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2.
  • Patel, Riyaz S., et al. (author)
  • Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
  • 2019
  • In: Circulation. - 2574-8300. ; 12:4
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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  • Patel, Riyaz S., et al. (author)
  • Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
  • 2019
  • In: Circulation. - 2574-8300. ; 12:4
  • Journal article (peer-reviewed)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.
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4.
  • Moëll, Daniel, et al. (author)
  • Large Eddy Simulation and Experimental Analysis of Combustion Dynamics in a Gas Turbine Burner
  • 2019
  • In: Journal of Engineering for Gas Turbines and Power. - : ASME International. - 0742-4795 .- 1528-8919. ; 141:7
  • Journal article (peer-reviewed)abstract
    • Large eddy simulations (LES) and experiments (planar laser-induced fluorescence of the hydroxyl radical (OH-PLIF) and pressure transducer) have been carried out on a gas turbine burner fitted to an atmospheric combustion rig. This burner, from the Siemens SGT-800 gas turbine, is a low NOx, partially premixed burner, where preheat air temperature, flame temperature, and pressure drop across the burner are kept similar to engine full load conditions. The large eddy simulations are based on a flamelet-generated manifold (FGM) approach for representing the chemistry and the Smagorinsky model for subgrid turbulence. The experimental data and simulation data are in good agreement, both in terms of time averaged and time-resolved quantities. From the experiments and LES, three bands of frequencies of pressure fluctuations with high power spectral density are found in the combustion chamber. The first two bands are found to be axial pressure modes, triggered by coherent flow motions from the burner, such as the flame stabilization location and the precessing vortex core (PVC). The third band is found to be a cross flow directional mode interacting with two of the four combustion chamber walls in the square section of the combustion chamber, triggered from general flow motions. This study shows that LES of real gas turbine components is feasible and that the results give important insight into the flow, flame, and acoustic interactions in a specific combustion system.
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5.
  • Moëll, Daniel, et al. (author)
  • Numerical and experimental investigations of the Siemens SGT-800 burner fitted to a water RIG
  • 2017
  • In: Combustion, Fuels and Emissions. - 9780791850848 ; 4A-2017
  • Conference paper (peer-reviewed)abstract
    • DLE (Dry Low Emission) technology is widely used in land based gas turbines due to the increasing demands on low NOx levels. One of the key aspects in DLE combustion is achieving a good fuel and air mixing where the desired flame temperature is achieved without too high levels of combustion instabilities. To experimentally study fuel and air mixing it is convenient to use water along with a tracer instead of air and fuel. In this study fuel and air mixing and flow field inside an industrial gas turbine burner fitted to a water rig has been studied experimentally and numerically. The Reynolds number is approximately 75000 and the amount of fuel tracer is scaled to represent real engine conditions. The fuel concentration in the rig is experimentally visualized using a fluorescing dye in the water passing through the fuel system of the burner and recorded using a laser along with a CCD (Charge Couple Device) camera. The flow and concentration field in the burner is numerically studied using both the scale resolving SAS (Scale Adaptive Simulation) method and the LES (Large Eddy Simulation) method as well as using a traditional two equation URANS (Unsteady Reynolds Average Navier Stokes) approach. The aim of this study is to explore the differences and similarities between the URANS, SAS and LES models when applied to industrial geometries as well as their capabilities to accurately predict relevant features of an industrial burner such as concentration and velocity profiles. Both steady and unsteady RANS along with a standard two equation turbulence model fail to accurately predict the concentration field within the burner, instead they predict a concentration field with too sharp gradients, regions with almost no fuel tracer as well as regions with far too high concentration of the fuel tracer. The SAS and LES approach both predict a more smooth time averaged concentration field with the main difference that the tracer profile predicted by the LES has smoother gradients as compared to the tracer profile predicted by the SAS. The concentration predictions by the SAS model is in reasonable agreement with the measured concentration fields while the agreement for the LES model is excellent. The LES shows stronger fluctuations in velocity over time as compared to both URANS and SAS which is due to the reduced amounts of eddy viscosity in the LES model as compared to both URANS and SAS. This study shows that numerical methods are capable of predicting both velocity and concentration in a gas turbine burner. It is clear that both time and scale resolved methods are required to accurately capture the flow features of this and probably most industrial DLE gas turbine burners.
