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| 10. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 11. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 14. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 15. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 18. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 20. |
- Wang, Gang, et al.
(författare)
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Spirometric phenotypes from early childhood to young adulthood : a Chronic Airway Disease Early Stratification study
- 2021
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Ingår i: ERJ Open Research. - : ERS Publications. - 2312-0541. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts.Methods: We studied 49334 participants from 14 population-based cohorts in different age groups (⩽10, >10–15, >15–20, >20–25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ⩾LLN, and FVC z-score Results: The prevalence of obstructive and restrictive phenotypes varied from 3.2–10.9% and 1.8–7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14–3.04), preterm birth (aOR=1.84, 1.27–2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01–1.35) and family history of asthma (aOR=1.44, 95% CI 1.25–1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5–25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03–1.06 and aOR=0.81, 95% CI 0.78–0.85, per kg·m−2 increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05–1.46).Conclusion: Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
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| 21. |
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| 22. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 23. |
- Munch, Marie W., et al.
(författare)
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Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial
- 2021
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Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
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Tidskriftsartikel (refereegranskat)abstract
- Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID-19 and severe hypoxemia? Findings In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days. This multicenter randomized clinical trial compares the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and >= 1 serious adverse reactions at 28 days). RESULTS Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
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| 24. |
- Arridge, Christopher S., et al.
(författare)
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Uranus Pathfinder : exploring the origins and evolution of Ice Giant planets
- 2012
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 33:2-3, s. 753-791
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Tidskriftsartikel (refereegranskat)abstract
- The "Ice Giants" Uranus and Neptune are a different class of planet compared to Jupiter and Saturn. Studying these objects is important for furthering our understanding of the formation and evolution of the planets, and unravelling the fundamental physical and chemical processes in the Solar System. The importance of filling these gaps in our knowledge of the Solar System is particularly acute when trying to apply our understanding to the numerous planetary systems that have been discovered around other stars. The Uranus Pathfinder (UP) mission thus represents the quintessential aspects of the objectives of the European planetary community as expressed in ESA's Cosmic Vision 2015-2025. UP was proposed to the European Space Agency's M3 call for medium-class missions in 2010 and proposed to be the first orbiter of an Ice Giant planet. As the most accessible Ice Giant within the M-class mission envelope Uranus was identified as the mission target. Although not selected for this call the UP mission concept provides a baseline framework for the exploration of Uranus with existing low-cost platforms and underlines the need to develop power sources suitable for the outer Solar System. The UP science case is based around exploring the origins, evolution, and processes at work in Ice Giant planetary systems. Three broad themes were identified: (1) Uranus as an Ice Giant, (2) An Ice Giant planetary system, and (3) An asymmetric magnetosphere. Due to the long interplanetary transfer from Earth to Uranus a significant cruise-phase science theme was also developed. The UP mission concept calls for the use of a Mars Express/Rosetta-type platform to launch on a Soyuz-Fregat in 2021 and entering into an eccentric polar orbit around Uranus in the 2036-2037 timeframe. The science payload has a strong heritage in Europe and beyond and requires no significant technology developments.
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| 26. |
- Bonnert, M., et al.
(författare)
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Internet-delivered cognitive behavior therapy for adolescents with functional gastrointestinal disorders - An open trial
- 2014
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Ingår i: Internet Interventions. - : Elsevier BV. - 2214-7829. ; 1:3, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Functional gastrointestinal disorders (FGID), including irritable bowel syndrome, functional dyspepsia and functional abdominal pain, are common in adolescents and are associated with substantially decreased quality of life. Cognitive behavior therapy for children and adolescents with FGID is one of few treatments that have shown effect, but treatment access is limited. In adults with irritable bowel syndrome, exposure-based internet-delivered CBT (ICBT) leads to reduced symptoms and increased quality of life, but studies in children are lacking. This open pilot aimed to evaluate feasibility and the potential efficacy of an exposure-based ICBT-program for adolescents with pain-predominant FGID. Twenty-nine adolescents (age 13-17), with FGID were included. The ICBT-program lasted for 8. weeks with weekly online therapist support. The protocol for adolescents included exposure to abdominal symptoms, while the protocol for parents aimed at increasing parents' attention to adolescent healthy behaviors. Assessment points were baseline, post-treatment and 6-month follow-up. The primary outcome was the Gastrointestinal Symptoms Rating Scale-IBS (GSRS-IBS). Effect sizes were calculated using Cohen's d in an intent to treat analysis. GSRS-IBS improved significantly from baseline to post-treatment (mean difference 6.48; 95% CI [2.37-10.58]) and to follow-up (mean difference 7.82; 95% CI [3.43-12.21]), corresponding to moderate effect sizes (within-group Cohen's d= 0.50; 95% CI [0.16-0.84] and d= 0.63; 95% CI [0.24-1.02], respectively). Treatment adherence was high with 22 of 29 (76%) adolescents completing the entire treatment period. High adherence indicates acceptability of format and content, while symptomatic improvement suggests potential efficacy for this ICBT intervention in adolescents with FGID. © 2014.
