| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- 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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| 4. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 5. |
- Granholm, Anders, et al.
(författare)
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Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial
- 2022
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Ingår i: Intensive Care Medicine. - : SPRINGER. - 0342-4642 .- 1432-1238. ; 48:1, s. 45-55
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Tidskriftsartikel (refereegranskat)abstract
- Purpose We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. Methods We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. Results The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. Conclusion We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.
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| 6. |
- Granholm, Anders, et al.
(författare)
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Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis
- 2021
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 65:5, s. 702-710
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Tidskriftsartikel (refereegranskat)abstract
- Background Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. Methods This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. Discussion This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. Trial registration ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.
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| 7. |
- Granholm, Anders, et al.
(författare)
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Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia
- 2022
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Ingår i: Intensive Care Medicine. - : SPRINGER. - 0342-4642 .- 1432-1238. ; 48, s. 580-589
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Tidskriftsartikel (refereegranskat)abstract
- Purpose We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. Methods We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. Results We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). Conclusion Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.
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| 8. |
- Jin, Shoko, et al.
(författare)
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The wide-field, multiplexed, spectroscopic facility WEAVE : Survey design, overview, and simulated implementation
- 2024
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 530:3, s. 2688-2730
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Tidskriftsartikel (refereegranskat)abstract
- WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, saw first light in late 2022. WEAVE comprises a new 2-deg field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959nm at R similar to 5000, or two shorter ranges at . After summarizing the design and implementation of WEAVE and its data systems, we present the organization, science drivers, and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for similar to 3 million stars and detailed abundances for similar to 1.5 million brighter field and open-cluster stars; (ii) survey similar to 0.4 million Galactic-plane OBA stars, young stellar objects, and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey similar to 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionized gas in z < 0.5 cluster galaxies; (vi) survey stellar populations and kinematics in field galaxies at 0.3 less than or similar to z less than or similar to 0.7; (vii) study the cosmic evolution of accretion and star formation using >1 million spectra of LOFAR-selected radio sources; and (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.
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| 9. |
- 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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| 10. |
- Lind, Lars, et al.
(författare)
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Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)
- 2021
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
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| 11. |
- 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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| 12. |
- Mishra, A, et al.
(författare)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Tidskriftsartikel (refereegranskat)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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| 13. |
- Munch, Marie Warrer, et al.
(författare)
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Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial : Protocol and statistical analysis plan
- 2021
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 65:6, s. 834-845
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Tidskriftsartikel (refereegranskat)abstract
- Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. Methods The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. Discussion The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.
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| 14. |
- Sharma, Sanjib, et al.
(författare)
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Fundamental relations for the velocity dispersion of stars in the Milky Way
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 506:2, s. 1761-1776
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Tidskriftsartikel (refereegranskat)abstract
- We explore the fundamental relations governing the radial and vertical velocity dispersions of stars in the Milky Way, from combined studies of complementary surveys including GALAH, LAMOST, APOGEE, the NASA Kepler and K2 missions, and Gaia DR2. We find that different stellar samples, even though they target different tracer populations and employ a variety of age estimation techniques, follow the same set of fundamental relations. We provide the clearest evidence to date that, in addition to the well-known dependence on stellar age, the velocity dispersions of stars depend on orbital angular momentum Lz, metallicity, and height above the plane |z|, and are well described by a multiplicatively separable functional form. The dispersions have a power-law dependence on age with exponents of 0.441 ± 0.007 and 0.251 ± 0.006 for σz and σR, respectively, and the power law is valid even for the oldest stars. For the solar neighbourhood stars, the apparent break in the power law for older stars, as seen in previous studies, is due to the anticorrelation of Lz with age. The dispersions decrease with increasing Lz until we reach the Sun’s orbital angular momentum, after which σz increases (implying flaring in the outer disc) while σR flattens. For a given age, the dispersions increase with decreasing metallicity, suggesting that the dispersions increase with birth radius. The dispersions also increase linearly with |z|. The same set of relations that work in the solar neighbourhood also work for stars between 3 < R/kpc < 20. Finally, the high-[α/Fe] stars follow the same relations as the low-[α/Fe] stars.
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| 15. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 16. |
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| 17. |
- Andersen, Mikkel Rathsach, et al.
(författare)
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Tibial Component Undersizing Is Related to High Degrees of Implant Migration Following Cementless Total Knee Arthroplasty : A Study of Radiostereometric Analysis Data for 111 Patients with 2-Year Follow-up
- 2023
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Ingår i: JBJS Open Access. - 2472-7245. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radiostereometric analysis (RSA) studies have shown that the continuous migration of tibial components is predictive of aseptic loosening following total knee arthroplasty (TKA). In the present study, we investigated whether accurate sizing and placement of tibial components are related to the degree of implant migration as measured with use of RSA.Methods:A total of 111 patients who underwent TKA surgery with a cementless tibial component were followed for a period of 2 years postoperatively, during which implant migration was assessed with use of RSA. RSA was performed within 7 days postoperatively and after 3, 6, 12, and 24 months. Postoperative radiographs were evaluated for component size and placement in the tibia. The evaluations were performed by experienced knee surgeons who were blinded to the migration data and clinical outcomes. A multivariable linear regression analysis was conducted.Results:Continuous implant migration (i.e., migration occurring between 12 and 24 months postoperatively) had a negative association with tibial component size (coefficient [B], -0.2; 95% confidence interval [CI], -0.33 to -0.08). Subsidence was associated with the absence of posterior cortical bone support (B, -0.7; 95% CI, -1.09 to -0.28), the absence of lateral cortical bone support (B, 0.8; 95% CI, 0.29 to 1.37), frontal-plane varus malalignment (B, 0.6; 95% CI, 0.12 to 1.16), and component undersizing (B, -0.4; 95% CI, -0.06 to -0.68). Posterior tilt was associated only with undersizing (B, 0.6; 95% CI, 0.27 to 1.11).Conclusions:Undersized cementless tibial components are at a higher risk for poor fixation with continuous migration following TKA. Therefore, a higher risk of aseptic loosening should be expected.Level of Evidence:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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| 18. |
- Buder, Sven, et al.
