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1.
  • Forouzanfar, Mohammad H, et al. (författare)
  • Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
  • 2015
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
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3.
  • Lozano, Rafael, et al. (författare)
  • Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
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  • Huyghe, Jeroen R., et al. (författare)
  • Discovery of common and rare genetic risk variants for colorectal cancer
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
  • Tidskriftsartikel (refereegranskat)abstract
    • To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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  • Leebens-Mack, James H., et al. (författare)
  • One thousand plant transcriptomes and the phylogenomics of green plants
  • 2019
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 574:7780, s. 679-
  • Tidskriftsartikel (refereegranskat)abstract
    • Green plants (Viridiplantae) include around 450,000-500,000 species(1,2) of great diversity and have important roles in terrestrial and aquatic ecosystems. Here, as part of the One Thousand Plant Transcriptomes Initiative, we sequenced the vegetative transcriptomes of 1,124 species that span the diversity of plants in a broad sense (Archaeplastida), including green plants (Viridiplantae), glaucophytes (Glaucophyta) and red algae (Rhodophyta). Our analysis provides a robust phylogenomic framework for examining the evolution of green plants. Most inferred species relationships are well supported across multiple species tree and supermatrix analyses, but discordance among plastid and nuclear gene trees at a few important nodes highlights the complexity of plant genome evolution, including polyploidy, periods of rapid speciation, and extinction. Incomplete sorting of ancestral variation, polyploidization and massive expansions of gene families punctuate the evolutionary history of green plants. Notably, we find that large expansions of gene families preceded the origins of green plants, land plants and vascular plants, whereas whole-genome duplications are inferred to have occurred repeatedly throughout the evolution of flowering plants and ferns. The increasing availability of high-quality plant genome sequences and advances in functional genomics are enabling research on genome evolution across the green tree of life.
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  • Goldsmith, Paul F., et al. (författare)
  • Herschel Measurements of Molecular Oxygen in Orion
  • 2011
  • Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 737:2, s. 96 (1-17)
  • Tidskriftsartikel (refereegranskat)abstract
    • We report observations of three rotational transitions of molecular oxygen (O2) in emission from the H2 Peak 1 position of vibrationally excited molecular hydrogen in Orion. We observed the 487 GHz, 774 GHz, and 1121 GHz lines using the Heterodyne Instrument for the Far Infrared on the Herschel Space Observatory, having velocities of 11 km s–1 to 12 km s–1 and widths of 3 km s–1. The beam-averaged column density is N(O2) = 6.5 × 1016 cm–2, and assuming that the source has an equal beam-filling factor for all transitions (beam widths 44, 28, and 19''), the relative line intensities imply a kinetic temperature between 65 K and 120 K. The fractional abundance of O2 relative to H2 is (0.3-7.3) × 10–6. The unusual velocity suggests an association with a ~5'' diameter source, denoted Peak A, the Western Clump, or MF4. The mass of this source is ~10 Msun and the dust temperature is ≥150 K. Our preferred explanation of the enhanced O2 abundance is that dust grains in this region are sufficiently warm (T ≥ 100 K) to desorb water ice and thus keep a significant fraction of elemental oxygen in the gas phase, with a significant fraction as O2. For this small source, the line ratios require a temperature ≥180 K. The inferred O2 column density sime5 × 1018 cm–2 can be produced in Peak A, having N(H2) sime 4 × 1024 cm–2. An alternative mechanism is a low-velocity (10-15 km s–1) C-shock, which can produce N(O2) up to 1017 cm–2.
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  • Cammareri, Patrizia, et al. (författare)
  • Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5 +ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5 +ve cells also results in cSCC development. These findings indicate that LGR5 +ve stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
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  • Ahmadi, Nasser, 1958, et al. (författare)
  • Clinical characteristics of asymptomatic left ventricular diastolic dysfunction and its association with self-rated health and N-terminal B-type natriuretic peptide: a cross-sectional study
  • 2016
  • Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 3:3, s. 205-211
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Left ventricular hypertrophy, obesity, hypertension, and N-terminal B-type natriuretic peptide (Nt-proBNP) predict left ventricular diastolic dysfunction with preserved systolic function (DD-PSF). Self-rated health (SRH) is shown to be associated with chronic diseases, but the association of SRH with DD-PSF is unclear. In light of the clinical implications of DD-PSF, the following goals are of considerable importance: (1) to determine the role of SRH in patients with DD-PSF in the general population and (2) to study the association between Nt-proBNP and DD-PSF. Methods and results The current study is a cross-sectional study conducted on a random sampling of a rural population. Individuals 30-75 years of age were consecutively subjected to conventional echocardiography and tissue velocity imaging. Data were collected on 500 (48%) men and 538 (52%) women (n = 1038). DD-PSF was the main outcome, and SRH and Nt-proBNP were the primary indicators. Diabetes mellitus, hypertension, and obesity were accounted for as major confounders of the association with SRH. DD-PSF was identified in 137 individuals, namely, 79 men (15.8%) and 58 women (10.8%). In a multivariate regression model, SRH (OR 2.95; 95% CI 1.02-8.57) and Nt-proBNP (quartile 4 vs. quartile 1 OR 4.23; 95% CI 1.74-10.26) were both independently associated with DD-PSF. Conclusions SRH, evaluated based on a descriptive question on general health, should be included in the diagnostic process of DD-PSF. In agreement with previous studies, our study confirms that Nt-proBNP is a major indicator of DD-PSF.
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10.
  • Alkerwi, Ala'a, et al. (författare)
  • Adherence to physical activity recommendations and its associated factors: an interregional population-based study.
  • 2015
  • Ingår i: Journal of Public Health Research. - : SAGE Publications. - 2279-9028 .- 2279-9036. ; 4:1, s. 406-406
  • Tidskriftsartikel (refereegranskat)abstract
    • Though the influence of physical activity in preventing cardiovascular diseases is well documented, only a few comparative studies have determined the degree of adherence to physical activity recommendations among populations and identified the demographic, socioeco-nomic, behavioural and health-related factors associated with good compliance.