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| 27. |
- de Pater, Imke, et al.
(författare)
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An Energetic Eruption With Associated SO 1.707 Micron Emissions at Io's Kanehekili Fluctus and a Brightening Event at Loki Patera Observed by JWST
- 2023
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Ingår i: Journal of Geophysical Research - Planets. - : American Geophysical Union (AGU). - 2169-9097 .- 2169-9100. ; 128:8
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Tidskriftsartikel (refereegranskat)abstract
- We observed Io with the James Webb Space Telescope (JWST) while the satellite was in eclipse, and detected thermal emission from several volcanoes. The data were taken as part of our JWST-ERS program #1373 on 15 November 2022. Kanehekili Fluctus was exceptionally bright, and Loki Patera had most likely entered a new brightening phase. Spectra were taken with NIRSpec/IFU at a resolving power R ≈ 2,700 between 1.65 and 5.3 µm. The spectra were matched by a combination of blackbody curves that showed that the highest temperature, ∼1,200 K, for Kanehekili Fluctus originated from an area ∼0.25 km2 in size, and for Loki Patera this high temperature was confined to an area of ∼0.06 km2. Lower temperatures, down to 300 K, cover areas of ∼2,000 km2 for Kanehekili Fluctus, and ∼5,000 km2 for Loki Patera. We further detected the a1Δ ⇒ X3Σ− 1.707 µm rovibronic forbidden SO emission band complex over the southern hemisphere, which peaked at the location of Kanehekili Fluctus. This is the first time this emission has been seen above an active volcano, and suggests that the origin of such emissions is ejection of SO molecules directly from the vent in an excited state, after having been equilibrated at temperatures of ∼1,500 K below the surface, as was previously hypothesized.
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| 31. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 32. |
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| 33. |
- Mousis, O., et al.
(författare)
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Scientific rationale for Saturn's in situ exploration
- 2014
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Ingår i: Planetary and Space Science. - : Elsevier BV. - 0032-0633 .- 1873-5088. ; 104, s. 29-47
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Tidskriftsartikel (refereegranskat)abstract
- Remote sensing observations meet some limitations when used to study the bulk atmospheric composition of the giant planets of our solar system. A remarkable example of the superiority of in situ probe measurements is illustrated by the exploration of Jupiter, where key measurements such as the determination of the noble gases' abundances and the precise measurement of the helium mixing ratio have only been made available through in situ measurements by the Galileo probe. This paper describes the main scientific goals to be addressed by the future in situ exploration of Saturn placing the Galileo probe exploration of Jupiter in a broader context and before the future probe exploration of the more remote ice giants. In situ exploration of Saturn's atmosphere addresses two broad themes that are discussed throughout this paper: first, the formation history of our solar system and second, the processes at play in planetary atmospheres. In this context, we detail the reasons why measurements of Saturn's bulk elemental and isotopic composition would place important constraints on the volatile reservoirs in the protosolar nebula. We also show that the in situ measurement of CO (or any other disequilibrium species that is depleted by reaction with water) in Saturn's upper troposphere may help constraining its bulk O/H ratio. We compare predictions of Jupiter and Saturn's bulk compositions from different formation scenarios, and highlight the key measurements required to distinguish competing theories to shed light on giant planet formation as a common process in planetary systems with potential applications to most extrasolar systems. In situ measurements of Saturn's stratospheric and tropospheric dynamics, chemistry and cloud-forming processes will provide access to phenomena unreachable to remote sensing studies. Different mission architectures are envisaged, which would benefit from strong international collaborations, all based on an entry probe that would descend through Saturn's stratosphere and troposphere under parachute down to a minimum of 10 bar of atmospheric pressure. We finally discuss the science payload required on a Saturn probe to match the measurement requirements.
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| 34. |
- Pfeiffer, L., et al.
(författare)
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DNA methylation of lipid-related genes affects blood lipid levels
- 2015
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Ingår i: Circ Cardiovasc Genet. ; 8:2, s. 334-42
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (beta coefficient=-0.049; P=8.26E-17) and triglyceride levels (beta=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.
