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51.
  • Tragante, Vinicius, et al. (författare)
  • Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
  • 2014
  • Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297. ; 94:3, s. 349-360
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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52.
  • Holmes, Michael V., et al. (författare)
  • Mendelian randomization of blood lipids for coronary heart disease
  • 2015
  • Ingår i: European Heart Journal. - : Oxford University Press. - 1522-9645. ; 36:9, s. 539-539
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a priormeta-analysis (threshold P < 2 x 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestrictedallele score (48SNPs) was associated with CHD(OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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53.
  • Jung, Christian, et al. (författare)
  • A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
  • 2019
  • Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery. 
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54.
  • Yoneyama, Sachiko, et al. (författare)
  • Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations
  • 2014
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906. ; 23:9, s. 2498-2510
  • Tidskriftsartikel (refereegranskat)abstract
    • Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 2080 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes 50 000 cosmopolitan tagged SNPs across 2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P 2.4 10(6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR ( SE, 0.048 0.008, P 7.7 10(9)) as was rs7302703-G in HOXC10 ( 0.044 0.008, P 2.9 10(7)) and rs936108-C in PEMT ( 0.035 0.007, P 1.9 10(6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 ( 0.10 0.02, P 1.9 10(6)) and rs1037575-A in ATBDB4 ( 0.046 0.01, P 2.2 10(6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
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55.
  • Estes, James A., et al. (författare)
  • Trophic Downgrading of Planet Earth
  • 2011
  • Ingår i: Science. - 0036-8075 .- 1095-9203. ; 333:6040, s. 301-306
  • Forskningsöversikt (refereegranskat)abstract
    • Until recently, large apex consumers were ubiquitous across the globe and had been for millions of years. The loss of these animals may be humankind's most pervasive influence on nature. Although such losses are widely viewed as an ethical and aesthetic problem, recent research reveals extensive cascading effects of their disappearance in marine, terrestrial, and freshwater ecosystems worldwide. This empirical work supports long-standing theory about the role of top-down forcing in ecosystems but also highlights the unanticipated impacts of trophic cascades on processes as diverse as the dynamics of disease, wildfire, carbon sequestration, invasive species, and biogeochemical cycles. These findings emphasize the urgent need for interdisciplinary research to forecast the effects of trophic downgrading on process, function, and resilience in global ecosystems.
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56.
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57.
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58.
  • Calderón-Contreras, Rafael, et al. (författare)
  • A regional PECS node built from place-based social-ecological sustainability research in Latin America and the Caribbean
  • 2022
  • Ingår i: Ecosystems and People. - 2639-5908 .- 2639-5916. ; 18:1, s. 1-14
  • Tidskriftsartikel (refereegranskat)abstract
    • Sustainability requires a combination of meaningful co-production of locally relevant solutions, synthesis of insights gained across regions, and increased cooperation between science, policy and practice. The Programme for Ecosystem Change and Society (PECS) has been coordinating Place-Based Social-Ecological Sustainability Research (PBSESR) across the globe and emphasizes the need for regional scientific nodes from diverse biocultural regions to inform sustainability science and action. In this paper, we assess the strengths of the PBSESR communities in Latin America and the Caribbean (LAC). We provide an overview of PBSESR literature associated with this region and highlight the achievements of two prominent regional networks: The Social-Ecological Systems and Sustainability Research Network from Mexico (SocioEcoS) and the South American Institute for Resilience and Sustainability Studies from Uruguay (SARAS Institute). Finally, we identify the potential in these nodes to constitute a regional PECS node in Latin America and discuss the capacity needed to ensure such function. The results of the literature review show that while still loosely interconnected across the region, networks play key roles in connecting otherwise cloistered teams and we illustrate how the SocioEcoS network (focusing on transdisciplinary co-production of knowledge towards sustainability) and the SARAS Institute (focusing on innovative approaches for looking at complex social-ecological problems, rooted in slow science and arts) operate as key connectors in the region. We conclude that these organizations combined can embody a Latin American node for PECS, and would thereby not only contribute to regional but also global capacities to advance the sustainability agenda. 
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59.
  • Castner, Ashleigh T., et al. (författare)
  • Microscopic Insights into Cation-Coupled Electron Hopping Transport in a Metal-Organic Framework
  • 2022
  • Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:13, s. 5910-5920
  • Tidskriftsartikel (refereegranskat)abstract
    • Electron transport through metal-organic frameworks by ahopping mechanism between discrete redox active sites is coupled to diffusion-migration of charge-balancing counter cations. Experimentally determinedapparent diffusion coefficients,Deapp, that characterize this form of chargetransport thus contain contributions from both processes. While this is wellestablished for MOFs, microscopic descriptions of this process are largelylacking. Herein, we systematically lay out different scenarios for cation-coupledelectron transfer processes that are at the heart of charge diffusion throughMOFs. Through systematic variations of solvents and electrolyte cations, it isshown that theDeappfor charge migration through a PIZOF-type MOF,Zr(dcphOH-NDI) that is composed of redox-active naphthalenediimide(NDI) linkers, spans over 2 orders of magnitude. More importantly, however,the microscopic mechanisms for cation-coupled electron propagation arecontingent on differing factors depending on the size of the cation and its propensity to engage in ion pairs with reduced linkers,either non-specifically or in defined structural arrangements. Based on computations and in agreement with experimental results, weshow that ion pairing generally has an adverse effect on cation transport, thereby slowing down charge transport. In Zr(dcphOH-NDI), however, specific cation-linker interactions can open pathways for concerted cation-coupled electron transfer processes thatcan outcompete limitations from reduced cationflux.
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60.
  • Klintman, Marie, et al. (författare)
  • The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer
  • 2013
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off >= 10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95% CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95% CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95% CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95% CI: 1.1-6.7), and cyclin A (HR=2.7, 95% CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.
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