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  • Andersson, Susanne, 1957, et al. (författare)
  • The association between self-rated health and impaired glucose tolerance in Swedish adults: A cross-sectional study
  • 2013
  • Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 31:2, s. 111-118
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To investigate gender differences in the association between self-rated health (SRH) and impaired glucose tolerance (IGT) in subjects unaware of their glucose tolerance. Design. A cross-sectional population-based study. Setting. The two municipalities of Vara and Skövde in south-western Sweden. Subjects. A total of 2502 participants (1301 women and 1201 men), aged 30–75, were randomly selected from the population. Main outcome measures. IGT was regarded as the outcome measure and SRH as the main risk factor. Results. The prevalence of IGT was significantly higher in women (11.9%) than in men (10.1%), (p = 0.029), as was the prevalence of low SRH (women: 35.4%; men: 22.1%, p = 0.006). Both men and women with low SRH had a poorer risk factor profile than those with high SRH, and a statistically significant crude association between SRH and IGT was found in both men (OR = 2.8, 95% CI 1.8–4.4) and women (OR = 1.5, 95% CI 1.0–2.2, p = 0.033). However, after controlling for several lifestyle factors and biomedical variables, the association was attenuated and remained statistically significant solely in men (OR = 2.3, 95% CI 1.2–4.3). Conclusion. The gender-specific associations found between SRH and IGT suggest that SRH may be a better indicator of IGT in men than in women. Future studies should evaluate the utility of SRH in comparison with objective health measures as a potential aid to health practitioners when deciding whether to screen for IGT and T2DM.
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  • Bennet, Louise, et al. (författare)
  • Diastolic dysfunction is associated with sedentary leisure time physical activity and smoking in females only
  • 2010
  • Ingår i: SCANDINAVIAN JOURNAL OF PRIMARY HEALTH CARE. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 28:3, s. 172-178
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. Left ventricular diastolic dysfunction with preserved systolic function (DD-PSF) is associated with an increased risk of morbidity and mortality. Population-based surveys studying the associations between DD-PSF and lifestyle-associated risk factors, such as leisure time physical activity (LTPA) and smoking, are scarce. Thus, the aims were to explore the associations between DD-PSF and LTPA and smoking, employing optimal echocardiographic techniques. Design. Cross-sectional study conducted from 2001 to 2003. Setting.The study was conducted in a random sample of a rural Swedish population. Subjects. Men and women of 30–75 years of age were consecutively invited for conventional echocardiography and tissue velocity imaging (n = 1149). Structured questionnaires and physical examinations were conducted using standardized methods. Main outcome measures. DD-PSF was defined according to the European Society of Cardiology criteria excluding subjects with ejection fraction < 45%, or a self-reported history of heart failure. Results. Complete information was available in 500 men and 538 women. In a multivariate model, DD-PSF was independently associated with sedentary LTPA and smoking in females; sedentary LTPA odds ratio (OR) 2.91, 95% confidence interval (CI) 1.02 to 8.27, and smoking OR 3.42, 95% CI 1.35 to 8.64. The probability of identifying DD-PSF in females with a sedentary LTPA was 37% and increased to 80% if they also had hypertension and were obese. Conclusions. Sedentary LTPA and smoking are independently associated with DD-PSF in females. Identification of a sedentary lifestyle in females increases the probability of diagnosing DD-PSF.
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  • Bøg-Hansen, Erik, et al. (författare)
  • Predictors of acute myocardial infarction mortality in hypertensive patients treated in primary care.
  • 2007
  • Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 25:4, s. 237-243
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To explore risk factors for acute myocardial infarction (AMI) mortality in hypertensive patients treated in primary care. Design. Community-based cohort study. Setting. Hypertension outpatient clinic in primary health care. Subjects. Patients who consecutively underwent an annual follow-up during 1992-1993 (n =894; 377 men and 517 women). Methods. All events of fatal AMI were ascertained by record linkage to the National Mortality Register to December 31, 2002. Gender-specific predictors for AMI mortality were analysed by Cox regression. Main outcome measure. AMI mortality. Results. During a mean follow-up of 8.7 years 32 cases (8.5%) of fatal AMI were observed in men and 31 cases (6.0%) were observed in women. Most important predictors for AMI mortality in men were microalbuminuria (HR 3.8, CI 1.8-8.0) and left ventricular hypertrophy (HR 4.0, CI 1.7-9.4), whilst in women type 2 diabetes (HR 4.8, CI 2.4-9.8) was an important predictor. In hypertensive patients without diabetes male gender was associated with high AMI mortality (HR 2.7, CI 1.4-5.3), but in patients with both hypertension and type 2 diabetes the higher risk in men disappeared (HR 0.8, CI 0.4-1.7). Conclusion. Cardiovascular disease risk factors remain strong predictors of AMI mortality in hypertensive patients but with a different pattern in the two genders. Markers of organ damage are more important predictors in men, whereas markers of impaired glucose metabolism are more important predictors in women.
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16.
  • Cantor-Graae, Elizabeth, et al. (författare)
  • Long-term psychiatric consequences of exposure to trauma in Cambodia: A regional household survey.
  • 2014
  • Ingår i: Social Science and Medicine. - : Elsevier BV. - 1873-5347 .- 0277-9536. ; 123, s. 133-140
  • Tidskriftsartikel (refereegranskat)abstract
    • The long-term psychiatric consequences of exposure to war and/or mass conflict continue to be of great concern and particularly in Cambodia. The current cross-sectional study examined the relationship between history of trauma and current psychiatric and functional morbidity in 3200 randomly selected adults aged 18-60 in Cambodia. Structured interviews were conducted from November 2011 until May 2012 in two predominantly rural regions purposively selected for differing duration of exposure to the Khmer Rouge occupation. Information was also collected regarding ongoing daily stressors and intimate partner violence. Despite high prevalence rates of conflict/war-related trauma, current rates of psychiatric disorders (depression, post-traumatic stress disorder) were relatively low, suggesting that the effects of trauma and extreme hardship in civilian populations may be modified by contextual factors and/or the passage of time. Poor to fair physical health was, however, reported by nearly 60% of the sample. Daily stressors were more important for current morbidity levels than history of trauma, especially in the region with shorter Khmer Rouge occupation. The results suggest that a focus exclusively on past trauma may overlook the contribution of adverse daily life circumstances towards current levels of well-being in civilian populations affected by war and/or mass conflict.