(författare)
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The GALAH plus survey : Third data release
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
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Tidskriftsartikel (refereegranskat)abstract
- The ensemble of chemical element abundance measurements for stars, along with precision distances and orbit properties, provides high-dimensional data to study the evolution of the Milky Way. With this third data release of the Galactic Archaeology with HERMES (GALAH) survey, we publish 678 423 spectra for 588 571 mostly nearby stars (81.2 per cent of stars are within <2 kpc), observed with the HERMES spectrograph at the Anglo-Australian Telescope. This release (hereafter GALAH+ DR3) includes all observations from GALAH Phase 1 (bright, main, and faint survey, 70 per cent), K2-HERMES (17 per cent), TESS-HERMES (5 per cent), and a subset of ancillary observations (8 per cent) including the bulge and >75 stellar clusters. We derive stellar parameters T-eff, logg, [Fe/H], v(mic), v(broad), and v(rad) using our modified version of the spectrum synthesis code Spectroscopy Made Easy (SME) and 1D MARCS model atmospheres. We break spectroscopic degeneracies in our spectrum analysis with astrometry from Gaia DR2 and photometry from 2MASS. We report abundance ratios [X/Fe] for 30 different elements (11 of which are based on non-LTE computations) covering five nucleosynthetic pathways. We describe validations for accuracy and precision, flagging of peculiar stars/measurements and recommendations for using our results. Our catalogue comprises 65 per cent dwarfs, 34 per cent giants, and 1 per cent other/unclassified stars. Based on unflagged chemical composition and age, we find 62 per cent young low-alpha, 9 per cent young high-alpha, 27 per cent old high-alpha, and 2 per cent stars with [Fe/H] <= -1. Based on kinematics, 4 per cent are halo stars. Several Value-Added-Catalogues, including stellar ages and dynamics, updated after Gaia eDR3, accompany this release and allow chrono-chemodynamic analyses, as we showcase.
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| 19. |
- Buder, Sven, et al.
(författare)
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The GALAH+ survey : Third data release
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 506:1, s. 150-201
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Tidskriftsartikel (refereegranskat)abstract
- The ensemble of chemical element abundance measurements for stars, along with precision distances and orbit properties, provides high-dimensional data to study the evolution of the Milky Way. With this third data release of the Galactic Archaeology with HERMES (GALAH) survey, we publish 678 423 spectra for 588 571 mostly nearby stars (81.2 per cent of stars are within <2 kpc), observed with the HERMES spectrograph at the Anglo-Australian Telescope. This release (hereafter GALAH+ DR3) includes all observations from GALAH Phase 1 (bright, main, and faint survey, 70 per cent), K2-HERMES (17 per cent), TESS-HERMES (5 per cent), and a subset of ancillary observations (8 per cent) including the bulge and >75 stellar clusters. We derive stellar parameters Teff, log g, [Fe/H], vmic, vbroad, and vrad using our modified version of the spectrum synthesis code Spectroscopy Made Easy (sme) and 1D marcs model atmospheres. We break spectroscopic degeneracies in our spectrum analysis with astrometry from Gaia DR2 and photometry from 2MASS. We report abundance ratios [X/Fe] for 30 different elements (11 of which are based on non-LTE computations) covering five nucleosynthetic pathways. We describe validations for accuracy and precision, flagging of peculiar stars/measurements and recommendations for using our results. Our catalogue comprises 65 per cent dwarfs, 34 per cent giants, and 1 per cent other/unclassified stars. Based on unflagged chemical composition and age, we find 62 per cent young low-α, 9 per cent young high-α, 27 per cent old high-α, and 2 per cent stars with [Fe/H] ≤ −1. Based on kinematics, 4 per cent are halo stars. Several Value-Added-Catalogues, including stellar ages and dynamics, updated after Gaia eDR3, accompany this release and allow chrono-chemodynamic analyses, as we showcase.
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| 20. |
- Buder, Sven, et al.
(författare)
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The GALAH Survey : chemical tagging and chrono-chemodynamics of accreted halo stars with GALAH+DR3 and Gaia eDR3
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 510:2, s. 2407-2436
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Tidskriftsartikel (refereegranskat)abstract
- Since the advent of Gaia astrometry, it is possible to identify massive accreted systems within the Galaxy through their unique dynamical signatures. One such system, Gaia-Sausage-Enceladus (GSE), appears to be an early ‘building block’ given its virial mass >1010M⊙ at infall (z ∼ 1−3). In order to separate the progenitor population from the background stars, we investigate its chemical properties with up to 30 element abundances from the GALAH+ Survey Data Release 3 (DR3). To inform our choice of elements for purely chemically selecting accreted stars, we analyse 4164 stars with low-α abundances and halo kinematics. These are most different to the Milky Way stars for abundances of Mg, Si, Na, Al, Mn, Fe, Ni, and Cu. Based on the significance of abundance differences and detection rates, we apply Gaussian mixture models to various element abundance combinations. We find the most populated and least contaminated component, which we confirm to represent GSE, contains 1049 stars selected via [Na/Fe] versus [Mg/Mn] in GALAH+ DR3. We provide tables of our selections and report the chrono-chemodynamical properties (age, chemistry, and dynamics). Through a previously reported clean dynamical selection of GSE stars, including 30<√JR/kpckms−1<55, we can characterize an unprecedented 24 abundances of this structure with GALAH+ DR3. With our chemical selection we characterize the dynamical properties of the GSE, for example mean √JR/kpckms−1=26+9−14. We find only (29±1) per cent of the GSE stars within the clean dynamical selection region. Our methodology will improve future studies of accreted structures and their importance for the formation of the Milky Way.
