| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 3. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 5. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 6. |
- Jang, Seon-Kyeong, et al.
(författare)
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Rare genetic variants explain missing heritability in smoking.
- 2022
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 6:11, s. 1577-1586
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Tidskriftsartikel (refereegranskat)abstract
- Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
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| 7. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 8. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 9. |
- Botvinik-Nezer, Rotem, et al.
(författare)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Tidskriftsartikel (refereegranskat)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 10. |
- Saner, Flurina A. M., et al.
(författare)
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Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
- 2024
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Ingår i: CLINICAL CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 30:16, s. 3481-3498
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8(+) lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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| 11. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 12. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 13. |
- Middha, Pooja K., et al.
(författare)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 14. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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| 15. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 16. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 17. |
- Zhou, Wei, et al.
(författare)
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Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
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Ingår i: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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| 18. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 19. |
- Erzurumluoglu, A. Mesut, et al.
(författare)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 20. |
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The Seventeenth Data Release of the Sloan Digital Sky Surveys : Complete Release of MaNGA, MaStar, and APOGEE-2 Data
- 2022
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Ingår i: Astrophysical Journal Supplement Series. - : Institute of Physics (IOP). - 0067-0049 .- 1538-4365. ; 259:2
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Tidskriftsartikel (refereegranskat)abstract
- This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys.
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| 21. |
- van Akkooi, Alexander C. J., et al.
(författare)
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Neoadjuvant Systemic Therapy (NAST) in Patients with Melanoma: Surgical Considerations by the International Neoadjuvant Melanoma Consortium (INMC)
- 2022
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Ingår i: ANNALS OF SURGICAL ONCOLOGY. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 29:6, s. 3694-3708
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Tidskriftsartikel (refereegranskat)abstract
- Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.
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| 22. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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| 23. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 24. |
- Andriuta, Daniela, et al.
(författare)
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Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONWe investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases.METHODSA mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative.RESULTSPVS was significantly associated with sEF (c = -0.125 +/- 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH.DISCUSSIONIn this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia.HIGHLIGHTS Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.
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| 25. |
- Azevedo, Flavio, et al.
(författare)
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Social and moral psychology of COVID-19 across 69 countries
- 2023
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Ingår i: Scientific Data. - : NATURE PORTFOLIO. - 2052-4463. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.
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| 26. |
- Conley, Robert B., et al.
(författare)
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Secondary Fracture Prevention : Consensus Clinical Recommendations from a Multistakeholder Coalition
- 2020
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Ingår i: Journal of Orthopaedic Trauma. - 0890-5339. ; 34:4, s. 125-141
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).
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| 27. |
- Conley, Robert B., et al.
(författare)
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Secondary Fracture Prevention : Consensus Clinical Recommendations from a Multistakeholder Coalition
- 2020
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Ingår i: Orthopaedic Nursing. - 0744-6020. ; 39:3, s. 145-161
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk offuture fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the riskfor second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring foradverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). (c) 2019 American Society for Bone and Mineral Research.
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| 28. |
- Costello, David M., et al.
(författare)
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Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
- 2022
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Ingår i: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
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Tidskriftsartikel (refereegranskat)abstract
- Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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| 29. |
- Gaziano, Liam, et al.
(författare)
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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19. Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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| 30. |
- Jiang, Mingkai, et al.
(författare)
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The fate of carbon in a mature forest under carbon dioxide enrichment
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7802, s. 227-231
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric carbon dioxide enrichment (eCO2) can enhance plant carbon uptake and growth1–5, thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration6. Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth3–5, it is unclear whether mature forests respond to eCO2 in a similar way. In mature trees and forest stands7–10, photosynthetic uptake has been found to increase under eCO2 without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO2 unclear4,5,7–11. Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO2 exposure. We show that, although the eCO2 treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO2, and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.
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| 31. |
- Kattner, Nicole, et al.