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  • Classen, Jean-Francois, et al. (författare)
  • Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis
  • 2009
  • Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:4, s. 1137-1144
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc. METHODS: Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center. RESULTS: Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFRalpha or PDGFRbeta in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal. CONCLUSION: The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.
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19.
  • Daka, Bledar, 1976, et al. (författare)
  • Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: A longitudinal observational study in the Vara-Skövde Cohort
  • 2015
  • Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2015 Daka et al.Background: The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden. Methods: In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time. Results: We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1-2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024). Conclusion: Circulating endothelin-1 levels may predict CHD in women.
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20.
  • Daka, Bledar, 1976, et al. (författare)
  • Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden
  • 2013
  • Ingår i: Endocrine Connections. - 2049-3614. ; 2:1, s. 18-22
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population. DESIGN AND METHODS: Between 2001 and 2005, a random sample of 2816 participants aged 30-74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population. RESULTS: WE FOUND SIGNIFICANT INVERSE ASSOCIATION BETWEEN LEVELS OF SHBG AND FASTING SERUM INSULIN IN BOTH GENDERS (MEN: β=-0.090, P=0.001; women: β=-0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=-0.062, P=0.022; women: β=-0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9nmol/l, P<0.001; women: δ=71.1nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1nmol/l, P<0.001; women: δ=72.9nmol/l, P<0.001) independent of age, BMI and fasting glucose levels. CONCLUSION: These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.
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21.
  • Daka, Bledar, 1976, et al. (författare)
  • Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus
  • 2015
  • Ingår i: Bmc Endocrine Disorders. - : Springer Science and Business Media LLC. - 1472-6823. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes. Methods: The study comprised 1109 subjects >= 40 years of age (mean age 62 +/- 12 years) participating in a baseline survey in Sweden in 1993-94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO's 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011. Results: The prevalence of type 2 diabetes at baseline was 10.0 % in men and 7.5 % in women. During a mean follow-up of 14.1 years (+/- 5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75-0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61-0.92)). Conclusion: Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes.
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22.
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23.
  • Daka, Bledar, et al. (författare)
  • Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population
  • 2013
  • Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population. Methods: The study is based on a random sample of a Swedish population of men and women aged 30-74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 x (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7. Results: In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: beta=-0.143 p<0.001) and systolic blood pressure (systolic blood pressure beta=-0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: beta=-0.113 p<0.001; systolic blood pressure beta=-0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=-0.024 p<0.001) and women (B=-0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=-0.014, p=0.008). Conclusion: In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.
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24.
  • Eggertsen, Maria, 1981-, et al. (författare)
  • Different environmental variables predict distribution and cover of the introduced red seaweed Eucheuma denticulatum in two geographical locations
  • 2021
  • Ingår i: Biological Invasions. - : Springer. - 1387-3547 .- 1573-1464. ; 23, s. 1049-1067
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study we examined abiotic and biotic factors that could potentially influence the presence of a non-indigenous seaweed, Eucheuma denticulatum, in two locations, one outside (Kane’ohe Bay, Hawai’i, USA) and one within (Mafia Island, Tanzania) its natural geographical range. We hypothesized that the availability of hard substrate and the amount of wave exposure would explain distribution patterns, and that higher abundance of herbivorous fishes in Tanzania would exert stronger top–down control than in Hawai’i. To address these hypotheses, we surveyed E. denticulatum in sites subjected to different environmental conditions and used generalized linear mixed models (GLMM) to identify predictors of E. denticulatum presence. We also estimated grazing intensity on E. denticulatum by surveying the type and the amount of grazing scars. Finally, we used molecular tools to distinguish between indigenous and non-indigenous strains of E. denticulatum on Mafia Island. In Kane’ohe Bay, the likelihood of finding E. denticulatum increased with wave exposure, whereas on Mafia Island, the likelihood increased with cover of coral rubble, and decreased with distance from areas of introduction (AOI), but this decrease was less pronounced in the presence of coral rubble. Grazing intensity was higher in Kane’ohe Bay than on Mafia Island. However, we still suggest that efforts to reduce non-indigenous E. denticulatum should include protection of important herbivores in both sites because of the high levels of grazing close to AOI. Moreover, we recommend that areas with hard substrate and high structural complexity should be avoided when farming non-indigenous strains of E. denticulatum.
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25.
  • Eklund-Jonsson, Charlotte, et al. (författare)
  • Reduction of phytate content while preserving minerals during whole grain cereal tempe fermentation
  • 2006
  • Ingår i: Journal of Cereal Science. - : Elsevier BV. - 0733-5210 .- 1095-9963. ; 44:2, s. 154-160
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of different pretreatments on phytate and mineral contents were investigated in whole grain barley and oat tempe fermented with Rhizopus oligosporus. Different varieties of barley and oats were exposed to pretreatments such as pearling, rolling, moistening, autoclaving and soaking before fermentation. Pearling was the most effective pretreatment for reduction of phytate content for both oats and barley. Nevertheless, mineral contents were reduced, and most likely cell wall rich fractions were also reduced by this process. In the first experiments the phytate content reduction in the oats and barley samples were reduced by 74% (3.3 μmol/g, d.m.) and 89% (1.4 μmol/g, d.m.), respectively. However, to improve iron absorption the phytate levels should not exceed 0.5 μmol/g, and further phytate degradation was necessary. Therefore, in the final experiments barley samples were exposed to an optimised process with prolonged soaking at a higher temperature and the pearling residues were returned before fermentation. When the outer layers of the barley kernels were returned before fermentation the phytate content was successfully reduced by 97% to 0.4 μmol/g (d.m.) and Fe and Zn levels were well preserved. © 2006.
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26.
