepts and goals. Here, we provide a classification of translocations based on specific genetic goals for both threatened species and ecological restoration, separating targets based on ‘genetic rescue’ of current population fitness from those focused on maintaining adaptive potential. We then provide a framework for assessing the genetic benefits and risks associated with translocations and provide guidelines for managers focused on conserving biodiversity and evolutionary processes. Case studies are developed to illustrate the framework.
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12. |
- Agrawal, Mridul, et al.
(författare)
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TET2-mutant clonal hematopoiesis and risk of gout
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140:10, s. 1094-1103
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Tidskriftsartikel (refereegranskat)abstract
- Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
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13. |
- Barrat, Jean-Louis, et al.
(författare)
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Soft matter roadmap
- 2024
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Ingår i: Journal of Physics. - : Institute of Physics Publishing (IOPP). - 2515-7639. ; 7:1
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Forskningsöversikt (refereegranskat)abstract
- Soft materials are usually defined as materials made of mesoscopic entities, often self-organised, sensitive to thermal fluctuations and to weak perturbations. Archetypal examples are colloids, polymers, amphiphiles, liquid crystals, foams. The importance of soft materials in everyday commodity products, as well as in technological applications, is enormous, and controlling or improving their properties is the focus of many efforts. From a fundamental perspective, the possibility of manipulating soft material properties, by tuning interactions between constituents and by applying external perturbations, gives rise to an almost unlimited variety in physical properties. Together with the relative ease to observe and characterise them, this renders soft matter systems powerful model systems to investigate statistical physics phenomena, many of them relevant as well to hard condensed matter systems. Understanding the emerging properties from mesoscale constituents still poses enormous challenges, which have stimulated a wealth of new experimental approaches, including the synthesis of new systems with, e.g. tailored self-assembling properties, or novel experimental techniques in imaging, scattering or rheology. Theoretical and numerical methods, and coarse-grained models, have become central to predict physical properties of soft materials, while computational approaches that also use machine learning tools are playing a progressively major role in many investigations. This Roadmap intends to give a broad overview of recent and possible future activities in the field of soft materials, with experts covering various developments and challenges in material synthesis and characterisation, instrumental, simulation and theoretical methods as well as general concepts.
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15. |
- Kininmonth, Stuart, et al.
(författare)
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Strategies in scheduling marine protected area establishment in a network system
- 2019
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Ingår i: Ecological Applications. - : Wiley. - 1051-0761 .- 1939-5582. ; 29:1
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Tidskriftsartikel (refereegranskat)abstract
- Instantaneous implementation of systematic conservation plans at regional scales is rare. More typically, planned actions are applied incrementally over periods of years or decades. During protracted implementation, the character of the connected ecological system will change as a function of external anthropogenic pressures, local metapopulation processes, and environmental fluctuations. For heavily exploited systems, habitat quality will deteriorate as the plan is implemented, potentially influencing the schedule of protected area implementation necessary to achieve conservation objectives. Understanding the best strategy to adopt for applying management within a connected environment is desirable, especially given limited conservation resources. Here, we model the sequential application of no-take marine protected areas (MPAs) in the central Philippines within a metapopulation framework, using a range of network-based decision rules. The model was based on selecting 33 sites for protection from 101 possible sites over a 35-yr period. The graph-theoretic network criteria to select sites for protection included PageRank, maximum degree, closeness centrality, betweenness centrality, minimum degree, random, and historical events. We also included a dynamic strategy called colonization-extinction rate that was updated every year based on the changing capacity of each site to produce and absorb larvae. Each rule was evaluated in the context of achieving the maximum metapopulation mean lifetime at the conclusion of the implementation phase. MPAs were designated through the alteration of the extinction risk parameter. The highest ranked criteria were PageRank while the actual implementation from historical records ranked lowest. Our results indicate that protecting the sites ranked highest with regard to larval supply is likely to yield the highest benefit for fish abundance and fish metapopulation persistence. Model results highlighted the benefits of including network processes in conservation planning.