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  • Abel, I, et al. (author)
  • Overview of the JET results with the ITER-like wall
  • 2013
  • In: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
  • Journal article (peer-reviewed)abstract
    • Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
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8.
  • Adamson, Carly, et al. (author)
  • Dapagliflozin for Heart Failure According to Body Mass Index : The DELIVER Trial.
  • 2022
  • In: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:41, s. 4406-4417
  • Journal article (peer-reviewed)abstract
    • AIMS: Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. METHODS AND RESULTS: Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation +/- 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). CONCLUSIONS: Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.
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  • Adamson, Carly, et al. (author)
  • Efficacy of Dapagliflozin in Heart Failure with Reduced Ejection Fraction According to Body Mass Index.
  • 2021
  • In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:10, s. 1662-1672
  • Journal article (peer-reviewed)abstract
    • AIMS: In heart failure with reduced ejection fraction (HFrEF), there is an ’obesity paradox’, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium-glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse- outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS: Body mass index was examined using standard categories, i.e. underweight ($<$18.5 kg/m(2) ); normal weight (18.5-24.9 kg/m(2) ); overweight (25.0-29.9 kg/m(2) ); obesity class I (30.0-34.9 kg/m(2) ); obesity class II (35.0-39.9 kg/m(2) ); and obesity class III ($>$/=40 kg/m(2) ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal- weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) kg (P $<$ 0.001). CONCLUSION: We confirmed an ’obesity survival paradox’ in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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  • Adamson, Carly, et al. (author)
  • IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction : Findings From DAPA-HF.
  • 2023
  • In: JACC. Heart failure. - : Elsevier BV. - 2213-1779 .- 2213-1787. ; 11:3, s. 291-304
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. OBJECTIVES: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. METHODS: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B- type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. RESULTS: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). CONCLUSIONS: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
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  • Adamson, Carly, et al. (author)
  • Liver Tests and Outcomes in Heart Failure with Reduced Ejection Fraction : Findings from DAPA-HF.
  • 2022
  • In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1856-1868
  • Journal article (peer-reviewed)abstract
    • AIMS: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium- glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. METHODS AND RESULTS: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end-of-study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT-proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37-2.17], p $<$ 0.001; and 1.52 [1.12-2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow-up, dapagliflozin had no effect on liver tests. CONCLUSION: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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  • Andersson, Urban, 1965, et al. (author)
  • Författaridentifikatorer och publiceringsdatabaser – scenarier och utvecklingsmöjligheter
  • 2013
  • Reports (other academic/artistic)abstract
    • Syftet med projektet är att ge underlag för att införa författaridentifikatorer i svenska tjänster och system inom vetenskaplig kommunikation. ORCID (Open Researcher and Contributor ID) är en internationell de-facto standard under uppbyggnad med många viktiga aktörer involverade. Implementering av ORCID kräver samverkan mellan flera aktörer, både nationellt och på lärosätena. Projektgruppen lämnar ett antal rekommendationer baserade på de uppgifter som redovisas i rapporten.
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  • Ariöz, Candan, 1983-, et al. (author)
  • Heterologous overexpression of a monotopic glucosyltransferase (MGS) induces fatty acid remodeling in Escherichia coli membranes :
  • 2014
  • In: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736 .- 1879-2642. ; 1838:7, s. 1862-1870
  • Journal article (peer-reviewed)abstract
    • The membrane protein monoglucosyldiacylglycerol synthase (MGS) from Acholeplasma laidlawii is responsible for the creation of intracellular membranes when overexpressed in Escherichia coli (E. coli). The present study investigates time dependent changes in composition and properties of E. coli membranes during 22 h of MGS induction. The lipid/protein ratio increased by 38% in MGS-expressing cells compared to control cells. Time-dependent screening of lipids during this period indicated differences in fatty acid modeling. (1) Unsaturation levels remained constant for MGS cells (~ 62%) but significantly decreased in control cells (from 61% to 36%). (2) Cyclopropanated fatty acid content was lower in MGS producing cells while control cells had an increased cyclopropanation activity. Among all lipids, phosphatidylethanolamine (PE) was detected to be the most affected species in terms of cyclopropanation. Higher levels of unsaturation, lowered cyclopropanation levels and decreased transcription of the gene for cyclopropane fatty acid synthase (CFA) all indicate the tendency of the MGS protein to force E. coli membranes to alter its usual fatty acid composition.