  • Hantke, Max F., et al. (författare)
  • A data set from flash X-ray imaging of carboxysomes
  • 2016
  • Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 3
  • Tidskriftsartikel (refereegranskat)abstract
    • Ultra-intense femtosecond X-ray pulses from X-ray lasers permit structural studies on single particles and biomolecules without crystals. We present a large data set on inherently heterogeneous, polyhedral carboxysome particles. Carboxysomes are cell organelles that vary in size and facilitate up to 40% of Earth’s carbon fixation by cyanobacteria and certain proteobacteria. Variation in size hinders crystallization. Carboxysomes appear icosahedral in the electron microscope. A protein shell encapsulates a large number of Rubisco molecules in paracrystalline arrays inside the organelle. We used carboxysomes with a mean diameter of 115±26 nm from Halothiobacillus neapolitanus. A new aerosol sample-injector allowed us to record 70,000 low-noise diffraction patterns in 12 min. Every diffraction pattern is a unique structure measurement and high-throughput imaging allows sampling the space of structural variability. The different structures can be separated and phased directly from the diffraction data and open a way for accurate, high-throughput studies on structures and structural heterogeneity in biology and elsewhere.
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27.
  • Hedin, Charlotte Rose Hawkey, et al. (författare)
  • Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis
  • 2020
  • Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 18:10, s. 2-2304
  • Tidskriftsartikel (refereegranskat)abstract
    • Background & Aims: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. Methods: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Results: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P =.035). Factors associated with lower ALP were normal ALP at baseline (P <.01), treatment with adalimumab (P =.090), and treatment in Europe (P =.083). Conclusions: In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.
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28.
  • Hellgren, Margareta, 1955, et al. (författare)
  • C-Reactive Protein Concentrations and Level of Physical Activity in Men and Women With Normal and Impaired Glucose Tolerance: A Cross-Sectional Population-Based Study in Sweden
  • 2016
  • Ingår i: Journal of Physical Activity & Health. - : Human Kinetics. - 1543-3080 .- 1543-5474. ; 13:6, s. 625-631
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aimed to explore the association between self-reported leisure time physical activity (LTPA) and C-reactive protein (CRP) concentrations in men and women with and without impaired glucose tolerance (IGT). Methods: In a cross-sectional study, a random sample (n = 2,816) was examined with an oral glucose tolerance test, CRP and information about LTPA. Those with IGT or normal glucose tolerance (NGT) and CRP value <= 10 mg/L were selected (n = 2,367) for the study. Results: An inverse association between LTPA and CRP concentrations was observed in the population (P < .001), though, only in men with IGT (P = .023) and in women with NGT. Men with IGT, reporting slight physical activity up to 4 hours a week presented significantly higher CRP concentrations than normoglycemic men (Delta 0.6 mg/L, P = .004). However, this difference could not be found in men with IGT reporting more intense physical activity (Delta 0.01 mg/L, P = .944). Conclusions: Physical inactivity seems to have greater inflammatory consequences for men (vs. women) with IGT. More importantly, although 4 hours of physical activity per week is more than the usual minimum recommendation, an even greater intensity of LTPA appears to be required to limit subclinical inflammation in men with IGT.
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29.
  • Hellgren, Margareta, et al. (författare)
  • HbA1c räcker inte vid screening för störd glukosmetabolism - Även glukosbelastning behövs, visar svensk prospektiv epidemiologisk studie.
  • 2015
  • Ingår i: Läkartidningen. - 1652-7518. ; 112
  • Tidskriftsartikel (refereegranskat)abstract
    • An HbA1c threshold of ≥42 mmol/mol has been proposed to diagnose prediabetes. The sensitivity, specificity and positive predictive value of the proposed threshold for detection of individuals with prediabetes was examined in a study of 573 randomly selected individuals from Vara and Skövde. In addition, the utility of the FINDRISC questionnaire and of a fasting glucose test in combination with three short questions concerning BMI, heredity for type 2 diabetes and known hypertension was examined. Results from an oral glucose tolerance test were used as reference. The sensitivity of HbA1c and FINDRISC to detect individuals with IGT was 16 and 26 per cent respectively. Questions regarding BMI, heredity and hypertension together with a fasting glucose test yielded a sensitivity of 50%, but a lower specificity and positive predictive value. We conclude that HbA1c inefficiently detected individuals with impaired glucose tolerance and that oral glucose tolerance tests can still preferably be recommended.
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30.
  • Hellgren, Margareta, 1955, et al. (författare)
  • Insulin resistance predicts early cardiovascular morbidity in men without diabetes mellitus, with effect modification by physical activity
  • 2015
  • Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 22:7, s. 940-949
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: to assess how well insulin resistance predicts cardiovascular disease (CVD) in non-diabetic men and women and to explore the influence of physical activity. Methods: in this prospective study 2563 men and women without diabetes were examined with an oral glucose tolerance test, anthropometric measurements and blood pressure assessment. Questionnaires about lifestyle and physical activity were completed. Insulin resistance was estimated by fasting concentrations of plasma insulin and by HOMA index for insulin resistance. Participants were followed up for cardiovascular morbidity and mortality during an 8-year period, using information from the National Swedish Inpatient and Mortality registers. Results: at follow-up, HOMAir predicted CVD morbidity in males (50 events) and females (28 events) combined (HRage/sex-adj 1.4, 95% CI 1.1-1.7); however, when stratified by gender HOMAir was predictive solely in men (HRage-adj 1.8, 95% CI 1.3-2.4), whereas no association was found in women (HRage-adj 1.1, 95% CI 0.8-1.5). When stratifying the data for high and low physical activity, the predictive value of insulin resistance became stronger in sedentary men (HRage-adj 2.3, 95% CI 1.5-3.4) but was abolished in men performing moderate to vigorous physical activity (HRage-adj 1.0, 95% CI 0.6-1.6). The results remained when step-wise adjusted also for BMI, ApoB/ApoA1 and hypertension, as well as for smoking, alcohol consumption and education. Outcome for fasting plasma insulin was similar to HOMAir. Conclusions: insulin resistance predicts CVD in the general population; however, men may be more vulnerable to increased insulin resistance than women, and physically inactive men seem to be at high risk.
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31.
  • Jarl, Johan, et al. (författare)
  • Trauma and Poor Mental Health in Relation to Economic Status: The Case of Cambodia 35 Years Later.
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Cambodia is one of the poorest countries in south-east Asia and is still emerging from the events of the Khmer Rouge reign. It has been suggested that the atrocities experienced by the Cambodian population can explain why Cambodia continues to lag behind its neighbours in economic outcomes. The purpose of this study is to investigate whether there is an association between exposure to past trauma and/or current poor mental health and current economic status in Cambodia.