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17. |
- Robinette, Michelle L., et al.
(författare)
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Association of Somatic TET2 Mutations With Giant Cell Arteritis
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Ingår i: Arthritis and Rheumatology. - 2326-5191.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. Results: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). Conclusions: CH increases risk for development of GCA in a genotype-specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.
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19. |
- Blum, J, et al.
(författare)
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Treatment of incomplete abortion and miscarriage with misoprostol
- 2007
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Ingår i: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. - : Wiley. - 0020-7292. ; 9999 Suppl 2, s. S186-S189
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Tidskriftsartikel (refereegranskat)
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20. |
- Cruz, Jose Almeida, et al.
(författare)
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RNA-Puzzles : A CASP-like evaluation of RNA three-dimensional structure prediction
- 2012
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Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 18:4, s. 610-625
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of a first, collective, blind experiment in RNA three-dimensional (3D) structure prediction, encompassing three prediction puzzles. The goals are to assess the leading edge of RNA structure prediction techniques; compare existing methods and tools; and evaluate their relative strengths, weaknesses, and limitations in terms of sequence length and structural complexity. The results should give potential users insight into the suitability of available methods for different applications and facilitate efforts in the RNA structure prediction community in ongoing efforts to improve prediction tools. We also report the creation of an automated evaluation pipeline to facilitate the analysis of future RNA structure prediction exercises.
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22. |
- Davis, B, et al.
(författare)
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Voices of chemical biology
- 2021
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Ingår i: Nature chemical biology. - : Springer Science and Business Media LLC. - 1552-4469 .- 1552-4450. ; 17:1, s. 1-4
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Tidskriftsartikel (refereegranskat)
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23. |
- Fiala, C, et al.
(författare)
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Securing reproductive rights
- 2004
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Ingår i: Lancet (London, England). - 1474-547X. ; 363:9413, s. 989-990
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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24. |
- Gemell-Danielsson, K, et al.
(författare)
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Misoprostol to treat missed abortion in the first trimester
- 2007
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Ingår i: International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. - : Wiley. - 0020-7292. ; 9999 Suppl 2, s. S182-S185
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Tidskriftsartikel (refereegranskat)
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25. |
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26. |
- Gould, Rebecca, et al.
(författare)
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Acceptance and Commitment Therapy for people living with motor neuron disease : an uncontrolled feasibility study
- 2023
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Ingår i: Pilot and Feasibility Studies. - : Springer Nature. - 2055-5784. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND.Methods: PlwMND aged >= 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (>= 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (>= 70% completing >= 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months.Results: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended >= 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status.Conclusions: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway.
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28. |
- Gumuser, Esra D., et al.
(författare)
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Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease
- 2023
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Ingår i: Journal of the American College of Cardiology. - 0735-1097. ; 81:20, s. 1996-2009
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. Methods: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. Results: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). Conclusions: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.
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30. |
- Saadatagah, Seyedmohammad, et al.