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| 35. |
- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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| 36. |
- Vinnars, Marie-Therese, et al.
(författare)
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Treatments for hyperemesis gravidarum: A systematic review
- 2024
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Ingår i: Acta Obstetricia Et Gynecologica Scandinavica. - : John Wiley & Sons. - 0001-6349 .- 1600-0412. ; 103:1, s. 13-29
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionHyperemesis gravidarum affects 0.3%-3% of pregnant women each year and is the leading cause of hospitalization in early pregnancy. Previous systematic reviews of available treatments have found a lack of consistent evidence, and few studies of high quality. Since 2016, no systematic review has been conducted and an up-to date review is requested. In a recent James Lind Alliance collaboration, it was clear that research on effective treatments is a high priority for both patients and clinicians.Material and methodsSearches without time limits were performed in the AMED, CINAHL, Cochrane Library, EMBASE, Medline, PsycINFO, and Scopus databases until June 26, 2023. Studies published before October 1, 2014 were identified from the review by O'Donnell et al., 2016. Selection criteria were randomized clinical trials and non-randomized studies of interventions comparing treatment of hyperemesis gravidarum with another treatment or placebo. Outcome variables included were: degree of nausea; vomiting; inability to tolerate oral fluids or food; hospital treatment; health-related quality of life, small-for-gestational-age infant; and preterm birth. Abstracts and full texts were screened, and risk of bias of the studies was assessed independently by two authors. Synthesis without meta-analysis was performed, and certainty of evidence was assessed using the GRADE approach. PROSPERO (CRD42022303150).ResultsTwenty treatments were included in 25 studies with low or moderate risk of bias. The certainty of evidence was very low for all treatments except for acupressure in addition to standard care, which showed a possible moderate decrease in nausea and vomiting, with low certainty of evidence.ConclusionsSeveral scientific knowledge gaps were identified. Studies on treatments for hyperemesis gravidarum are few, and the certainty of evidence for different treatments is either low or very low. To establish more robust evidence, it is essential to use validated scoring systems, the recently established diagnostic criteria, clear descriptions and measurements of core outcomes and to perform larger studies. The certainty of evidence according to GRADE (The Grading of Recommendations Assessment, Development and Evaluation) was very low for all treatments of hyperemesis gravidarum except for acupressure in addition to standard care, which showed a possible moderate decrease in nausea and vomiting, with low certainty of evidence.image
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| 37. |
- Waite, J. H., Jr., et al.
(författare)
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Chemical interactions between Saturn's atmosphere and its rings
- 2018
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 362:6410
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Tidskriftsartikel (refereegranskat)abstract
- The Pioneer and Voyager spacecraft made close-up measurements of Saturn's ionosphere and upper atmosphere in the 1970s and 1980s that suggested a chemical interaction between the rings and atmosphere. Exploring this interaction provides information on ring composition and the influence on Saturn's atmosphere from infalling material. The Cassini Ion Neutral Mass Spectrometer sampled in situ the region between the D ring and Saturn during the spacecraft's Grand Finale phase. We used these measurements to characterize the atmospheric structure and material influx from the rings. The atmospheric He/H-2 ratio is 10 to 16%. Volatile compounds from the rings (methane; carbon monoxide and/or molecular nitrogen), as well as larger organic-bearing grains, are flowing inward at a rate of 4800 to 45,000 kilograms per second.
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| 38. |
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| 39. |
- Yildiz, B, et al.
(författare)
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Live well, die well - an international cohort study on experiences, concerns and preferences of patients in the last phase of life: the research protocol of the iLIVE study
- 2022
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Ingår i: BMJ OPEN. - : BMJ. - 2044-6055. ; 12:8
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Adequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families.Methods and analysisThe iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights.Ethics and disseminationThe cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying.Trial registration numberNCT04271085.
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| 40. |
- Zhai, Guangju, et al.
(författare)
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Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.
- 2011
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
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| 41. |
- Zhao, J. H., et al.
(författare)
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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
- 2023
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Ingår i: Nature Immunology. - : Springer Nature. - 1529-2908 .- 1529-2916. ; 24:9, s. 1540-1551
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
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| 42. |
- Adermark, Louise, 1974, et al.