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32.
  • Johansson, Lovisa, et al. (författare)
  • Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity.
  • 2008
  • Ingår i: European Journal of Endocrinology. - 1479-683X. ; 159:5, s. 577-583
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The insulin responsive adiponutrin (PNPLA3 or ADPN) gene shows association with obesity and in vitro adipocyte lipolysis. This study aimed to replicate the association between PNPLA3 variants and obesity, and to investigate their effect on insulin resistance and beta-cell function. Methods: rs738409 (Met148Ile) and rs2072907 (C to G) were genotyped using TaqMan allelic discrimination assay in a Swedish population-based sample (n=1811). Results: Both variant alleles were associated with decreased prevalence of obesity (p<0.05); OR 0.75 [0.61-0.93] per carried Ile-allele for rs738409 and 0.80 [0.64-1.00] per carried G-allele for rs2072907. As a quantitative trait, there was no association in the whole population, but in obese subjects BMI (p=0.023) and waist (p=0.0098) was higher in carriers of the Ile-allele. They also displayed decreased insulin secretion in response to oral glucose tolerance test (30 minutes insulin; p=0.007, insulinogenic index; p=0.0051) with no significant difference in fasting plasma glucose (p=0.31), beta-cell function (disposition index; p=0.17) or insulin resistance (HOMA-IR; p=0.063). The correlation between BMI and HOMA-IR differed (Met/X vs. Ile/Ile, p=0.028), Met-allele carriers seemingly more insulin resistant at a lower BMI. The rs2072907 variant show similar results for insulin secretion. The findings were independent of age, gender and level of self reported leisure time physical activity. Conclusion: We confirm the association between PNPLA3 and obesity. In addition, the rs738409 variant was associated with insulin secretion. There seem to be a differential effect of the Ile-allele depending on the degree of obesity, possibly as a consequence of insulin resistance.
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33.
  • Landgren, Anton J., 1989, et al. (författare)
  • Serum IL-23 significantly decreased in obese patients with psoriatic arthritis six months after a structured weight loss intervention.
  • 2023
  • Ingår i: Arthritis research & therapy. - 1478-6362. ; 25:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with psoriatic arthritis (PsA) are frequently obese. We have previously shown decreased disease activity in patients with PsA with a body mass index (BMI)≥33kg/m2 following weight loss treatment with Very Low Energy Diet (VLED), resulting in a median weight loss of 18.6% at six months (M6) after baseline (BL). In this study we assessed the effects of VLED on cytokines and adipokines at M6 in the same patients with PsA and controls (matched on sex, age and weight).VLED (640kcal/day) during 12 or 16weeks, depending on BL BMI<40 or≥40kg/m2, was taken and followed by an energy-restricted diet. Cytokines and adipokines were measured with Magnetic Luminex Assays at BL and M6.Serum interleukin (IL)-23, (median (interquartile range) 0.40 (0.17-0.54) ng/mL vs. 0.18 (0.10-0.30) ng/mL, p<0.001) and leptin (26.28 (14.35-48.73) ng/mL vs. 9.25 (4.40-16.24) ng/mL, p<0.001) was significantly decreased in patients with PsA. Serum total (tot)-adiponectin and high molecular weight (HMW) adiponectin increased significantly. Similar findings were found in controls. Also, in patients with PsA, ∆BMI was positively correlated with ∆IL-23 (rS=0.671, p<0.001). In addition, significant positive correlations were found between ΔBMI and ΔDisease Activity Score (DAS28CRP), ΔCRP, Δtumor necrosis factor (TNF)-α, ΔIL-13, ∆IL-17 and Δleptin, and negative correlations between ΔBMI and Δtot-adiponectin.Weight loss was associated with decreased levels of leptin and cytokines, in particular IL-23. These findings may partly explain the anti-inflammatory effect of weight reduction in PsA.ClinicalTrials.gov identifier: NCT02917434, registered on September 21, 2016, retrospectively registered.
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34.
  • Landgren, Anton J., 1989, et al. (författare)
  • Sex differences in cytokines and adipokines in obese patients with PsA and controls undergoing a weight loss intervention.
  • 2024
  • Ingår i: RMD open. - 2056-5933. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In this post hoc analysis of a previously published study, we compared cytokines and adipokine levels in women and men with psoriatic arthritis (PsA) at baseline (BL) and 6 months (M6) following a weight loss intervention.Patients with PsA (n=41) between 25 and 75 years of age, with body mass index (BMI)≥33 kg/m2 were included in a weight loss intervention with a very low energy diet (VLED) for 12 or 16 weeks depending on BL BMI<40 or ≥40 kg/m2. As controls (n=39), obese individuals, already planned for VLED treatment were recruited and matched for sex, age and weight to the patients with PsA. Cytokines and adipokines were measured at BL and M6.At BL, serum levels of interleukin (IL)-23, leptin and high molecular weight-adiponectin were higher in women with PsA compared with men, whereas serum levels of interferon (IFN)-γ, IL-12/IL-23 p40 and IL-13 were significantly lower in women. Serum IL-23 was significantly reduced at M6 compared with BL in women but not in men with PsA. In women with PsA, the reduction in IL-23 at M6, ∆IL-23, were positively correlated with ∆Disease Activity Score 28 C reactive protein (CRP) (Spearman's correlation (rS)=0.486, p=0.016), ∆CRP (rS=0.468, p=0.021), ∆leptin (rS=0.683, p<0.001) and negatively correlated with ∆total-adiponectin (rS=-0.433, p=0.035). Also in women, ∆Disease Activity in Psoriatic Arthritis was positively correlated with ∆tumour necrosis factor-α (rS=0.417, p=0.034), ∆IL-1β (rS=0.550, p=0.034), ∆IFN-γ (rS=0.414, p=0.035) and ∆leptin (rS=0.410, p=0.038). None of these correlations were significant in men with PsA.Women and men with PsA differed with regard to serum levels of cytokines and adipokines before and after weight loss.
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35.
