| 1. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
|
|
| 2. |
- Emerging Risk Factors, Collaboration, et al.
(författare)
-
The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases
- 2007
-
Ingår i: Eur J Epidemiol. - 0393-2990. ; 22:12, s. 839-69
-
Tidskriftsartikel (refereegranskat)abstract
- Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
|
|
| 3. |
- Kaptoge, S., et al.
(författare)
-
World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions
- 2019
-
Ingår i: Lancet Global Health. - : Elsevier BV. - 2214-109X. ; 7:10
-
Tidskriftsartikel (refereegranskat)abstract
- Background To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. Methods In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. Findings Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0.685 (95% CI 0 . 629-0 741) to 0.833 (0 . 783-0- 882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. Interpretation We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
|
|
| 4. |
- Jaworek, T., et al.
(författare)
-
Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
- 2022
-
Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
|
|
| 5. |
- Hageman, S., et al.
(författare)
-
SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe
- 2021
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 42:25, s. 2439-2454
-
Tidskriftsartikel (refereegranskat)abstract
- Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe. Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Lumbers, R. T., et al.
(författare)
-
The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
-
Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
-
Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
|
|
| 9. |
- Gregson, J., et al.
(författare)
-
Cardiovascular Risk Factors Associated With Venous Thromboembolism
- 2019
-
Ingår i: JAMA Cardiology. - : American Medical Association (AMA). - 0965-2590 .- 2380-6583 .- 2380-6591. ; 4:2, s. 163-173
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE Older age, smoking, and adiposity were consistently associated with higher VTE risk.
|
|
| 10. |
- Carninci, P, et al.
(författare)
-
The transcriptional landscape of the mammalian genome
- 2005
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
-
Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
|
|
| 11. |
- Eicher, John D., et al.
(författare)
-
Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
- 2016
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 40-55
-
Tidskriftsartikel (refereegranskat)abstract
- Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
|
|
| 12. |
- Munch, Marie W., et al.
(författare)
-
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
-
Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
-
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.
|
|
| 13. |
- Patel, Riyaz S., et al.
(författare)
-
Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
-
Ingår i: Circulation. - 2574-8300. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
|
|
| 14. |
|
|
| 15. |
- Bournias-Varotsis, A., et al.
(författare)
-
Selectively anodised aluminium foils as an insulating layer for embedding electronic circuitry in a metal matrix via ultrasonic additive manufacturing
- 2016
-
Ingår i: Solid Freeform Fabrication 2016. - : Laboratory for Freeform Fabrication. ; , s. 2260-2270
-
Konferensbidrag (refereegranskat)abstract
- Ultrasonic Additive Manufacturing (UAM) is a hybrid Additive Manufacturing (AM) process that involves layer-by-layer ultrasonic welding of metal foils and periodic machining to achieve the desired shape. Prior investigative research has demonstrated the potential of UAM for the embedding of electronic circuits inside a metal matrix. In this paper, a new approach for the fabrication of an insulating layer between an aluminium (Al) matrix and embedded electronic interconnections is presented. First, an Anodic Aluminium Oxide (AAO) layer is selectively grown onto the surface of Al foils prior to bonding. The pre-treated foils are then welded onto a UAM fabricated aluminium substrate. The bonding step can be repeated for the full encapsulation of the electronic interconnections or components. This ceramic AAO insulating layer provides several advantages over the alternative organic materials used in previous works.
|
|
| 16. |
- Engstrom, P.E., et al.
(författare)
-
Electrically mediated drug delivery for treatment of an adenocarcinoma transplanted into rat liver
- 2001
-
Ingår i: Anticancer research. - 1791-7530. ; 21:3B, s. 1817-1822
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In this study, electrochemotherapy (ECT), i.e. tumour treatment based on local augmentation of intracellular drug delivery from short, intense electric pulses, was evaluated in rats with an adenocarcinoma implanted into the liver. Tumour response and concentrations of macrophages and T-lymphocytes (CD4 and CD8) in and around the tumour were measured.MATERIALS AND METHODS: Rats were treated with permeabilizing electric pulses, bleomycin, or both, eight days after implantation of the tumour, while one group received sham treatment.RESULTS: Treatment with electric pulses and bleomycin resulted in a significantly reduced lesion volume and 92% cure rate (12 out of 13, p<0.0002 compared to the other treatment groups). The highest concentration of CD8 lymphocytes was found in tumours treated with electric pulses and bleomycin. Macrophages were found mainly in tumours treated with electric pulses, with or without bleomycin.CONCLUSION: Electrochemotherapy using millisecond exponential pulses and bleomycin is efficient in a rat liver tumour model and appears to stimulate the host's immune system.
|
|
| 17. |
|
|
| 18. |
- Heathcote, A. J., et al.