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| 21. |
- Byrgazov, Konstantin, et al.
(författare)
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Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes
- 2021
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Ingår i: Bone Reports. - : Elsevier. - 2352-1872. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.
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| 22. |
- Cajander, Åsa, Professor, 1971-, et al.
(författare)
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Effects of patient accessible electronic health records on nurses' work environment : a survey study on expectations in Sweden
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The introduction of information and communication technology influences the work environment of large groups of employees in healthcare. In Sweden, a national healthcare service providing patient accessible electronic health records (PAEHR) has been deployed, and this paper investigates nurses' expected effects of this implementation.SETTING: Nurses associated with the Swedish Association of Health Professionals working in healthcare such as primary care, hospitals and midwives in Sweden. Before a full-scale national implementation of PAEHR, a web survey study was distributed nationally. The respondents represented all 21 Swedish regions. Questions included five-point Likert scale questions and open questions.PARTICIPANTS: A survey link was distributed via email to 8460 registered nurses, midwives and union representatives in Sweden. The response rate was 35.4% (2867 respondents: registered nurses 84%; midwives 6%; chief position 5%; in projects 2% and other 3%). Three reminders were sent out, all of them increasing the response rate. A majority of the respondents were female (89.9%), 8.4% male, whereas 1.7% did not indicate their gender. 31.4% were under 40 years old, 53.8% 40-59 and 13.7% over 60.RESULTS: Data were analysed using exploratory factor analysis with principal component analysis as the extraction method. The analysis revealed three distinct factors related to nurses' expectations of PAEHR: (1) PAEHR improves the quality of care, (2) PAEHR improves the quality of the work environment and (3) risk and fears concerning patients' well-being. Some interesting results include that more experienced nurses are more favourable to PAEHR. Our analysis also shows that the view of the nurse-patient relationship is an essential underlying factor related to positive or negative expectations.CONCLUSIONS: Results show that the expectations and perceptions of PAEHR vary depending on the nurse's view of who the electronic record belongs to. Younger nurses are somewhat more negative towards PAEHR than older nurses.
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| 23. |
- Cajander, Åsa, Professor, 1971-, et al.
(författare)
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Experiences of Extensive User Involvement through Vision Seminars in a Large IT Project
- 2023
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Ingår i: Interacting with computers. - : Oxford University Press. - 0953-5438 .- 1873-7951. ; 35:4, s. 543-552
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Tidskriftsartikel (refereegranskat)abstract
- As the complexity of IT systems increases, the demand for methods taking the whole work situation into account grows. The Vision Seminar (VS) process addresses the future usage of technologies in complex digital work environments. This paper describes the experiences of conducting the VS process in the context of a large IT project to improve study-administrative work. The participants and stakeholders' experiences of participating in VS workshops were studied as the effect the participants and stakeholders believed the vision might have. Data were gathered through interviews and a survey. The participants were confident that the time spent on workshops was worthwhile and that achieving the future described in the resulting vision was feasible. The stakeholders perceived the VS process as rigorous. They were happily surprised by the positive spirit and engagement displayed by the participants. The utility of the resulting vision not being obvious was the most notable weakness mentioned.
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| 24. |
- Cajander, Åsa, Professor, 1971-, et al.
(författare)
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Walking in the Jungle with a Machete : ICT Leaders' Perspectives on User-Centred Systems Design
- 2022
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Ingår i: Behavior and Information Technology. - : John Wiley & Sons. - 0144-929X .- 1362-3001. ; 41:6, s. 1230-1244
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Tidskriftsartikel (refereegranskat)abstract
- Previous research has established that leaders in information and communication technology (ICT) are crucial for establishing a user-centred systems design perspective in ICT for work-related tasks. This paper therefore describes the perspectives of 18 ICT leaders in three kinds of leadership roles (managers, project leaders and specialists) in order to understand their views of user-centred systems design concerning ICT. It uses the concept of technological frames of reference to analyse three domains: technology-in-use, technology strategy and nature of technology. The results show that many specialists see user involvement as a critical factor in successfully establishing new information and communication technologies, but that these systems are currently built around the needs of management rather than end users. Looking forward, all three relevant social groups are optimistic about how ICT will become more user-centred and more strategically aligned in the future. However, changes in ICT are described as extremely energy-consuming and difficult – akin to ‘walking in the jungle with a machete’. Finally, we discuss the relevance of technological frames and present some implications for the successful establishment of user-centred system design as a perspective in organisations.
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| 25. |
- Carlson, Sara, et al.
(författare)
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Using Cognitive Work Analysis to Model the Impact of Digitalization on Intensive Care Nursing
- 2024
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Ingår i: Journal of Cognitive Engineering and Decision Making. - London : Sage Publications. - 1555-3434 .- 2169-5032.
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Tidskriftsartikel (refereegranskat)abstract
- The continuous development of health IT fuels a process of ongoing digitalization that affects the work of hospital staff. A Cognitive Work Analysis methodology was used to investigate the impact of digitalization through a Clinical Information System (CIS), an addition to the basic Electronic Medical Record, on one intensive care unit (ICU). Both observations and semi-structured interviews were performed. The replacement of a paper charting system with a digital CIS that meant some of the administrative tasks could be automated and other tasks being performed on a computer screen instead of using paper. The nurses’ work domain was modeled and compared to a study performed prior to the implementation of the CIS. The study demonstrates the potential utility of the Cognitive Work Analysis approach (when applied both pre and post-implementation) to evaluate the impact of a CIS on ICU nurses.