  • Larsson, Charlotte A, et al. (författare)
  • Clusters of AMI risk factors and their association with left ventricular hypertrophy: A population-based study within the Skaraborg Project, Sweden.
  • 2013
  • Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 168:6, s. 5416-5421
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Risk factors for acute myocardial infarction (AMI) are known to cluster and to be differently distributed in men and women. The aim of this study was to sex-specifically explore clusters of acknowledged AMI risk factors by factor analysis, and to study whether such clusters are associated with left ventricular hypertrophy (LVH), used as a subclinical measure of CHD. METHODS: In 2001-2005, 2328 subjects (30-74years) were randomly selected from two municipalities in Sweden (participation-rate 76%) and were assessed with regard to cardiovascular risk factors; 852 participants also had an echocardiographic examination performed. RESULTS: Factor analysis identified three identical factors in men and women. WHR, HOMA-ir, systolic blood pressure, and ApoB/ApoA1 loaded significantly on the principal "metabolic factor", leisure-time physical activity and self-rated health loaded significantly on the "vitality factor", and smoking and alcohol consumption loaded significantly on the "addiction factor". The metabolic factor was associated with LVH in both men (P<0.001) and women (P<0.001), whereas the addiction factor was associated with LVH solely in men (P=0.002). CONCLUSIONS: The consistent pattern in the clustering of acknowledged AMI risk factors suggests common underlying mechanisms in both men and women. However, whereas the metabolic factor was paramount in both men and women in the association with LVH, the addiction factor had an impact solely in men. As LVH often precedes AMI, a deeper understanding of risk factors for LVH, including consideration of the supposed sex differences, can be useful in order to explore prevention strategies for AMI. © 2013.
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36.
  • Larsson, Charlotte A (författare)
  • Common risk factors associated with acute myocardial infarction: Population-based studies with a focus on gender differences
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The overall aim of this thesis was to explore how the risk for AMI, and the associations between several of its risk factors, differs by gender. Information was collected from four Swedish cohorts: one patient cohort from Skara (1992-1993, n=1149) and three population-based cohorts, i.e. from Skara (1993-1994, n=1109), Vara (2001-2004, n=1811), and Skövde (2003-2005, n=1005). Participants were examined and filled out questionnaires regarding lifestyle and health. An interaction between gender and type 2 diabetes was found with regard to the risk of fatal AMI, showing that the impact of type 2 diabetes on AMI is greater in women than in men. Gender differences were also found in several AMI risk factors and in the associations between these risk factors: • Basal salivary cortisol was generally higher in women than in men (and in older subjects in general as compared to younger). • Low morning salivary cortisol and low diurnal variation of cortisol was associated with high waist-hip ratio solely in women. • Leisure time physical activity was negatively associated with insulin resistance and obesity in both men and women. However, the association with regard to insulin resistance and leisure time physical activity was stronger in women than in men. • Occupational physical activity was positively associated with insulin resistance and general and abdominal obesity in women only. • Factor analysis of AMI risk factors yielded three identical clusters in both genders: a “metabolic factor”, a “vitality factor”, and an “addiction factor”. However, these factors partly differed in their association with left ventricular hypertrophy, with significant associations with regard to the metabolic factor in both genders, and to the addiction factor in men. These findings show that gender differences with regard to AMI are present both in the risk of developing the disease and in how different risk factors for the disease interrelate. Thus, this thesis highlights the need for considering and addressing potential gender differences at all stages of preventive and interventional work aiming to reduce the burden of AMI.
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37.
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38.
  • Larsson, Charlotte A, et al. (författare)
  • Leisure time and occupational physical activity in relation to obesity and insulin resistance: a population-based study from the Skaraborg Project in Sweden.L
  • 2012
  • Ingår i: Metabolism. - : Elsevier BV. - 0026-0495. ; 61:4, s. 590-598
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective was to study obesity and insulin resistance in relation to leisure time physical activity (LTPA) and occupational physical activity (OPA) in a Swedish population, with particular focus on sex differences. Using a cross-sectional design, waist circumference, body mass index (BMI), glucose/insulin metabolism, blood pressure, heart rate, self-reported education, smoking, alcohol consumption, LTPA, and OPA were assessed in 1745 men and women (30-74 years) randomly chosen from 2 municipalities in southwestern Sweden. In both men and women, LTPA was inversely associated with BMI, waist circumference, and the homeostasis model assessment of insulin resistance (HOMA-IR), respectively. These associations remained statistically significant after adjustments for age, OPA, education, alcohol consumption, smoking, and study area, and also for BMI in the analyses concerning waist circumference and HOMA-IR. A statistically significant interaction term (P = .030), adjusted for multiple confounders, revealed a stronger association between LTPA and HOMA-IR in women compared with men. Occupational physical activity was positively associated with BMI (P < .001), waist circumference (P < .001), and HOMA-IR (P = .001), however, only in women. These associations remained when adjusting for multiple confounders. The sex differences were confirmed by statistically significant interaction terms between sex and OPA in association with BMI, waist circumference, and HOMA-IR, respectively. The observed sex differences regarding the strength of the association between LTPA and insulin resistance, and the positive association between OPA and obesity and insulin resistance found solely in women, warrant further investigation. Although exploration of the metabolic effects of OPA appears to be needed, thorough measurement of potential confounders is also vital to understand contextual effects.
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39.
  • Larsson, Charlotte A, et al. (författare)
  • Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study.