(författare)
-
Diatom floristic change and lake paleoproduction as evidence of recent eutrophication in shallow lakes of the midwestern USA
- 2015
-
Ingår i: Journal of Paleolimnology. - : Springer Netherlands. - 0921-2728 .- 1573-0417. ; 53:1, s. 17-34
-
Tidskriftsartikel (refereegranskat)abstract
- Intensive agricultural practices can dramatically change the landscape, thereby increasing the concentrations and rates at which nutrients are delivered to aquatic ecosystems. In the United States, concerns about accelerating rates of lake eutrophication related to increases in nutrient loading require a method of quantifying ecological changes that have occurred since European settlement. Because the application of traditional quantitative total phosphorus transfer functions in paleolimnology has proven difficult in shallow, hypereutrophic lakes, we used several approaches in this study to assess ecosystem changes associated with eutrophication of 32 natural lakes in the state of Iowa, USA. In addition to traditional transfer function methods, we estimated changes in primary productivity from the flux of biogenic silica (BSi) and organic carbon accumulation rates (OC AR). Additionally, we compared pre-disturbance diatom communities to modern diatom communities, i.e. floristic change, using non-metric multi-dimensional scaling and square chord distance. OC AR and BSi fluxes increased over time and were positively correlated with the time period of agricultural intensification in the region (post-1940). Ninety-one percent of the lakes in this study showed evidence for eutrophication based on geochemical proxies, and 88 % of lakes showed major floristic change in the diatom community. Whereas geochemical indicators showed consistent increases in productivity across most lakes, floristic changes reflected more complex interactions between other environmental drivers. The magnitude of floristic change did not directly correlate to nutrient-driven increases in primary production, but was driven by ecological diatom assembly related to lake depth. Transfer functions consistently perform poorly, especially for shallow lakes, and other techniques that combine geochemistry and diatom ecology are recommended for reconstructions of eutrophication.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Shah, S, et al.
(författare)
-
Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
-
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.
|
|
| 25. |
|
|
| 26. |
- Alexander, Peter, et al.
(författare)
-
Drivers for global agricultural land use change: The nexus of diet, population, yield and bioenergy
- 2015
-
Ingår i: Global Environmental Change. - : Elsevier BV. - 0959-3780. ; 35, s. 138-147
-
Tidskriftsartikel (refereegranskat)abstract
- The nexus of population growth and changing diets has increased the demands placed on agriculture to supply food for human consumption, animal feed and fuel. Rising incomes lead to dietary changes, from staple crops, towards commodities with greater land requirements, e.g. meat and dairy products. Despite yield improvements partially offsetting increases in demand, agricultural land has still been expanding, causing potential harm to ecosystems, e.g. through deforestation. We use country-level panel data (1961-2011) to allocate the land areas used to produce food for human consumption, waste and biofuels, and to attribute the food production area changes to diet, population and yields drivers. The results show that the production of animal products dominates agricultural land use and land use change over the 50-year period, accounting for 65% of land use change. The rate of extensification of animal production was found to have reduced more recently, principally due to the smaller effect of population growth. The area used for bioenergy was shown to be relatively small, but formed a substantial contribution (36%) to net agricultural expansion in the most recent period. Nevertheless, in comparison to dietary shifts in animal products, bioenergy accounted for less than a tenth of the increase in demand for agricultural land. Population expansion has been the largest driver for agricultural land use change, but dietary changes are a significant and growing driver. China was a notable exception, where dietary transitions dominate food consumption changes, due to rapidly rising incomes. This suggests that future dietary changes will become the principal driver for land use change, pointing to the potential need for demand-side measures to regulate agricultural expansion. (C) 2015 Elsevier Ltd. All rights reserved.
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Boork, Magdalena, et al.
(författare)
-
R(e)flect: The reflective teaching material about energy, behaviour and product development
- 2014
-
Ingår i: CSEDU 2014 - Proceedings of the 6th International Conference on Computer Supported Education. - : SCITEPRESS - Science and and Technology Publications. - 9789897580215 ; , s. 336-341
-
Konferensbidrag (refereegranskat)abstract
- R(e)flect is a tangible curriculum kit for students age 10-15 to reflect on energy behaviour and make better informed choices about energy use. Along with web-based material, the kit includes a minicomputer, smart plugs (sensors), and an electricity visualization tool especially designed to be used in the classroom to conduct experiments and measurements, perform project work in product development, and increase the understanding of the kWh concept. The curriculum is closely connected to the new Swedish National curriculum and supplies the teachers with appropriate support for assessment of different skills. The project was initiated in 2011 and a first version of the curriculum was tested and evaluated with students and teachers. The feedback from this trial influenced the second iteration of the kit. The new version will be tested in at least 20 schools during the spring of 2014 and this second phase will continue until 2015. The physical r(e)flect material can be borrowed by teachers free of charge, and the web-based platform is open and accessible to anyone.
|
|
| 31. |
- Brunner, Fabian J., et al.
(författare)
-
Application of non-HDL cholesterol for population-based cardiovascular risk stratification : results from the Multinational Cardiovascular Risk Consortium
- 2019
-
Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 394:10215, s. 2173-2183
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
- Cristiani, R, et al.