(författare)
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Prospective association between use of electronic cigarettes and use of conventional cigarettes: a systematic review and meta-analysis
- 2021
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Ingår i: Erj Open Research. - Sheffield : European Respiratory Society (ERS). - 2312-0541. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this systematic review and meta-analysis was to assess the association between e-cigarette use and subsequent initiation or recurrence of cigarette smoking. Data sources A systematic literature search was finalised on 11 November 2019 using PubMed (including MEDLINE), EMBASE, Cochrane Library, Scopus, PubMed Health, NICE Evidence Search, PROSPERO, CRD and PsycInfo. Study selection Studies were included if meeting the following criteria: reporting empirical results; longitudinal observational design with a minimum of 3 months of follow-up; including general population samples; allowing for the comparison between users and nonusers of e-cigarettes. Studies rated as having high risk of bias were excluded. Studies were independently assessed by at least two authors. The procedures described by PRISMA were followed, and the quality of evidence was rated using GRADE. Data synthesis 30 longitudinal studies from 22 different cohorts assessing e-cigarette use among nonsmokers or never-smokers at baseline, and subsequent use of cigarette smoking at follow-up, were included in this review. A random-effects meta-analysis based on 89076 participants showed a pooled unadjusted odds ratio (OR) of cigarette smoking among baseline nonsmoker e-cigarette users compared with nonusers of 4.68 (CI 3.64-6.02), while the adjusted OR was 3.37 (CI 2.68-4.24). These results were consistent irrespective of whether the outcome was measured as ever-smoking or as past 30-day smoking. The evidence was graded as moderate. Conclusions Use of e-cigarettes may predict the initiation or recurrence of cigarette smoking.
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| 43. |
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| 44. |
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| 45. |
- Amsallem, Myriam, et al.
(författare)
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Quantifying the Influence of Wedge Pressure, Age, and Heart Rate on the Systolic Thresholds for Detection of Pulmonary Hypertension
- 2020
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Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The strong linear relation between mean (MPAP) and systolic (SPAP) pulmonary arterial pressure (eg, SPAP=1.62xMPAP) has been mainly reported in precapillary pulmonary hypertension. This study sought to quantify the influence of pulmonary arterial wedge pressure (PAWP), heart rate, and age on the MPAP-SPAP relation. METHODS AND RESULTS: An allometric equation relating invasive MPAP and SPAP was developed in 1135 patients with pulmonary arterial hypertension, advanced lung disease, chronic thromboembolic pulmonary hypertension, or left heart failure. The equation was validated in 60 885 patients from the United Network for Organ Sharing (UNOS) database referred for heart and/or lung transplant. The MPAP/SPAP longitudinal stability was assessed in pulmonary arterial hypertension with repeated right heart catheterization. The equation obtained was SPAP=1.39xMPAPxPAWP(-0.07)x(60/heart rate)(0.12)xage(0.08) (P<0.001). It was validated in the UNOS cohort (R-2=0.93, P<0.001), regardless of the type of organ(s) patients were listed for (mean bias [-1.96 SD; 1.96 SD] was 0.94 [-8.00; 9.88] for heart, 1.34 [-7.81; 10.49] for lung and 0.25 [-16.74; 17.24] mm Hg for heart-lung recipients). Thresholds of SPAP for MPAP=25 and 20 mm Hg were lower in patients with higher PAWP (37.2 and 29.8 mm Hg) than in those with pulmonary arterial hypertension (40.1 and 32.0 mm Hg). In 186 patients with pulmonary arterial hypertension, the predicted MPAP/SPAP was stable over time (0.63 +/- 0.03 at baseline and follow-up catheterization, P=0.43). CONCLUSIONS: This study quantifies the impact of PAWP, and to a lesser extent heart rate and age, on the MPAP-SPAP relation, supporting lower SPAP thresholds for pulmonary hypertension diagnosis in patients with higher PAWP for echocardiography-based epidemiological studies.
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| 46. |
- Andersson, Gerhard, et al.
(författare)
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Internet-Based Vs. Face-To-Face Cognitive Behaviour Therapy for Psychiatric and Somatic Disorders : a Systematic Review and Meta-Analysis
- 2014
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Ingår i: Abstracts from the 44th Congress of the European Association for Behavioural & Cognitive Therapies. - Utrecht : EABCT.