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  • Arthur, Frank, et al. (author)
  • The impact of volcanism on Scandinavian climate and human societies during the Holocene: Insights into the Fimbulwinter eruptions (536/540 AD)
  • 2024
  • In: The Holocene. - 0959-6836 .- 1477-0911.
  • Journal article (peer-reviewed)abstract
    • Recent paleoclimatic research has revealed that volcanic events around 536–540 AD caused severe, short-term global cooling. For this same period, archeological research from various regions evidences significant cultural transformation. However, there is still a lack of understanding of how human societies responded and adapted to extreme climate variability and new circumstances. This study focuses on the effects of the 536/540 AD volcanic event in four Scandinavian regions by exploring the shift in demographic and land use intensity before, during, and after this abrupt climate cooling. To achieve this, we performed climate simulations with and without volcanic eruptions using a dynamically downscaled climate model (iLOVECLIM) at a high resolution (0.25° or ~25 km). We integrated the findings with a comprehensive collection of radiocarbon dates from excavated archeological sites across various Scandinavian regions. Our Earth System Model simulates pronounced cooling (maximum ensemble mean −1.1°C), an abrupt reduction in precipitation, and a particularly acute drop in growing degree days (GDD0) after the volcanic event, which can be used to infer likely impacts on agricultural productivity. When compared to the archeological record, we see considerable regional diversity in the societal response to this sudden environmental event. As a result, this study provides a more comprehensive insight into the demographic chronology of Scandinavia and a deeper understanding of the land-use practices its societies depended on during the 536/540 AD event. Our results suggest that this abrupt climate anomaly amplified a social change already in progress.
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  • Berg, David D., et al. (author)
  • Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction : An Analysis of the DAPA-HF Trial.
  • 2022
  • In: Circulation. ; 145:3, s. 158-169
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. METHODS: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction $<$/=40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. RESULTS: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a $>$/=10% relative increase or decrease in hsTnT concentrations, and 43.5% had a $>$/=20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076). CONCLUSIONS: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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  • Bhatt, Ankeet S., et al. (author)
  • Operational Challenges and Mitigation Measures during the COVID-19 Pandemic-Lessons from DELIVER.
  • 2023
  • In: American heart journal. ; 263, s. 133-140
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real- world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. METHODS: We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. CONCLUSION: Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. CLINICALTRIAL: gov: NCT03619213. CLINICALTRIAL: GOV: NCT03619213.
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  • Borg, Sabina, et al. (author)
  • Factors associated with non-attendance at exercise-based cardiac rehabilitation
  • 2019
  • In: BMC Sports Science, Medicine and Rehabilitation. - : BMC. - 2052-1847. ; 11
  • Journal article (peer-reviewed)abstract
    • BackgroundDespite its well-established positive effects, exercise-based cardiac rehabilitation (exCR) is underused in patients following an acute myocardial infarction (AMI). The aim of the study was to identify factors associated with non-attendance at exCR in patients post-AMI in a large Swedish cohort.MethodsA total of 31,297 patients who have suffered an AMI, mean age 62.4 ± 4 years, were included from the SWEDEHEART registry during the years 2010–2016. Comparisons between attenders and non-attenders at exCR were done at baseline for the following variables: age, sex, body mass index, occupational status, smoking, previous diseases, type of index cardiac event and intervention, and left ventricular function. Distance of residence from the hospital and type of hospital were added as structural variables in logistic regression analyses, with non-attendance at exCR at one-year follow-up as dependent, and with individual and structural variables as independent variables.ResultsIn total, 16,214 (52%) of the patients did not attend exCR. The strongest predictor for non-attendance was distance to the exCR centre (OR 1.75 [95% CI: 1.64–1.86]). Other predictors for non-attendance included smoking, history of stroke, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), AMI or diabetes, male sex, being retired vs. being employed, and being followed-up at a county hospital. Patients with ST-elevation myocardial infarction (STEMI) and those intervened with PCI or CABG were more likely to attend exCR.ConclusionsA distance greater than 16 km was associated with increased probability of non-attendance at exCR, as were smoking, a higher burden of comorbidities, and male sex. A better understanding of individual and structural factors can support the development of future rehabilitation services.