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| 26. |
- Casagrande, Luca, et al.
(författare)
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The GALAH survey : effective temperature calibration from the InfraRed Flux Method in the Gaia system
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 507:2, s. 2684-2696
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Tidskriftsartikel (refereegranskat)abstract
- In order to accurately determine stellar properties, knowledge of the effective temperature of stars is vital. We implement Gaia and 2MASS photometry in the InfraRed Flux Method and apply it to over 360000 stars across different evolutionary stages in the GALAH DR3 survey. We derive colour-effective temperature relations that take into account the effect of metallicity and surface gravity over the range 4000K ⪅ T-eff ⪅ 8000 K, from very metal-poor stars to supersolar metallicities. The internal uncertainty of these calibrations is of order 40-80 K depending on the colour combination used. Comparison against solar-twins, Gaia benchmark stars, and the latest interferometric measurements validates the precision and accuracy of these calibrations from F to early M spectral types. We assess the impact of various sources of uncertainties, including the assumed extinction law, and provide guidelines to use our relations. Robust solar colours are also derived.
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| 27. |
- Clark, Jake T., et al.
(författare)
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The GALAH Survey : improving our understanding of confirmed and candidate planetary systems with large stellar surveys
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 510:2, s. 2041-2060
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Tidskriftsartikel (refereegranskat)abstract
- Pioneering photometric, astrometric, and spectroscopic surveys is helping exoplanetary scientists better constrain the fundamental properties of stars within our galaxy and the planets these stars host. In this study, we use the third data release from the stellar spectroscopic GALAH Survey, coupled with astrometric data of eDR3 from the Gaia satellite, and other data from NASA's Exoplanet Archive, to refine our understanding of 279 confirmed and candidate exoplanet host stars and their exoplanets. This homogenously analysed data set comprises 105 confirmed exoplanets, along with 146 K2 candidates, 95 TESS Objects of Interest (TOIs), and 52 Community TOIs (CTOIs). Our analysis significantly shifts several previously (unknown) planet parameters while decreasing the uncertainties for others. Our radius estimates suggest that 35 planet candidates are more likely brown dwarfs or stellar companions due to their new radius values. We are able to refine the radii and masses of WASP-47 e, K2-106 b, and CoRoT-7 b to their most precise values yet to less than 2.3 per cent and 8.5 per cent, respectively. We also use stellar rotational values from GALAH to show that most planet candidates will have mass measurements that will be tough to obtain with current ground-based spectrographs. With GALAH's chemical abundances, we show through chemo-kinematics that there are five planet hosts that are associated with the galaxy's thick disc, including NGTS-4, K2-183, and K2-337. Finally, we show that there is no statistical difference between the chemical properties of hot Neptune and hot rocky exoplanet hosts, with the possibility that short-period rocky worlds might be the remnant cores of hotter, gaseous worlds.
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| 28. |
- Deland, Lily, et al.
(författare)
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Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma.
- 2022
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Ingår i: Cancer genomics & proteomics. - : Anticancer Research USA Inc.. - 1109-6535 .- 1790-6245. ; 19:6, s. 711-726
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Tidskriftsartikel (refereegranskat)abstract
- Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusion-positive solid tumors.Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed.Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient.We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse.
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| 29. |
- Dyreborg, Karen, et al.
(författare)
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Evaluation of different coatings of the tibial tray in uncemented total knee arthroplasty. A randomized controlled trial with 5 years follow-up with RSA and DEXA
- 2021
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Ingår i: Knee. - : Elsevier BV. - 0968-0160. ; 29, s. 208-215
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Tidskriftsartikel (refereegranskat)abstract
- Background: Regenerex® is a porous titanium construct with a 3D interconnecting pore structure and biomechanical characteristics close to that of normal trabecular bone. This study aimed to compare the Regenerex (VR) to the non-interconnecting pore structure Porous Plasma Spray (VP) on tibial implants for total knee arthroplasty (TKA) at 5 years. Methods: We enrolled and randomized 61 patients (mean age = 63(49–71) years, Female/Male = 35/26) who were planned for an uncemented Vanguard TKA (Biomet, Warsaw, Indiana, USA) to receive either a VR or a VP coated tibial component (31/29). We performed radiostereometric analysis (RSA) and Dual Energy X-ray Absorptiometry (DEXA) postoperatively, and at three, six, 12, 24 and 60 months with measurements of migration. In total 55 patients attended the 5-year follow-up. Results: One patient died and four were reoperated during the 60-months period; none due to aseptic loosening. All reoperations were in the VR-group. The mean (range) 60-months MTPM was 1.4 mm (0.5–3.7) for the VP-group and 1.8 mm (0.4–4.9) for the VR-group (p = 0.8). The 24 to 60-months mean (range) MTPM was −0.3 mm (−5 to 1.24) in the VP-group and 0.2 mm (−0.4 to 3.5) in the VR-group (p = 0.8). Conclusion: We did not find any statistically significant differences between the VP- and VR-group and both groups show recognizable migration. We will continue to follow the groups for years to come.
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| 30. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 31. |
- Gao, Xudong, et al.