(författare)
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Development and validation of a quantitative electron microscopy score to assess acute cellular stress in the human exocrine pancreas
- 2021
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Ingår i: Journal of Pathology: Clinical Research. - : Wiley. - 2056-4538. ; 7:2, s. 173-187
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Tidskriftsartikel (refereegranskat)abstract
- The pancreas is particularly sensitive to acute cellular stress, but this has been difficult to evaluate using light microscopy. Pancreatic ischaemia associated with deceased organ donation negatively impacts whole-organ and isolated-islet transplantation outcomes. Post-mortem changes have also hampered accurate interpretation of ante-mortem pancreatic pathology. A rigorous histological scoring system accurately quantifying ischaemia is required to experimentally evaluate innovations in organ preservation and to increase rigour in clinical/research evaluation of underlying pancreatic pathology. We developed and validated an unbiased electron microscopy (EM) score of acute pancreatic exocrine cellular stress in deceased organ donor cohorts (development [n = 28] and validation [n = 16]). Standardised assessment led to clearly described numerical scores (0–3) for nuclear, mitochondrial and endoplasmic reticulum (ER) morphology and intracellular vacuolisation; with a maximum (worst) aggregate total score of 12. In the Validation cohort, a trend towards higher scores was observed for tail versus head regions (nucleus score following donation after brainstem death [DBD]: head 0.67 ± 0.19; tail 0.86 ± 0.11; p = 0.027) and donation after circulatory death (DCD) versus DBD (mitochondrial score: DCD (head + tail) 2.59 ± 0.16; DBD (head + tail) 2.38 ± 0.21; p = 0.004). Significant mitochondrial changes were seen ubiquitously even with short cold ischaemia, whereas nuclear and vacuolisation changes remained mild even after prolonged ischaemia. ER score correlated with cold ischaemia time (CIT) following DBD (pancreatic tail region: r = 0.796; p = 0.018). No relationships between CIT and EM scores were observed following DCD. In conclusion, we have developed and validated a novel EM score providing standardised quantitative assessment of subcellular ultrastructural morphology in pancreatic acinar cells. This provides a robust novel tool for gold standard measurement of acute cellular stress in studies evaluating surrogate measures of peri-transplant ischaemia, organ preservation technologies and in samples obtained for detailed pathological examination of underlying pancreatic pathology.
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| 32. |
- Lewin, Harris A., et al.
(författare)
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The Earth BioGenome Project 2020 : Starting the clock
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 33. |
- Morales, Daniel R, et al.
(författare)
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Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.
- 2021
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Ingår i: The Lancet Digital health. - 2589-7500. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.Among 1355349 antihypertensive users (363785 ACEI or ARB monotherapy users, 248915 CCB or THZ monotherapy users, 711799 ACEI or ARB combination users, and 473076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of >40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.
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| 34. |
- Tan, Eng Hooi, et al.
(författare)
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COVID-19 in patients with autoimmune diseases: characteristics and outcomes in a multinational network of cohorts across three countries.
- 2021
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 60:SI
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Tidskriftsartikel (refereegranskat)abstract
- Patients with autoimmune diseases were advised to shield to avoid coronavirus disease 2019 (COVID-19), but information on their prognosis is lacking. We characterized 30-day outcomes and mortality after hospitalization with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza.A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center [USA, Optum (USA), Department of Veterans Affairs (USA), Information System for Research in Primary Care-Hospitalization Linked Data (Spain) and claims data from IQVIA Open Claims (USA) and Health Insurance and Review Assessment (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalized between January and June 2020 with COVID-19, and similar patients hospitalized with influenza in 2017-18 were included. Outcomes were death and complications within 30days of hospitalization.We studied 133589 patients diagnosed and 48418 hospitalized with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50years with previous comorbidities. The prevalence of hypertension (45.5-93.2%), chronic kidney disease (14.0-52.7%) and heart disease (29.0-83.8%) was higher in hospitalized vs diagnosed patients with COVID-19. Compared with 70660 hospitalized with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2-4.3% vs 6.32-24.6%).Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality.
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| 35. |
- Van Bavel, Jay J., et al.
(författare)
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National identity predicts public health support during a global pandemic
- 2022
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Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic. Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.
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| 36. |
- Zanne, Amy E, et al.
(författare)
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Fungal functional ecology: bringing a trait-based approach to plant-associated fungi.