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20.
  • Buccheri, Sergio, et al. (author)
  • Assessing the Nationwide Impact of a Registry-Based Randomized Clinical Trial on Cardiovascular Practice The TASTE Trial in Perspective
  • 2019
  • In: Circulation. Cardiovascular Interventions. - : Lippincott Williams & Wilkins. - 1941-7640 .- 1941-7632. ; 12:3
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Registry-based randomized clinical trials have emerged as useful tools to provide evidence on the comparative efficacy and safety of different therapeutic strategies. However, it remains unknown whether the results of registry-based randomized clinical trials have a sizable impact on daily clinical practice. We sought, therefore, to describe the temporal trends in thrombus aspiration (TA) use in Sweden before, during, and after dissemination of the TASTE trial (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) results.METHODS AND RESULTS: From January 1, 2006, to December 31, 2017, we included all consecutive patients with ST-segment-elevation myocardial infarction undergoing percutaneous revascularization in Sweden. All patients were registered in the Swedish Coronary Angiography and Angioplasty Registry. A total of 55 809 ST-segment-elevation myocardial infarction patients were included. TA use in Sweden substantially decreased after dissemination of TASTE results (from 39.8% to 11.8% during and after TASTE, respectively). Substantial variability in TA use across treating centers was observed before TASTE (TA use ranging from 0% to 70%), but after TASTE both the interhospital variability and the frequency of TA use were markedly reduced. A constant shift in medical practice was seen about 4 months after dissemination of the TASTE trial results. Time trends for all-cause mortality and definite stent thrombosis at 30 days were not associated with variations in TA use (P values >0.05 using the Granger test).CONCLUSIONS: In Sweden, the results of the TASTE trial were impactful in daily clinical practice and led to a relevant decrease in TA use in ST-segment-elevation myocardial infarction patients undergoing percutaneous revascularization.
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21.
  • Buccheri, Sergio, et al. (author)
  • Bioabsorbable polymer everolimus-eluting stents in patients with acute myocardial infarction : A report from the Swedish Coronary Angiography and Angioplasty Registry
  • 2018
  • In: EuroIntervention. - 1774-024X .- 1969-6213. ; 14:5, s. 562-569
  • Journal article (peer-reviewed)abstract
    • Aims: The clinical performance of the SYNERGY drug-eluting stent (DES) in patients with acute myocardial infarction (MI) has not been investigated in detail. We sought to report on the outcomes after SYNERGY DES (Boston Scientific, Marlborough, MA, USA) implantation in patients with MI undergoing percutaneous revascularisation (PCI). Methods and results: We included all consecutive patients with MI undergoing PCI with the SYNERGY DES and newer-generation DES (n-DES group) in Sweden. From March 2013 to September 2016, a total of 36,292 patients, of whom 39.7% presented with ST-elevation MI, were included. As compared to patients in the n-DES group (n=31,403), patients in the SYNERGY group (n=4,889) were older and presented more often with left main or three-vessel disease involvement, as well as with restenotic lesions (p<0.001 for all parameters). The Kaplan-Meier estimates of ST at two years in the SYNERGY and n-DES groups were 0.69% and 0.81%, respectively (adjusted HR 1.00, 95% CI: 0.69-1.46; p=0.99). Clinically relevant restenosis was encountered in 1.48% and 1.25% of patients in the SYNERGY and n-DES groups, respectively (adjusted HR 1.05, 95% CI: 0.81-1.37; p=0.72). No differences in the risk of all-cause death and recurrent MI were found between the two groups after adjustment (adjusted HR 1.12, 95% CI: 0.98-1.28; p=0.10, and adjusted HR 0.95, 95% CI: 0.82-1.10; p=0.49, respectively). Conclusions: In a large and unselected cohort of patients with MI undergoing percutaneous revascularisation with the SYNERGY DES, stent performance and clinical outcomes did not differ compared with other n-DES up to two years.