  • 2009
  • Ingår i: BMC endocrine disorders. - : Springer Science and Business Media LLC. - 1472-6823. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Most studies on cortisol have focused on smaller, selected samples. We therefore aimed to sex-specifically study the diurnal cortisol pattern and explore its association with abdominal obesity in a large unselected population. METHODS: In 2001-2004, 1811 men and women (30-75 years) were randomly selected from the Vara population, south-western Sweden (81% participation rate). Of these, 1671 subjects with full information on basal morning and evening salivary cortisol and anthropometric measurements were included in this cross-sectional study. Differences between groups were examined by general linear model and by logistic and linear regression analyses. RESULTS: Morning and Delta-cortisol (morning - evening cortisol) were significantly higher in women than men. In both genders older age was significantly associated with higher levels of all cortisol measures, however, most consistently with evening cortisol. In women only, age-adjusted means of WHR were significantly lower in the highest compared to the lowest quartile of morning cortisol (p = 0.036) and Delta-cortisol (p < 0.001), respectively. Furthermore, when comparing WHR above and below the mean, the age-adjusted OR in women for the lowest quartile of cortisol compared to the highest was 1.5 (1.0-2.2, p = 0.058) for morning cortisol and 1.9 (1.3-2.8) for Delta-cortisol. All findings for Delta-cortisol remained after adjustments for multiple covariates and were also seen in a linear regression analysis (p = 0.003). CONCLUSION: In summary, our findings of generally higher cortisol levels in women than men of all ages are novel and the stronger results seen for Delta-cortisol as opposed to morning cortisol in the association with WHR emphasise the need of studying cortisol variation intra-individually. To our knowledge, the associations in this study have never before been investigated in such a large population sample of both men and women. Our results therefore offer important knowledge on the descriptive characteristics of cortisol in relation to age and gender, and on the impact that associations previously seen between cortisol and abdominal obesity in smaller, selected samples have on a population level.
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40.
  • Lindblad, Ulf, 1950, et al. (författare)
  • Prevalence, awareness, treatment and controll of hypertension - rule of thirds in The Skaraborg Project.
  • 2012
  • Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 30:2, s. 88-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To describe the prevalence, awareness, and control of hypertension in a Swedish population during the early 2000s to address implications for care and prevention. Design. A cross-sectional population survey. Setting. Primary health care in Skaraborg, a rural part of western Sweden. Subjects. Participants (n =2816) in a population survey of a random sample of men and women between 30 and 75 years of age in the municipalities of Vara (81% participation rate) and Skövde (70%), in western Sweden during 2001–2005. Main outcome measures. Anthropometric measures, blood pressure, leisure-time physical activity, current smoking, fasting glucose, and cholesterol. Hypertension was defined as ongoing treatment for hypertension, or three consecutive blood pressure readings ≥140 systolic and/or ≥90 mmHg diastolic. Hypertension was considered controlled when the blood pressure was <140/90 mm Hg (both). Results. The prevalence of hypertension was 20% in both men and women with a steep increase by age. Among hypertensive subjects, 33% were unaware, 36% aware but uncontrolled, and 31% aware and controlled, with no statistically significant differences between men and women. Patients with diabetes had a higher awareness (87% vs. 64%, p <0.001), but the same control rate (56% vs. 44%, p =0.133), when compared with those without diabetes. Conclusion. A large proportion of subjects with hypertension are still unaware of their condition, or aware but not controlled. It is important to emphasize population-based prevention to reduce the prevalence of hypertension, to perform screening to increase awareness, and to improve implementation of expert guidelines in clinical practice to improve control.
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41.
  • Moen, Janne, et al. (författare)
  • Factors associated with multiple medication use in different age groups
  • 2009
  • Ingår i: The Annals of Pharmacotherapy. - 1060-0280 .- 1542-6270. ; 43:12, s. 1978-1985
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Multiple medicine use among elderly persons is likely to be the result of treatment regimens developed over a long period of time. By learning more about how multiple medication use develops, the quality of prescribing may be improved across the adult lifespan. OBJECTIVE: To describe patterns of multiple medicine use in the general Swedish population and its association with sociodemographic, lifestyle, and health status factors. METHODS: Data from a cross-sectional population health survey collected during 2001-2005 from 2816 randomly selected Swedish residents (age 30-75 y; response rate 76%) were analyzed. Multiple medicine use was restricted to prescription drugs and defined as the 75th percentile; that is, the 25% of the study group using the highest number of drugs per individual. RESULTS: Seventy-one percent of the respondents used some kind of drug, 51.5% used one or more prescription drug, 38.4% used one or more over-the-counter (OTC) medication, and 8.3% used one or more herbal preparation. The cutoff amounts defining multiple medicine use were: 2 or more medications for 30- to 49-year-olds, 3 or more for 50- to 64-year-olds, and 5 or more for 65- to 75-year-olds. No association between use of multiple medicines and use of OTC drugs or herbal preparations was found. When drugs were classified into therapeutic subgroups, 76.3% of those aged 30-49 years, 97.9% of those aged 50-64 years, and 100% of those aged 65-75 years were taking a unique combination of drugs. Multivariate analyses showed that diabetes and poor self-rated health were associated with multiple medicine use in all age cohorts. Female sex and hypertension were associated with multiple medicine use among those aged 30-49 and 50-64 years, current smoking among those aged 50-64 years, and obesity among those aged 65-75 years. CONCLUSIONS: Multiple medicine use was associated with morbidity and poor self-rated health across all age groups. The vast majority of users of multiple drugs are taking a unique combination of medications.
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42.
  • Moen, Janne, 1980-, et al. (författare)
  • Multiple medicine use: factors of importance in different age groups
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • BACKGROUND: Multiple medicine use among elderly persons is likely to be the result of treatment regimens developed over a long time. By learning more about this development, it might be possible to increase quality in management of multiple medicine use across the adult lifespan. OBJECTIVE: To describe patterns of multiple medicine use in a general population in association with sociodemographic factors, lifestyle, and health status. METHODS: Data from a cross-sectional population health survey collected during 2001-2005 in 2,816 randomly selected Swedish residents (age 30-75 years; response rate 76%). Multiple medicine use was defined as the upper quartile in each age cohort. RESULTS: The cut-offs defining multiple medicine use were: ≥2 for 30-49 year olds, ≥3 for 50-64 year olds, and ≥5 for 65-75 year olds. When drugs were classified into the second level of the ATC code, 76.3% of the 30-49 year olds, 97.9% of the 50-64 year olds, and 100% of the 65-75 year olds used a unique combination of drugs. The multivariate analyses showed that diabetes and poor self-rated health were associated with multiple medicine use in all age cohorts. Female gender and hypertension were associated with multiple medicine use among 30-49 and 50-64 year olds, ex-smoking among 50-64 year olds, and obesity among 65-75 year olds. CONCLUSIONS: Different cut-offs should be used in defining multiple medicine use in different age groups. A vast majority of users of multiple medicines have a unique drug combination. Multiple medicine use is associated with morbidity and poor self-rated health across all age groups, suggesting that multiple medicine use is not due to drug over-consumption.