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Konferensbidrag (refereegranskat)abstract
- Internet-delivered cognitive behaviour therapy (ICBT) has been tested in many research trials but to a lesser extent been directly compared against face-to-face delivered cognitive behaviour therapy (CBT). We conducted a systematic review and meta-analysis on trials in which guided ICBT was directly compared against face-to-face CBT within the same trial. Studies on psychiatric and somatic conditions were included. Systematic searches resulted in 13 studies (total N=1053) that met all review criteria and were included in the review. There were 3 studies on social anxiety disorder, 3 on panic disorder, 2 on depressive symptoms, 2 on body dissatisfaction, 1 on tinnitus, 1 on male sexual dysfunction, and 1 on spider phobia. Face-to-face CBT was either in the individual format (n=6 ) or in the group format (n=7). We also assessed quality and risk of bias. Results showed a pooled effect size at post-treatment across of Hedges g = -0.01 (95% CI, -0.13 to 0.12), indicating that ICBT and face-to-face treatment produce equivalent overall effects. Study quality did not affect outcomes. While the overall results indicate equivalence, there are still few studies for each psychiatric and somatic condition and many for which guided ICBT has not been compared against face-to-face treatment. Thus, more research is needed to establish equivalence of the two treatment formats.
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| 47. |
- Berman, Anne H., et al.
(författare)
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Clinician experiences of healthy lifestyle promotion and perceptions of digital interventions as complementary tools for lifestyle behavior change in primary care
- 2018
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Ingår i: Bmc Family Practice. - : Springer Science and Business Media LLC. - 1471-2296. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence-based practice for healthy lifestyle promotion in primary health care is supported internationally by national policies and guidelines but implementation in routine primary health care has been slow. Referral to digital interventions could lead to a larger proportion of patients accessing structured interventions for healthy lifestyle promotion, but such referral might have unknown implications for clinicians with patients accessing such interventions. This qualitative study aimed to explore the perceptions of clinicians in primary care on healthy lifestyle promotion with or without digital screening and intervention. Methods: Focus group interviews were conducted at 10 primary care clinics in Sweden with clinicians from different health professions. Transcribed interviews were analyzed using content analysis, with inspiration from a phenomenological-hermeneutic method involving naive understanding, structural analysis and comprehensive understanding. Results: Two major themes captured clinicians' perceptions on healthy lifestyle promotion: 1) the need for structured professional practice and 2) deficient professional practice as a hinder for implementation. Sub-themes in theme 1 were striving towards professionalism, which for participants meant working in a standardized fashion, with replicable routines regardless of clinic, as well as being able to monitor statistics on individual patient and group levels; and embracing the future with critical optimism, meaning expecting to develop professionally but also being concerned about the consequences of integrating digital tools into primary care, particularly regarding the importance of personal interaction between patient and provider. For theme 2, sub-themes were being in an unmanageable situation, meaning not being able to do what is perceived as best for the patient due to lack of time and resources; and following one's perception, meaning working from a gut feeling, which for our participants also meant deviating from clinical routines. Conclusions: In efforts to increase evidence-based practice and lighten the burden of clinicians in primary care, decision-and policy-makers planning the introduction of digital tools for healthy lifestyle promotion will need to explicitly define their role as complements to face-to-face encounters. Our overriding hope is that this study will contribute to maintaining meaningfulness in the patient-clinician encounter, when digital tools are added to facilitate patient behavior change of unhealthy lifestyle behaviors.
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| 48. |
- Bermúdez Barón, Nicolás, et al.
(författare)
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Among respiratory symptoms, wheeze associates most strongly with impaired lung function in adults with asthma: a long-term prospective cohort study
- 2021
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Ingår i: BMJ Open Respiratory Research. - : BMJ. - 2052-4439. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Asthma is a common disease and a major public health concern. Respiratory symptoms are related to its prognosis, which in turn associates with lung function. Still this association on a long-term basis is not entirely understood. Aim To study the association of the type and number of respiratory symptoms with FEV1 and FEV1 decline in women and men with asthma. Method A population-based cohort of adults with asthma was examined at study entry between 1986 and 2001 and at follow-up between 2012 and 2014, and n=977 had valid measurements of FEV1 on both occasions. Data regarding respiratory symptoms at study entry (recurrent wheeze, dyspnoea, longstanding cough and productive cough) were analysed in relation to FEV1 and annual decline in FEV1, both unadjusted and adjusted for other potentially associated factors by linear regression. Results For both sexes recurrent wheeze and dyspnoea were associated with lower FEV1 at study entry and follow-up, while productive cough was associated with lower FEV1 only at follow-up. No associations were found between the type of symptoms and annual decline in FEV1. In adjusted analyses, the association between recurrent wheeze and lower FEV1 both at study entry and follow-up remained significant among women. Also, the association between a higher number of symptoms with lower FEV1 both at study entry and follow-up were present for both sexes and remained after adjustment. Conclusions Particularly recurrent wheeze and a higher number of respiratory symptoms may predict lower lung function also in the long run among women and men with asthma.
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