- 2020
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Ingår i: Biological reviews of the Cambridge Philosophical Society. - : Wiley. - 1469-185X .- 1464-7931. ; 95:2, s. 409-433
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Tidskriftsartikel (refereegranskat)abstract
- Fungi play many essential roles in ecosystems. They facilitate plant access to nutrients and water, serve as decay agents that cycle carbon and nutrients through the soil, water and atmosphere, and are major regulators of macro-organismal populations. Although technological advances are improving the detection and identification of fungi, there still exist key gaps in our ecological knowledge of this kingdom, especially related to function. Trait-based approaches have been instrumental in strengthening our understanding of plant functional ecology and, as such, provide excellent models for deepening our understanding of fungal functional ecology in ways that complement insights gained from traditional and -omics-based techniques. In this review, we synthesize current knowledge of fungal functional ecology, taxonomy and systematics and introduce a novel database of fungal functional traits (FunFun ). FunFun is built to interface with other databases to explore and predict how fungal functional diversity varies by taxonomy, guild, and other evolutionary or ecological grouping variables. To highlight how a quantitative trait-based approach can provide new insights, we describe multiple targeted examples and end by suggesting next steps in the rapidly growing field of fungal functional ecology.
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| 37. |
- Doubek, Jonathan P., et al.
(författare)
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The extent and variability of storm-induced temperature changes in lakes measured with long-term and high-frequency data
- 2021
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Ingår i: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 66:5, s. 1979-1992
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Tidskriftsartikel (refereegranskat)abstract
- The intensity and frequency of storms are projected to increase in many regions of the world because of climate change. Storms can alter environmental conditions in many ecosystems. In lakes and reservoirs, storms can reduce epilimnetic temperatures from wind-induced mixing with colder hypolimnetic waters, direct precipitation to the lake's surface, and watershed runoff. We analyzed 18 long-term and high-frequency lake datasets from 11 countries to assess the magnitude of wind- vs. rainstorm-induced changes in epilimnetic temperature. We found small day-to-day epilimnetic temperature decreases in response to strong wind and heavy rain during stratified conditions. Day-to-day epilimnetic temperature decreased, on average, by 0.28 degrees C during the strongest windstorms (storm mean daily wind speed among lakes: 6.7 +/- 2.7 m s(-1), 1 SD) and by 0.15 degrees C after the heaviest rainstorms (storm mean daily rainfall: 21.3 +/- 9.0 mm). The largest decreases in epilimnetic temperature were observed >= 2 d after sustained strong wind or heavy rain (top 5(th) percentile of wind and rain events for each lake) in shallow and medium-depth lakes. The smallest decreases occurred in deep lakes. Epilimnetic temperature change from windstorms, but not rainstorms, was negatively correlated with maximum lake depth. However, even the largest storm-induced mean epilimnetic temperature decreases were typically <2 degrees C. Day-to-day temperature change, in the absence of storms, often exceeded storm-induced temperature changes. Because storm-induced temperature changes to lake surface waters were minimal, changes in other limnological variables (e.g., nutrient concentrations or light) from storms may have larger impacts on biological communities than temperature changes.
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| 38. |
- Egg, David, et al.
(författare)
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Therapeutic options for CTLA-4 insufficiency
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 149:2, s. 736-746
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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| 39. |
- Geerts, Bart, et al.
(författare)
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The COMBLE Campaign : A Study of Marine Boundary Layer Clouds in Arctic Cold-Air Outbreaks
- 2022
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 103:5, s. E1371-E1389
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Tidskriftsartikel (refereegranskat)abstract
- One of the most intense air mass transformations on Earth happens when cold air flows from frozen surfaces to much warmer open water in cold-air outbreaks (CAOs), a process captured beautifully in satellite imagery. Despite the ubiquity of the CAO cloud regime over high-latitude oceans, we have a rather poor understanding of its properties, its role in energy and water cycles, and its treatment in weather and climate models. The Cold-Air Outbreaks in the Marine Boundary Layer Experiment (COMBLE) was conducted to better understand this regime and its representation in models. COMBLE aimed to examine the relations between surface fluxes, boundary layer structure, aerosol, cloud, and precipitation properties, and mesoscale circulations in marine CAOs. Processes affecting these properties largely fall in a range of scales where boundary layer processes, convection, and precipitation are tightly coupled, which makes accurate representation of the CAO cloud regime in numerical weather prediction and global climate models most challenging. COMBLE deployed an Atmospheric Radiation Measurement Mobile Facility at a coastal site in northern Scandinavia (69°N), with additional instruments on Bear Island (75°N), from December 2019 to May 2020. CAO conditions were experienced 19% (21%) of the time at the main site (on Bear Island). A comprehensive suite of continuous in situ and remote sensing observations of atmospheric conditions, clouds, precipitation, and aerosol were collected. Because of the clouds’ well-defined origin, their shallow depth, and the broad range of observed temperature and aerosol concentrations, the COMBLE dataset provides a powerful modeling testbed for improving the representation of mixed-phase cloud processes in large-eddy simulations and large-scale models.
