| 1. |
- Winkler, TW, et al.
(författare)
-
Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
-
Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
-
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.
|
|
| 2. |
|
|
| 3. |
- Boisgontier, MP, et al.
(författare)
-
Adverse Childhood Experiences, Depressive Symptoms, Functional Dependence, and Physical Activity: A Moderated Mediation Model
- 2020
-
Ingår i: Journal of physical activity & health. - : Human Kinetics. - 1543-5474 .- 1543-3080. ; 17:8, s. 790-799
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Adverse childhood experiences, depressive symptoms, and functional dependence are interrelated. However, the mechanisms underlying these associations remain unclear. The authors investigated the potential of depressive symptoms to mediate the effect of adverse childhood experiences on functional dependence in older age and whether physical activity moderated this mediation. Method: Data from 25,775 adults aged 62 (9) years from the Survey of Health Ageing and Retirement in Europe were used in adjusted linear mixed-effects models to test whether depressive symptoms mediated the associations between adverse childhood experiences and functional dependence in activities of daily living (ADL) and instrumental ADL (IADL) and whether physical activity moderated these mediations. Results: The results showed a graded association between the number of adverse childhood experiences (0 vs 1 and 0 vs ≥2) and the number of functional limitations in both ADL (bs = 0.040 and 0.067) and IADL (bs = 0.046 and 0.076). These associations were mediated by depressive symptoms. Physical activity reduced the effect of adverse childhood experiences on depressive symptoms (bs = −0.179 and −0.515) and tempered the effect of depressive symptoms on functional dependence both in ADL (b = −0.073) and IADL (b = −0.100). As a result of these reductions, the effect of adverse childhood experiences and depressive symptoms on functional dependence in ADL (Ps > .081) and IADL (Ps > .528) was nonsignificant in physically active participants. Conclusions: These findings suggest that, after age 50, engaging in physical activity more than once a week protects functional independence from the detrimental effects of adverse childhood experiences and depression. In inactive individuals, the detrimental effects of adverse childhood experiences on functional dependence are mediated by depressive symptoms.
|
|
| 4. |
- Chan, Carol K, et al.
(författare)
-
Association of Depressive Symptoms With Postoperative Delirium and CSF Biomarkers for Alzheimer's Disease Among Hip Fracture Patients.
- 2021
-
Ingår i: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. - : Elsevier BV. - 1545-7214. ; 29:12, s. 1212-1221
-
Tidskriftsartikel (refereegranskat)abstract
- While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium.Patients 65 years old or older (N=199) who were undergoing hip fracture repair and enrolled in the study "A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients" completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aβ) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau)181.For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR=1.13, 95%CI=1.02-1.25). Both CSF Aβ42/t-tau (β=-1.52, 95%CI=-2.1 to -0.05) and Aβ42/p-tau181 (β=-0.29, 95%CI = -0.48 to -0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers.In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome.
|
|
| 5. |
- Fellinger, Joris, et al.
(författare)
-
Tungsten based divertor development for Wendelstein 7-X
- 2023
-
Ingår i: Nuclear Materials and Energy. - 2352-1791. ; 37
-
Tidskriftsartikel (refereegranskat)abstract
- Wendelstein 7-X, the world’s largest superconducting stellarator in Greifswald (Germany), started plasma experiments with a water-cooled plasma-facing wall in 2022, allowing for long pulse operation. In parallel, a project was launched in 2021 to develop a W based divertor, replacing the current CFC divertor, to demonstrate plasma performance of a stellarator with a reactor relevant plasma facing materials with low tritium retention. The project consists of two tasks: Based on experience from the previous experimental campaigns and improved physics modelling, the geometry of the plasma-facing surface of the divertor and baffles is optimized to prevent overloads and to improve exhaust. In parallel, the manufacturing technology for a W based target module is qualified. This paper gives a status update of project. It focusses on the conceptual design of a W based target module, the manufacturing technology and its qualification, which is conducted in the framework of the EUROfusion funded WPDIV program. A flat tile design in which a target module is made of a single target element is pursued. The technology must allow for moderate curvatures of the plasma-facing surface to follow the magnetic field lines. The target element is designed for steady state heat loads of 10 MW/m2 (as for the CFC divertor). Target modules of a similar size and weight as for the CFC divertor are assumed (approx. < 0.25 m2 and < 60 kg) using the existing water cooling infrastructure providing 5 l/s and roughly maximum 15 bar pressure drop per module. The main technology under qualification is based on a CuCrZr heat sink made either by additive manufacturing using laser powder bed fusion (LPBF) or by uniaxial diffusion welding of pre-machined forged CuCrZr plates. After heat treatment, the plasma-facing side of the heat sink is covered by W or if feasible by the more ductile WNiFe, preferably by coating or alternatively by hot isostatic pressing W based tiles with a soft OFE-Cu interlayer. Last step is a final machining of the plasma-exposed surface and the interfaces to the water supply lines and supports to correct manufacturing deformations.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Gorski, Mathias, et al.
(författare)
-
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
-
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.
|
|
| 9. |
- Gorski, Mathias, et al.
(författare)
-
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
-
Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
|
|
| 10. |
|
|