(författare)
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The GALAH survey : a new constraint on cosmological lithium and Galactic lithium evolution from warm dwarf stars
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966 .- 1745-3925 .- 1745-3933. ; 497:1, s. L30-L34
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Tidskriftsartikel (refereegranskat)abstract
- Lithium depletion and enrichment in the cosmos is not yet well understood. To help tighten constraints on stellar and Galactic evolution models, we present the largest high-resolution analysis of Li abundances A(Li) to date, with results for over 100000 GALAH (Galactic Archeology with HERMES) field stars spanning effective temperatures 5900K≲Teff≲7000K and metallicities −3 ≲ [Fe/H] ≲ +0.5. We separated these stars into two groups, on the warm and cool sides of the so-called Li dip, a localized region of the Kiel diagram wherein lithium is severely depleted. We discovered that stars in these two groups show similar trends in the A(Li)–[Fe/H] plane, but with a roughly constant offset in A(Li) of 0.4dex, the warm group having higher Li abundances. At [Fe/H]≳−0.5, a significant increase in Li abundance with increasing metallicity is evident in both groups, signalling the onset of significant Galactic production. At lower metallicity, stars in the cool group sit on the Spite plateau, showing a reduced lithium of around 0.4dex relative to the primordial value predicted from big bang nucleosynthesis (BBN). However, stars in the warm group between [Fe/H] = −1.0 and −0.5 form an elevated plateau that is largely consistent with the BBN prediction. This may indicate that these stars in fact preserve the primordial Li produced in the early Universe.
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| 32. |
- Gilmore, G., et al.
(författare)
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The Gaia-ESO Public Spectroscopic Survey : Motivation, implementation, GIRAFFE data processing, analysis, and final data products star
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 666
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Tidskriftsartikel (refereegranskat)abstract
- Context. The Gaia-ESO Public Spectroscopic Survey is an ambitious project designed to obtain astrophysical parameters and elemental abundances for 100 000 stars, including large representative samples of the stellar populations in the Galaxy, and a well-defined sample of 60 (plus 20 archive) open clusters. We provide internally consistent results calibrated on benchmark stars and star clusters, extending across a very wide range of abundances and ages. This provides a legacy data set of intrinsic value, and equally a large wide-ranging dataset that is of value for the homogenisation of other and future stellar surveys and Gaia's astrophysical parameters. Aims. This article provides an overview of the survey methodology, the scientific aims, and the implementation, including a description of the data processing for the GIRAFFE spectra. A companion paper introduces the survey results. Methods. Gaia-ESO aspires to quantify both random and systematic contributions to measurement uncertainties. Thus, all available spectroscopic analysis techniques are utilised, each spectrum being analysed by up to several different analysis pipelines, with considerable effort being made to homogenise and calibrate the resulting parameters. We describe here the sequence of activities up to delivery of processed data products to the ESO Science Archive Facility for open use. Results. The Gaia-ESO Survey obtained 202 000 spectra of 115 000 stars using 340 allocated VLT nights between December 2011 and January 2018 from GIRAFFE and UVES. Conclusions. The full consistently reduced final data set of spectra was released through the ESO Science Archive Facility in late 2020, with the full astrophysical parameters sets following in 2022. A companion article reviews the survey implementation, scientific highlights, the open cluster survey, and data products.
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| 33. |
- Glynn, Linn, et al.
(författare)
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Trends in Survival After First Myocardial Infarction in People With Diabetes
- 2024
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Ingår i: JOURNAL OF THE AMERICAN HEART ASSOCIATION. - 2047-9980. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- Background The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes.Methods and Results Between 2006 and 2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all-cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo-observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62 +/- 12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75 +/- 10.8 years; women, 38.1%), and individuals without diabetes (73 +/- 13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change -0.48% [95% CI, -0.52% to -0.44%]) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, -0.33% [95% CI, -0.43% to -0.24%]), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, -0.18% [95% CI, -0.53% to 0.17%]). Similar trends were observed with regard to 1-year death, cardiovascular death, and major adverse cardiovascular events.Conclusions During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.
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| 34. |
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| 35. |
- Hagberg, Cecilia, et al.
(författare)
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Lättviktsgrindar av höghållfast stål för säkrare djurhantering och arbetsmiljö
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Lightweight gates of high-strength steel for improved worker safety and cattle handling This report presents the work with developing a lightweight gate of high-strength steel for the handling of cattle. The project was conducted as a European Innovation Partnership (EIP) project. The project group consisted of co-workers from the unit of Agriculture and Horticulture and the unit of Process and Environmental Engineering at Research Institutes of Sweden (RISE Jordbruk och trädgård och RISE Kretsloppsteknik), Parsteel AB (former Nilssons Plåtindustri AB), SSAB EMEA AB, Sophie Atkinson at Smart Animal Handling, Swedish University of Agricultural Sciences (SLU) in Skara and the cattle farmer Lars Olsson. The main objectives of the project were to develop a lightweight gate weighing at least 50% less and being three times as strong as a traditional gate for cattle handling. The main motive was to improve the ergonomic conditions and working environment for the animal handlers. Additionally, for the safety of both animals and handlers, the gate must withstand the loads from cattle. Other objectives were to design and construct a gate that does not exceed the price of a high-quality gate and not contribute to increased negative environmental impact. A lightweight gate can be made of various materials such as plastic, fiberglass or steel. Regarding the project group's participants and their competencies, in addition to the numerous requirements placed on a lightweight gate, the choice fell on high-strength steel. High-strength steel is characterized by having high yield strengths, up to 1300 MPa, in comparison with traditional construction steel with yield strength of 355 MPa. For the specific lightweight gate, steel pipes with a yield strength of approximately 750 MPa were chosen. These pipes are mainly used in the automotive and engine industry, where high demands are placed on strength while at the same time a light construction is desired. The gate itself was designed during the project and several details were examined and developed in regard to functionality and safety for both cattle and handlers. The work environment legislation states that gates must be dimensioned and anchored so that the animals cannot break out (AFS 2008:17). The gates must also not pose a risk of injury to the cattle. In order to work safely with cattle, knowledge of cattle behavior is essential and consequently the report contains a chapter describing cattle senses and behavior. Both the lightweight gates and the handling system, built up by the gates, must be adapted to the cattle. In the project, the bud box handling system was tested. The handling system was originally developed to make use of the behavioral characteristics of cattle to encourage forward movement in the desired direction. In the project the handling system's functionality and safety, by using lightweight gates and additional equipment and components, were further designed. The handling system was tested in two groups of heifers at the SLU Götala Beef and Lamb Research Centre. The lightweight gates were also tested in a dairy herd and a beef herd, while hoof trimming, and at a small-scale abattoir. Generally, the light weight of the gates was considered an advantage as the handling of the gates is simplified also resulting in more frequent use of the gates, increasing safety for both animals and humans. During the project, several strength tests were performed by building unique test rigs. In one test rig, the weld of the pipes of the lightweight gate was tested. In another test rig, the strength of lightweight gates, compared with traditional gates on the market, were tested. The outcome of the tests confirmed the original aim of the project, a lightweight gate made of high-strength steel, about 50% lighter and at least three times as strong as traditional gates, had been developed and designed during the project period.