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| 40. |
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| 41. |
- Murray-Smith, Heidi, et al.
(författare)
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Updating the study protocol: Insight 46-a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3
- 2024
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Ingår i: BMC NEUROLOGY. - 1471-2377. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia.Methods/DesignPhase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46.DiscussionThe NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.
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| 42. |
- Treat, Claire C., et al.
(författare)
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Permafrost Carbon : Progress on Understanding Stocks and Fluxes Across Northern Terrestrial Ecosystems
- 2024
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 129:3
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Tidskriftsartikel (refereegranskat)abstract
- Significant progress in permafrost carbon science made over the past decades include the identification of vast permafrost carbon stocks, the development of new pan-Arctic permafrost maps, an increase in terrestrial measurement sites for CO2 and methane fluxes, and important factors affecting carbon cycling, including vegetation changes, periods of soil freezing and thawing, wildfire, and other disturbance events. Process-based modeling studies now include key elements of permafrost carbon cycling and advances in statistical modeling and inverse modeling enhance understanding of permafrost region C budgets. By combining existing data syntheses and model outputs, the permafrost region is likely a wetland methane source and small terrestrial ecosystem CO2 sink with lower net CO2 uptake toward higher latitudes, excluding wildfire emissions. For 2002–2014, the strongest CO2 sink was located in western Canada (median: −52 g C m−2 y−1) and smallest sinks in Alaska, Canadian tundra, and Siberian tundra (medians: −5 to −9 g C m−2 y−1). Eurasian regions had the largest median wetland methane fluxes (16–18 g CH4 m−2 y−1). Quantifying the regional scale carbon balance remains challenging because of high spatial and temporal variability and relatively low density of observations. More accurate permafrost region carbon fluxes require: (a) the development of better maps characterizing wetlands and dynamics of vegetation and disturbances, including abrupt permafrost thaw; (b) the establishment of new year-round CO2 and methane flux sites in underrepresented areas; and (c) improved models that better represent important permafrost carbon cycle dynamics, including non-growing season emissions and disturbance effects.
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| 43. |
- Womersley, Freya C., et al.
(författare)
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Identifying priority sites for whale shark ship collision management globally
- 2024
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Ingår i: SCIENCE OF THE TOTAL ENVIRONMENT. - 0048-9697 .- 1879-1026. ; 934
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Tidskriftsartikel (refereegranskat)abstract
- The expansion of the world 's merchant fleet poses a great threat to the ocean 's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark ( Rhincodon typus ) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation " sites are of significant ecological, socioeconomic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world ( >50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.
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| 44. |
- Abbott, Benjamin W., et al.
(författare)
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We Must Stop Fossil Fuel Emissions to Protect Permafrost Ecosystems
- 2022
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Ingår i: Frontiers in Environmental Science. - : Frontiers Media SA. - 2296-665X. ; 10
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Forskningsöversikt (refereegranskat)abstract
- Climate change is an existential threat to the vast global permafrost domain. The diverse human cultures, ecological communities, and biogeochemical cycles of this tenth of the planet depend on the persistence of frozen conditions. The complexity, immensity, and remoteness of permafrost ecosystems make it difficult to grasp how quickly things are changing and what can be done about it. Here, we summarize terrestrial and marine changes in the permafrost domain with an eye toward global policy. While many questions remain, we know that continued fossil fuel burning is incompatible with the continued existence of the permafrost domain as we know it. If we fail to protect permafrost ecosystems, the consequences for human rights, biosphere integrity, and global climate will be severe. The policy implications are clear: the faster we reduce human emissions and draw down atmospheric CO2, the more of the permafrost domain we can save. Emissions reduction targets must be strengthened and accompanied by support for local peoples to protect intact ecological communities and natural carbon sinks within the permafrost domain. Some proposed geoengineering interventions such as solar shading, surface albedo modification, and vegetation manipulations are unproven and may exacerbate environmental injustice without providing lasting protection. Conversely, astounding advances in renewable energy have reopened viable pathways to halve human greenhouse gas emissions by 2030 and effectively stop them well before 2050. We call on leaders, corporations, researchers, and citizens everywhere to acknowledge the global importance of the permafrost domain and work towards climate restoration and empowerment of Indigenous and immigrant communities in these regions.