(författare)
-
Medial Meniscus Resection Increases and Medial Meniscus Repair Preserves Anterior Knee Laxity: A Cohort Study of 4497 Patients With Primary Anterior Cruciate Ligament Reconstruction
- 2018
-
Ingår i: The American journal of sports medicine. - : SAGE Publications. - 1552-3365 .- 0363-5465. ; 46:2, s. 357-362
-
Tidskriftsartikel (refereegranskat)abstract
- There are still controversies regarding the effects on knee laxity of additional meniscus resection or repair in the setting of anterior cruciate ligament reconstruction (ACLR). Hypothesis/Purpose: The purpose was to determine the effects on knee laxity of resection or repair of medial meniscus (MM) or lateral meniscus (LM) injuries in the ACLR knee. The hypothesis was that patients with an additional meniscus resection would have significantly increased postoperative knee laxity versus that of an isolated ACLR, whereas patients with meniscus repair would have laxity comparable to that of an isolated ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: The KT-1000 arthrometer, with an anterior tibial load of 134 N, was used to evaluate knee laxity preoperatively and at 6-month postoperative follow-up for a total of 4497 patients with primary hamstring tendon ACLR. Patients with isolated ACLR or ACLR with additional MM resection, MM repair, LM resection, LM repair, or MM plus LM resection were compared, with the isolated ACLR group as a control. Results: All patients showed a significant reduction of knee laxity preoperatively (3.6 ± 3.1 mm) to postoperatively (1.9 ± 2.2 mm) ( P < 0.0001). Patients who had an ACLR with either an MM resection (2.2 ± 2.55 mm) or MM + LM resection (2.35 ± 2.30 mm) showed significant increased postoperative knee laxity versus isolated ACLR (1.74 mm ± 2.11 mm) ( P < 0.05), whereas patients with MM repair (1.69 ± 2.37 mm) did not show significantly different knee laxity when compared with the control group ( P > 0.05). LM resection or repair did not significantly affect knee laxity. Significantly more surgical failures, defined as side-to-side difference >5 mm, were found in the ACLR + MM resection group and the ACLR + MM + LM resection group. Conclusion: In ACLR, additional MM resection increased whereas MM repair preserved knee laxity in comparison with the ACLR knee with intact menisci. Neither LM resection or LM repair showed a significant effect on knee laxity. Surgeons should make every effort to repair the meniscus whenever possible to avoid the residual postoperative laxity present in the meniscus-deficient knee.
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
- Cristiani, R, et al.
(författare)
-
Regarding "Editorial Commentary: Meniscal Repair-Why Bother?"
- 2020
-
Ingår i: Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. - : Elsevier BV. - 1526-3231. ; 36:7, s. 1794-1795
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
- Di Angelantonio, Emanuele, et al.
(författare)
-
Association of Cardiometabolic Multimorbidity With Mortality : The Emerging Risk Factors Collaboration
- 2015
-
Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
- Engstrom, C., et al.
(författare)
-
Design, plasma studies, and ion assisted thin film growth in an unbalanced dual target magnetron sputtering system with a solenoid coil
- 2000
-
Ingår i: Vacuum. - 0042-207X .- 1879-2715. ; 56:2, s. 107-113
-
Tidskriftsartikel (refereegranskat)abstract
- An original design and solution to the problem of magnetic field interactions in a vacuum chamber between two unbalanced magnetron sputtering sources and a solenoid coil serving to increase plasma density in near substrate position, is presented. By changing the solenoid coil current strength and direction, plasma growth conditions in an argon discharge and Ti-magnetron cathodes were found to vary in a broad region. Langmuir probe analysis shows that an increase in the coil current from 0 to 6 A caused plasma and substrate floating potentials to change from -7 to -30 V and from +1 to -10 V, respectively, as well as increasing the ion densities to a biased substrate from 0.2 to 5.2 mA cm-2 for each of the magnetrons. By using a ferro-powder magnetic field model, as well as finite element method analysis, we demonstrate the interference of the three magnetic fields - those of the two magnetrons and the solenoid coil. X-ray diffraction and transmission electron microscopy were used to study the microstructure and morphology of Ti-films grown under different ion bombardment conditions. At low Ar-ion-to-Ti-atom arrival rate ratios, Jion/Jn to approximately 1.5, at the substrate, variations of the ion energy, Eion, from 8 to 70 eV has only a minor effect on the microstructure and film preferred crystallographic orientation, resulting in an open/porous structure with defect-rich grains. At a higher Jion/Jn value of approximately 20, films with a well-defined dense structure were deposited at ion energies of 80 eV. The increase in ion flux also resulted in changes of the Ti film preferred orientation, from an (0 0 0 2) preferred orientation to a mixture of (0 0 0 2) and (1 0 1¯ 1) orientations.
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
|
|