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| 36. |
- Halvorsen, K., et al.
(författare)
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Patients' experiences of well-being when being cared for in the intensive care unit—An integrative review
- 2022
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Ingår i: Journal of Clinical Nursing. - : Wiley. - 0962-1067 .- 1365-2702. ; 31:1-2, s. 3-19
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this integrative review was to identify facilitators and barriers to patients’ well-being when being cared for in an ICU setting, from the perspective of the patients. Background: To become critically ill and hospitalised in an ICU is a stressful, chaotic event due to the life-threatening condition itself, as well as therapeutic treatments and the environment. A growing body of evidence has revealed that patients often suffer from physical, psychological and cognitive problems after an ICU stay. Several strategies, such as sedation and pain management, are used to reduce stress and increase well-being during ICU hospitalisation, but the ICU experience nevertheless affects the body and mind. Design; Methods: Since research exploring patients’ sense of well-being in an ICU setting is limited, an integrative review approach was selected. Searches were performed in CINAHL, Medline, Psych Info, Eric and EMBASE. After reviewing 66 studies, 12 studies were included in the integrative review. Thematic analysis was used to analyse the studies. The PRISMA checklist for systematic reviews was used. Results: The results are presented under one main theme, ‘Well-being as a multidimensional experience—interwoven in barriers and facilitators’ and six sub-themes representing barriers to and facilitators of well-being in an ICU. Barriers identified were physical stressors, emotional stressors, environmental disturbances and insecurity relating to time and space. Facilitators were meeting physical needs and activities that included dimensions of a caring and relational environment. Conclusion: Our main findings were that experiences of well-being were multidimensional and included physical, emotional, relational and environmental aspects, and they were more often described through barriers than facilitators of well-being. Relevance for clinical practice: This integrative review has shown that it is necessary to adopt an individual focus on patient well-being in an ICU setting since physical, emotional, relational and environmental stressors might impact each patient differently. © 2021 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.
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| 37. |
- Hayden, Michael R., et al.
(författare)
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The GALAH survey : chemical clocks
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 517:4, s. 5325-5339
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Tidskriftsartikel (refereegranskat)abstract
- We present the first large-scale study that demonstrates how ages can be determined for large samples of stars through Galactic chemical evolution. Previous studies found that the elemental abundances of a star correlate directly with its age and metallicity. Using this knowledge, we derive ages for 214 577 stars in GALAH DR3 using only overall metallicities and chemical abundances. Stellar ages are estimated via the machine learning algorithm XGBoost for stars belonging to the Milky Way disc with metallicities in the range -1 < [Fe/H] < 0.5, using main-sequence turn-off stars as our training set. We find that stellar ages for the bulk of GALAH DR3 are precise to 1-2 Gyr using this method. With these ages, we replicate many recent results on the age-kinematic trends of the nearby disc, including the solar neighbourhood's age-velocity dispersion relationship and the larger global velocity dispersion relations of the disc found using Gaia and GALAH. These results show that chemical abundance variations at a given birth radius are small, and that strong chemical tagging of stars directly to birth clusters may prove difficult with our current elemental abundance precision. Our results highlight the need to measure abundances for as many nucleosynthetic production sites as possible in order to estimate reliable ages from chemistry. Our methods open a new door into studies of the kinematic structure and evolution of the disc, as ages may potentially be estimated to a precision of 1-2 Gyr for a large fraction of stars in existing spectroscopic surveys.
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| 38. |
- Henry, Albert, et al.
(författare)
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Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:16, s. 1205-1217
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets.Methods: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis.Results: Forty-four of ninety proteins were positively associated with risk of incident HF (P<6.0x10(-4)). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1.Conclusions: We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.
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| 39. |
- Hughes, Arvind C. N., et al.
(författare)
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The GALAH Survey : A New Sample of Extremely Metal-poor Stars Using a Machine-learning Classification Algorithm
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 930:1
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Tidskriftsartikel (refereegranskat)abstract
- Extremely metal-poor (EMP) stars provide a valuable probe of early chemical enrichment in the Milky Way. Here we leverage a large sample of ∼600,000 high-resolution stellar spectra from the GALAH survey plus a machine-learning algorithm to find 54 candidates with estimated [Fe/H] ≤−3.0, six of which have [Fe/H] ≤−3.5. Our sample includes ∼20% main-sequence EMP candidates, unusually high for EMP star surveys. We find the magnitude-limited metallicity distribution function of our sample is consistent with previous work that used more complex selection criteria. The method we present has significant potential for application to the next generation of massive stellar spectroscopic surveys, which will expand the available spectroscopic data well into the millions of stars.