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| 45. |
- Blaxter, Mark, et al.
(författare)
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Why sequence all eukaryotes?
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Life on Earth has evolved from initial simplicity to the astounding complexity we experience today. Bacteria and archaea have largely excelled in metabolic diversification, but eukaryotes additionally display abundant morphological innovation. How have these innovations come about and what constraints are there on the origins of novelty and the continuing maintenance of biodiversity on Earth? The history of life and the code for the working parts of cells and systems are written in the genome. The Earth BioGenome Project has proposed that the genomes of all extant, named eukaryotes-about 2 million species-should be sequenced to high quality to produce a digital library of life on Earth, beginning with strategic phylogenetic, ecological, and high-impact priorities. Here we discuss why we should sequence all eukaryotic species, not just a representative few scattered across the many branches of the tree of life. We suggest that many questions of evolutionary and ecological significance will only be addressable when whole-genome data representing divergences at all of the branchings in the tree of life or all species in natural ecosystems are available. We envisage that a genomic tree of life will foster understanding of the ongoing processes of speciation, adaptation, and organismal dependencies within entire ecosystems. These explorations will resolve long-standing problems in phylogenetics, evolution, ecology, conservation, agriculture, bioindustry, and medicine.
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| 46. |
- Furukawa, Toshi A., et al.
(författare)
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Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression : a systematic review and component network meta-analysis using individual data
- 2021
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Ingår i: Lancet psychiatry. - London, United Kingdom : Elsevier. - 2215-0374 .- 2215-0366. ; 8:6, s. 500-511
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Forskningsöversikt (refereegranskat)abstract
- Findings We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42.0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1.83 [95% credible interval (CrI) -2.90 to -0.80]) and that relaxation might be harmful (1.20 [95% CrI 0.17 to 2.27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0.32 [95% CrI 0.13 to 0.93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. 511
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| 47. |
- Laisk, Triin, et al.
(författare)
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The genetic architecture of sporadic and multiple consecutive miscarriage.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P=3.2 × 10-8, odds ratio (OR)=1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF=6.4%, P=1.3 × 10-8, OR=1.7; rs143445068, MAF=0.8%, P=5.2 × 10-9, OR=3.4; rs183453668, MAF=0.5%, P=2.8 × 10-8, OR=3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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| 48. |
- Novotny, Susan A., et al.
(författare)
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Do Weightbearing Restrictions Cause Excess Weight Gain in Children With LEGG-Calve-Perthes Disease?
- 2023
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Ingår i: Journal of Pediatric Orthopaedics. - : Lippincott Williams & Wilkins. - 0271-6798 .- 1539-2570. ; 43:1, s. 31-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: Restricted weight bearing is commonly prescribed in Legg-Calve-Perthes Disease (LCPD), raising concerns of causing overweight or obesity. This study utilizes prospectively collected data to address the following questions: (1) does body mass index (BMI) Z-score increase over the course of LCPD follow-up; (2) is having a BMI category of normal, overweight, or obese at baseline associated with BMI Z-score changes over the course of follow-up; and (3) is the duration of weight bearing restrictions (no restrictions, <3, 3 to <6, 6 to 9, or >9 mo) associated with BMI Z-score changes.Methods: Data of 130 children aged 5 to 12 years with unilateral early-stage LCPD were extracted from an international database. Nation-specific BMI Z-scores and percentile-based weight categories were determined, and the duration of follow-up and weight bearing restrictions were calculated. Longitudinal changes in BMI Z-scores were evaluated for the 3 study questions using mixed effects linear regression models with surgery as a covariate. Sensitivity analyses were used to determine the influence of socio-cultural background (USA vs. India) for each study question.Results: During the 35.5 +/- 15.9 months of follow-up, no statistically significant increase in BMI Z-scores was observed across the entire cohort, or following stratification by baseline weight categories or the duration of the weight bearing restriction. Sensitivity analyses indicated that patients in the USA had no change in their BMI Z-score. When stratified by weight categories, the normal weight of US children had a small increase in their BMI Z-score (0.005 per mo, 95% confidence interval: 0.0002, 0.009), but this was not seen in other BMI categories. The cohort of Indian children had a small but significant decrease in their BMI Z-score (-0.005/mo, 95% CI: -0.009, -0.0002). After stratification by weight categories, a small decrease of the BMI Z-score was observed only in the Indian overweight children (-0.016 per mo, 95% CI: -0.027, -0.005) and no other BMI category.Conclusions: Weightbearing restrictions over the course of follow-up for our cohort of children with early-stage LCPD were not associated with clinically meaningful increases of BMI Z-scores. Weight gain is multi-factorial and probably not caused by weight bearing restrictions alone.