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43.
  • Odeberg, Jacob, et al. (författare)
  • The Asp298 allele of endothelial nitric oxide synthase is a risk factor for myocardial infarction among patients with type 2 diabetes mellitus.
  • 2008
  • Ingår i: BMC cardiovascular disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Given the role of nitric oxide in the vascular system, we aimed to test hypotheses of synergy between the common endothelial nitric oxide synthase (eNOS) Asp298 allele and T2DM in predisposing to acute myocardial infarction (AMI). METHODS: In a population-based patient survey with 403 persons with T2DM and 799 healthy subjects from the population without diabetes or hypertension, we analysed the relation between T2DM, sex and the eNOS Asp298 allele versus the risk for AMI. RESULTS: In an overall analysis, T2DM was a significant independent risk factor for AMI. In patients with T2DM, homozygosity for the eNOS Asp298 allele was a significant risk factor (HR 3.12 [1.49-6.56], p = 0.003), but not in subjects without diabetes or hypertension. Compared to wild-type non-diabetic subjects, all patients with T2DM had a significantly increased risk of AMI regardless of genotype. This risk was however markedly higher in patients with T2DM homozygous for the Asp298 allele (HR 7.20 [3.01-17.20], p < 0.001), independent of sex, BMI, systolic blood pressure, serum triglycerides, HDL -cholesterol, current smoking, and leisure time physical activity. The pattern seemed stronger in women than in men. CONCLUSION: We show here a strong independent association between eNOS genotype and AMI in patients with T2DM. This suggests a synergistic effect of the eNOS Asp298 allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM.
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44.
  • Olausson, Josefin, 1983, et al. (författare)
  • Endothelin-1 as a predictor of impaired glucose tolerance and type 2 diabetes - A longitudinal study in the Vara-Skovde Cohort
  • 2016
  • Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227 .- 1872-8227. ; 113, s. 33-37
  • Tidskriftsartikel (refereegranskat)abstract
    • We addressed whether endothelin-1, a marker of endothelial dysfunction, predicts impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in a population study in south-western Sweden. Follow-up after 9.7 years showed an association between circulating endothelin-1 levels at baseline and development of IGT/T2DM in women but not in men.
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45.
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46.
  • Rolny, Charlotte, et al. (författare)
  • HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PIGF
  • 2011
  • Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 19:1, s. 31-44
  • Tidskriftsartikel (refereegranskat)abstract
    • Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HAG relies substantially on downregulation of placental growth factor (PIGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PIGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.
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47.
  • Siddiqui, Faiza, et al. (författare)
  • The Effect of Family History of Diabetes and Middle Eastern Background on Abdominal Obesity is Modified by Gender: A Population based Cross-Sectional Study
  • 2018
  • Ingår i: Current Research in Diabetes & Obesity Journal (CRDOJ). - 2476-1435. ; 6:1, s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Abdominal obesity is on the increase worldwide and ethnic minority groups are at high risk. However, studies of the underlying causes are scarce. The aims of this study were to investigate the prevalence of abdominal obesity and to identify metabolic, lifestyle and socio-demographic risk factors associated with abdominal obesity in male and female residents of Malmö, a city in southern Sweden, comparing those born in Iraq with those born in Sweden.Method: We conducted a population-based, cross-sectional study from 2010 to 2012. Both male and female residents of Malmö, aged 30-75 years, born in Iraq (n=1387) or Sweden (n=749), underwent a physical examination. Fasting blood samples were drawn and socio-demography and lifestyle were characterized using questionnaires. Associations with abdominal obesity were assessed by logistic regression analysis.Results: Abdominal obesity (waist circumference ≥80 cm in women and ≥94 cm in men) was highly prevalent and was most common in Iraqi-born women (Iraqi-born women 89.2% vs. Swedish women 73.1%, p<0.001, Iraqi-born men 70.2% vs. Swedish men 63.6%, p<0.003). Furthermore, family history of diabetes was more prevalent in participants born in Iraq than those born in Sweden (53.6% vs.28.5%, p<0.001). Based on the total study population, female gender, Middle Eastern background, family history of diabetes and depression conveyed higher odds of abdominal obesity. Family history of diabetes and Middle Eastern origin conveyed higher odds of abdominal obesity in females than in males (Pinteraction: Female gender*Family history=0.023; Pinteraction: Female gender*Middle Eastern origin =0.011).Conclusion: Abdominal obesity is highly prevalent irrespective of Middle Eastern or Caucasian background but most prevalent in Iraqi-born women. Our findings suggest that factors related to heritage such as genetics and traditional lifestyles, influence excess risk in Middle Eastern females in particular, which should be taken into consideration when planning preventive actions.Keywords: Abdominal obesity; Migration; Middle East; Family history of diabetes; GenderAbbreviations: BMI: Body Mass Index; CVD: Cardiovascular Disease; FPG: Fasting Plasma Glucose; HAD scale: Hospital Anxiety and Depression Scale; IDF: International Diabetes Federation; OGTT: Oral Glucose Tolerance Test; PA: Physical Activity; The MEDIM study: The Impact of Migration and Ethnicity on Diabetes in Malmö; T2D: Type 2 Diabetes; WHO: World Health Organization
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48.
  • Tjomsland, Vegard, et al. (författare)
  • The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma
  • 2011
  • Ingår i: Clinical & Developmental Immunology. - : Hindawi Publishing Corporation. - 1740-2522 .- 1740-2530. ; 2011:212810
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGF beta, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.
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49.
  • van de Luitgaarden, Inge A T, et al. (författare)
  • Alcohol consumption in relation to cardiovascular diseases and mortality : a systematic review of Mendelian randomization studies
  • 2022
  • Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 37:7, s. 655-669
  • Forskningsöversikt (refereegranskat)abstract
    • The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.
  •  
50.
  • van der Laan, Sander W., et al. (författare)
  • Cystatin C and Cardiovascular Disease : A Mendelian Randomization Study
  • 2016
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:9, s. 934-945
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
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