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| 40. |
- Isaksson, Sofia Sterner, et al.
(författare)
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Discordance between mean glucose and time in range in relation to HbA1c in individuals with type 1 diabetes: results from the GOLD and SILVER trials
- 2024
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Ingår i: DIABETOLOGIA. - : SPRINGER. - 0012-186X .- 1432-0428. ; 67, s. 1517-1526
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA(1c) values. The aim of this study was to further elucidate how MG and TIR are associated with HbA(1c). Methods Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA(1c)/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. Results In the GOLD trial, the mean age of the participants (+/- SD) was 44 +/- 13 years, 63 (44%) were female, and the mean HbA(1c) (+/- SD) was 72 +/- 9.8 mmol/mol (8.7 +/- 0.9%). When correlating MG with HbA(1c), MG explained 63% of the variation in HbA(1c) (r=0.79, p<0.001). The variation in HbA(1c) explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA(1c) relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA(1c) of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA(1c) based on the overall association between MG and TIR with HbA(1c). TBR and TAR level 2 significantly influenced the association between TIR and HbA(1c). At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA(1c) (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA(1c) (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA(1c) when accounting for MG. Conclusions/interpretation Inter-individual variations exist between MG and HbA(1c), as well as between TIR and HbA(1c), with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions.
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| 41. |
- Jhun, Mina-A, et al.
(författare)
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A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups. Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.
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| 42. |
- Kajtez, Janko, et al.
(författare)
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Embedded 3D Printing in Self-Healing Annealable Composites for Precise Patterning of Functionally Mature Human Neural Constructs
- 2022
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Ingår i: Advanced science (Weinheim, Baden-Wurttemberg, Germany). - : Wiley. - 2198-3844. ; 9:25
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Tidskriftsartikel (refereegranskat)abstract
- Human in vitro models of neural tissue with tunable microenvironment and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing inside granular gels holds great promise as it allows precise patterning of extremely soft tissue constructs. However, granular printing support formulations are restricted to only a handful of materials. Therefore, there has been a need for novel materials that take advantage of versatile biomimicry of bulk hydrogels while providing high-fidelity support for embedded printing akin to granular gels. To address this need, Authors present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside Self-Healing Annealable Particle-Extracellular matrix (SHAPE) composites. SHAPE composites consist of soft microgels immersed in viscous extracellular-matrix solution to enable precise and programmable patterning of human stem cells and consequent generation mature subtype-specific neurons that extend projections into the volume of the annealed support. The developed approach further allows multi-ink deposition, live spatial and temporal monitoring of oxygen levels, as well as creation of vascular-like channels. Due to its modularity and versatility, SHAPE biomanufacturing toolbox has potential to be used in applications beyond functional modeling of mechanically sensitive neural constructs.
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| 43. |
- Karady, Julia, et al.
(författare)
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Coronary plaque in people with HIV vs non-HIV asymptomatic community and symptomatic higher-risk populations
- 2024
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Ingår i: JACC: Advances. - : Elsevier. - 2772-963X. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: People with HIV (PWH) have a high burden of coronary plaques; however, the comparison to people without known HIV (PwoH) needs clarification.Objectives: The purpose of this study was to determine coronary plaque burden/phenotype in PWH vs PwoH.Methods: Nonstatin using participants from 3 contemporary populations without known coronary plaques with coronary CT were compared: the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) studying PWH without cardiovascular symptoms at low-to-moderate risk (n = 755); the SCAPIS (Swedish Cardiopulmonary Bioimage Study) of asymptomatic community PwoH at low-to-intermediate cardiovascular risk (n = 23,558); and the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) of stable chest pain PwoH (n = 2,291). The coronary plaque prevalence on coronary CT was compared, and comparisons were stratified by 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and coronary artery calcium (CAC) presence.Results: Compared to SCAPIS and PROMISE PwoH, REPRIEVE PWH were younger (50.8 ± 5.8 vs 57.3 ± 4.3 and 60.0 ± 8.0 years; P < 0.001) and had lower ASCVD risk (5.0% ± 3.2% vs 6.0% ± 5.3% and 13.5% ± 11.0%; P < 0.001). More PWH had plaque compared to the asymptomatic cohort (48.5% vs 40.3%; P < 0.001). When stratified by ASCVD risk, PWH had more plaque compared to SCAPIS and a similar prevalence of plaque compared to PROMISE. CAC = 0 was more prevalent in PWH (REPRIEVE 65.2%; SCAPIS 61.6%; PROMISE 49.6%); among CAC = 0, plaque was more prevalent in PWH compared to the PwoH cohorts (REPRIEVE 20.8%; SCAPIS 5.4%; PROMISE 12.3%, P < 0.001).Conclusions: Asymptomatic PWH in REPRIEVE had more plaque than asymptomatic PwoH in SCAPIS but had similar prevalence to a higher-risk stable chest pain cohort in PROMISE. In PWH, CAC = 0 does not reliably exclude plaque.
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| 44. |
- Kos, Janez, et al.