(författare)
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Clonal Hematopoiesis Risk Score and All-Cause and Cardiovascular Mortality in Older Adults
- 2024
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Ingår i: JAMA Network Open. - 2574-3805. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value. Objective: To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH. Design, Setting, and Participants: This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were collected from 2011 to 2013, sequencing was performed in 2022, and data analysis was completed in 2023. Exposure: The exposure was a diagnosis of CH. CHRS scores (calculated using 8 demographic, complete blood cell count, and molecular factors) were used to categorize individuals with CH into low-risk (CHRS ≤9.5), intermediate-risk (CHRS >9.5 to <12.5), and high-risk (CHRS ≥12.5) groups. Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes were HM mortality, cardiovascular disease mortality, and death from other causes. Results: Among 3871 participants without a history of HM (mean [SD] age, 75.7 [5.2] years; 2264 [58.5%] female individuals; 895 [23.1%] Black individuals; 2976 White individuals [76.9%]), 938 (24.2%) had CH. According to the CHRS, 562 (59.9%) were low risk, 318 (33.9%) were intermediate risk, and 58 (6.2%) were high risk. During a median (IQR) follow-up of 7.13 (5.63-7.78) years, 570 participants without CH (19.4%) and 254 participants with CH (27.1%) died. Mortality by CHRS risk group was 128 deaths (22.8%) for low risk, 93 (29.2%) for intermediate risk, and 33 (56.9%) for high risk. By use of multivariable competing risk regression, subdistribution hazard ratios (sHRs) for all-cause mortality were 1.08 (95% CI, 0.89-1.31; P =.42) for low-risk CH, 1.12 (95% CI, 0.89-1.41; P =.31) for intermediate-risk CH, and 2.52 (95% CI, 1.72-3.70; P <.001) for high-risk CH compared with no CH. Among individuals in the high-risk CH group, the sHR of death from HM (6 deaths [10.3%]) was 25.58 (95% CI, 7.55-86.71; P <.001) and that of cardiovascular death (12 deaths [20.7%]) was 2.91 (95% CI, 1.55-5.47; P <.001). Conclusions and Relevance: In this cohort study, the CHRS was associated with all-cause, HM-related, and cardiovascular disease mortality in older adults with CH and may be useful in shared decision-making to guide clinical management and identify appropriate candidates for clinical trials.
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31. |
- Schuermans, Art, et al.
(författare)
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Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias
- 2024
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Ingår i: European Heart Journal. - 0195-668X. ; 45:10, s. 791-805
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Tidskriftsartikel (refereegranskat)abstract
- Background and Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutaAims tions, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.Methods UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. Results This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04–1.18; P = .001] and 1.13 (95% CI 1.05–1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01–1.19; P = .031) and 1.13 (95% CI 1.03–1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00–1.34; P = .049) and 1.22 (95% CI 1.03–1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07–1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. Conclusions CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.
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32. |
- Song, YT, et al.
(författare)
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Factors associated with the responsive behaviours of older adults living in long-term care homes towards staff: a systematic review protocol
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:5, s. e028416-
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Tidskriftsartikel (refereegranskat)abstract
- In the last decade, increasing research interest has been expressed in responsive behaviours of older adults living in long-term care (LTC) homes, including nursing homes and assisted living facilities. Responsive behaviours are not only a sign of underlying unmet needs, but when directed against (towards) paid staff can lead to decreased quality of work life, and may contribute to lower quality of care. In this systematic review, we aim to synthesise empirically based quantitative and qualitative evidence on factors and stakeholder (eg, staff and family members) experiences of factors associated with the responsive behaviours of people living in LTC directed towards staff.Methods and analysisThis study will be a systematic review of published and ‘grey’ literature. Twelve bibliographical databases will be searched, and for each database, we will use appropriate subject headings and keywords that cover two concepts: LTC and responsive behaviour. No publication date or language filter will be used. The title and abstract of each extracted record will be screened, followed by screening of full text of included papers. Then data extraction and quality assessments will be undertaken. Each stage will be completed independently by pairs of authors. For quantitative studies, meta-analysis will be conducted if pooling is possible; otherwise, a critical narrative analysis will be conducted. For qualitative studies, thematic analysis will be conducted. Factors will then be organised at the individual, interpersonal, institutional and larger societal levels. Sensitivity analysis will be conducted to explore the influence of risk of bias and publication bias on the results. Subgroup analysis will be conducted for people who live with dementia and those who do not.Ethics and disseminationEthics approval is not required for this systematic review. The results of this study will be disseminated via peer-reviewed publication and presentation at professional conferences.
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33. |
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34. |
- Weeks, A, et al.
(författare)
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Spontaneous miscarriage in the first trimester
- 2006
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Ingår i: BMJ (Clinical research ed.). - : BMJ. - 1756-1833 .- 0959-8138 .- 1468-5833. ; 332:7552, s. 1223-1224
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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