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| 49. |
- Watts, Jennifer D., et al.
(författare)
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Carbon uptake in Eurasian boreal forests dominates the high-latitude net ecosystem carbon budget
- 2023
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 29:7, s. 1870-1889
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Tidskriftsartikel (refereegranskat)abstract
- Arctic-boreal landscapes are experiencing profound warming, along with changes in ecosystem moisture status and disturbance from fire. This region is of global importance in terms of carbon feedbacks to climate, yet the sign (sink or source) and magnitude of the Arctic-boreal carbon budget within recent years remains highly uncertain. Here, we provide new estimates of recent (2003–2015) vegetation gross primary productivity (GPP), ecosystem respiration (Reco), net ecosystem CO2 exchange (NEE; Reco − GPP), and terrestrial methane (CH4) emissions for the Arctic-boreal zone using a satellite data-driven process-model for northern ecosystems (TCFM-Arctic), calibrated and evaluated using measurements from >60 tower eddy covariance (EC) sites. We used TCFM-Arctic to obtain daily 1-km2 flux estimates and annual carbon budgets for the pan-Arctic-boreal region. Across the domain, the model indicated an overall average NEE sink of −850 Tg CO2-C year−1. Eurasian boreal zones, especially those in Siberia, contributed to a majority of the net sink. In contrast, the tundra biome was relatively carbon neutral (ranging from small sink to source). Regional CH4 emissions from tundra and boreal wetlands (not accounting for aquatic CH4) were estimated at 35 Tg CH4-C year−1. Accounting for additional emissions from open water aquatic bodies and from fire, using available estimates from the literature, reduced the total regional NEE sink by 21% and shifted many far northern tundra landscapes, and some boreal forests, to a net carbon source. This assessment, based on in situ observations and models, improves our understanding of the high-latitude carbon status and also indicates a continued need for integrated site-to-regional assessments to monitor the vulnerability of these ecosystems to climate change.
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| 50. |
- Widemann, Thomas, et al.
(författare)
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Venus Evolution Through Time : Key Science Questions, Selected Mission Concepts and Future Investigations
- 2023
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Ingår i: Space Science Reviews. - : SPRINGER. - 0038-6308 .- 1572-9672. ; 219:7
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Forskningsöversikt (refereegranskat)abstract
- In this work we discuss various selected mission concepts addressing Venus evolution through time. More specifically, we address investigations and payload instrument concepts supporting scientific goals and open questions presented in the companion articles of this volume. Also included are their related investigations (observations & modeling) and discussion of which measurements and future data products are needed to better constrain Venus' atmosphere, climate, surface, interior and habitability evolution through time. A new fleet of Venus missions has been selected, and new mission concepts will continue to be considered for future selections. Missions under development include radar-equipped ESA-led EnVision M5 orbiter mission (European Space Agency 2021), NASA-JPL's VERITAS orbiter mission (Smrekar et al. 2022a), NASA-GSFC's DAVINCI entry probe/flyby mission (Garvin et al. 2022a). The data acquired with the VERITAS, DAVINCI, and EnVision from the end of this decade will fundamentally improve our understanding of the planet's long term history, current activity and evolutionary path. We further describe future mission concepts and measurements beyond the current framework of selected missions, as well as the synergies between these mission concepts, ground-based and space-based observatories and facilities, laboratory measurements, and future algorithmic or modeling activities that pave the way for the development of a Venus program that extends into the 2040s (Wilson et al. 2022).
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