(författare)
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The GALAH survey : Chemical homogeneity of the Orion complex
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 506:3, s. 4232-4250
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Tidskriftsartikel (refereegranskat)abstract
- Due to its proximity, the Orion star forming region is often used as a proxy to study processes related to star formation and to observe young stars in the environment they were born in. With the release of Gaia DR2, the distance measurements to the Orion complex are now good enough that the 3D structure of the complex can be explored. Here we test the hypothesis that, due to non-trivial structure and dynamics, and age spread in the Orion complex, the chemical enrichment of youngest stars by early core-collapse supernovae can be observed. We obtained spectra of 794 stars of the Orion complex with the HERMES spectrograph at the Anglo Australian telescope as a part of the GALAH and GALAH-related surveys. We use the spectra of similar to 300 stars to derive precise atmospheric parameters and chemical abundances of 25 elements for 15 stellar clusters in the Orion complex. We demonstrate that the Orion complex is chemically homogeneous and that there was no self-pollution of young clusters by core-collapse supernovae from older clusters; with a precision of 0.02 dex in relative alpha-elements abundance and 0.06 dex in oxygen abundance we would have been able to detect pollution from a single supernova, given a fortunate location of the SN and favourable conditions for ISM mixing. We estimate that the supernova rate in the Orion complex was very low, possibly producing no supernova by the time the youngest stars of the observed population formed (from around 21 to 8 Myr ago).
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| 45. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 46. |
- 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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| 47. |
- Lin, Jane, et al.
(författare)
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The GALAH survey : temporal chemical enrichment of the galactic disc
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 491:2, s. 2043-2056
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Tidskriftsartikel (refereegranskat)abstract
- We present isochrone ages and initial bulk metallicities ([Fe/H](bulk), by accounting for diffusion) of 163 722 stars from the GALAH Data Release 2, mainly composed of main-sequence turn-off stars and subgiants (7000 K > T-eff > 4000 K and log g > 3 dex). The local age-metallicity relationship (AMR) is nearly flat but with significant scatter at all ages; the scatter is even higher when considering the observed surface abundances. After correcting for selection effects, the AMR appears to have intrinsic structures indicative of two star formation events, which we speculate are connected to the thin and thick discs in the solar neighbourhood. We also present abundance ratio trends for 16 elements as a function of age, across different [Fe/H](bulk) bins. In general, we find the trends in terms of [X/Fe] versus age from our far larger sample to be compatible with studies based on small (similar to 100 stars) samples of solar twins, but we now extend them to both sub- and supersolar metallicities. The a-elements show differing behaviour: the hydrostatic alpha-elements O and Mg show a steady decline with time for all metallicities, while the explosive alpha-elements Si, Ca, and Ti are nearly constant during the thin-disc epoch (ages less than or similar to 12 Gyr). The s-process elements Y and Ba show increasing [X/Fe] with time while the r-process element Eu has the opposite trend, thus favouring a primary production from sources with a short time delay such as core-collapse supernovae over long-delay events such as neutron star mergers.
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| 48. |
- Lind, Lars, et al.
(författare)
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Life-Time Covariation of Major Cardiovascular Diseases : A 40-Year Longitudinal Study and Genetic Studies
- 2021
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 14:2, s. 213-222
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs.Methods: The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has been followed for 40 years regarding 4 major CVDs (incident myocardial infarction, ischemic stroke, heart failure, and atrial fibrillation). For the genetic analyses, publicly available data were used.Results: Using multistate modeling, significant relationships were seen between pairs of all of the 4 investigated CVDs. However, the risk of obtaining one additional CVD differed substantially both between different CVDs and between their temporal order. The relationship between heart failure and atrial fibrillation showed a high risk ratio (risk ratios, 24-26) regardless of the temporal order. A consistent association was seen also for myocardial infarction and atrial fibrillation but with a lower relative risk (risk ratios, 4-5). In contrast, the risk of receiving a diagnosis of heart failure following a myocardial infarction was almost twice as high as for the reverse temporal order (risk ratios, 16 versus 9). Genetic loci linked to traditional risk factors could partly explain the observed associations between the CVDs, but pathway analyses disclosed also other pathophysiological links.Conclusions: During 40 years, all of the 4 investigated CVDs were pairwise associated with each other regardless of the temporal order of occurrence, but the risk magnitude differed between different CVDs and their temporal order. Genetic analyses disclosed new pathophysiological links between CVDs.
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| 49. |
- Lind, Thomas, Docent, 1965-, et al.
(författare)
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Mast cell chymase has a negative impact on human osteoblasts
- 2022
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Ingår i: Matrix Biology. - : Elsevier. - 0945-053X .- 1569-1802. ; 112, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells have been linked to osteoporosis and bone fractures, and in a previous study we found that mice lacking a major mast cell protease, chymase, develop increased diaphyseal bone mass. These findings introduce the possibility that mast cell chymase can regulate bone formation, but the underlying mechanism(s) has not previously been investigated. Here we hypothesized that chymase might exert such effects through a direct negative impact on osteoblasts, i.e., the main bone-building cells. Indeed, we show that chymase has a distinct impact on human primary osteoblasts. Firstly, chymase was shown to have pronounced effects on the morphological features of osteoblasts, including extensive cell contraction and actin reorganization. Chymase also caused a profound reduction in the output of collagen from the osteoblasts, and was shown to degrade osteoblast-secreted fibronectin and to activate pro-matrix metallopeptidase-2 released by the osteoblasts. Further, chymase was shown to have a preferential impact on the gene expression, protein output and phosphorylation status of TGF beta-associated signaling molecules. A transcriptomic analysis was conducted and revealed a significant effect of chymase on several genes of importance for bone metabolism, including a reduction in the expression of osteoprotegerin, which was confirmed at the protein level. Finally, we show that chymase interacts with human osteoblasts and is taken up by the cells. Altogether, the present findings provide a functional link between mast cell chymase and osteoblast function, and can form the basis for a further evaluation of chymase as a potential target for intervention in metabolic bone diseases.
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| 50. |
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