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22.
  • Buccheri, Sergio, et al. (author)
  • Clinical and angiographic outcomes of bioabsorbable vs. permanent polymer drug-eluting stents in Sweden : a report from the Swedish Coronary and Angioplasty Registry (SCAAR)
  • 2019
  • In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 40:31, s. 2607-2615
  • Journal article (peer-reviewed)abstract
    • AIMS: Randomized clinical trials have consistently demonstrated the non-inferiority of bioabsorbable polymer drug-eluting stents (BP-DES) with respect to DES having permanent polymers (PP-DES). To date, the comparative performance of BP- and PP-DES in the real world has not been extensively investigated.METHODS AND RESULTS: From October 2011 to June 2016, we analysed the outcomes associated with newer generation DES use in Sweden. After stratification according to the type of DES received at the index procedure, a total of 16 504 and 79 106 stents were included in the BP- and PP-DES groups, respectively. The Kaplan-Meier estimates for restenosis at 2 years were 1.2% and 1.4% in BP- and PP-DES groups, respectively. Definite stent thrombosis (ST) was low in both groups (0.5% and 0.7% in BP- and PP-DES groups, respectively). The adjusted hazard ratio (HR) for either restenosis or definite ST did not differ between BP- and PP-DES [adjusted HR 0.95, 95% confidence interval (CI) 0.74-1.21; P = 0.670 and adjusted HR 0.79, 95% CI 0.57-1.09; P = 0.151, respectively]. Similarly, there were no differences in the adjusted risk of all-cause death and myocardial infarction (MI) between the two groups (adjusted HR for all-cause death 1.01, 95% CI 0.82-1.25; P = 0.918 and adjusted HR for MI 1.05, 95% CI 0.93-1.19; P = 0.404).CONCLUSION: In a large, nationwide, and unselected cohort of patients, percutaneous coronary intervention with BP-DES implantation was not associated with an incremental clinical benefit over PP-DES use at 2 years follow-up.
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23.
  • Butt, Jawad H., et al. (author)
  • Atrial Fibrillation and Dapagliflozin Efficacy in Patients With Preserved or Mildly Reduced Ejection Fraction.
  • 2022
  • In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:18, s. 1705-1717
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy. OBJECTIVES: This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial. METHODS: A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction $>$40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF. RESULTS: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P $<$ 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ- TSS. CONCLUSIONS: In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213).
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24.
  • Butt, Jawad H., et al. (author)
  • Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction : A Post Hoc Analysis of the DAPA- HF Trial.
  • 2022
  • In: Annals of internal medicine. ; 175:6, s. 820-830
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. OBJECTIVE: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA- HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DESIGN: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124). SETTING: 410 sites in 20 countries. PATIENTS: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. INTERVENTION: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MEASUREMENTS: The primary outcome was worsening HF or cardiovascular death. RESULTS: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI $<$/=0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI $>$/=0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. LIMITATION: Enrollment criteria precluded the inclusion of very high-risk patients. CONCLUSION: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. PRIMARY FUNDING SOURCE: AstraZeneca.
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25.
  • Butt, Jawad H., et al. (author)
  • Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure : A Prespecified Analysis of the DELIVER Trial.
  • 2022
  • In: Circulation. ; 146:16, s. 1210-1224
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). METHODS: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. RESULTS: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI $<$/=0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI $>$/=0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P$<$0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. CONCLUSIONS: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03619213.
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26.
  • Butt, Jawad H., et al. (author)
  • Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide : Insights From the DAPA-HF Trial.
  • 2021
  • In: Circulation. Heart failure. ; 14:12
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT- proBNP. METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction $<$/=40% and a NT-proBNP level $>$/=600 pg/mL ($>$/=600 ng/L; $>$/=400 pg/mL if hospitalized for HF within the previous 12 months or $>$/=900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement ($>$/=5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration $>$/=5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
  •  
27.
  • Butt, Jawad H., et al. (author)
  • Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction : A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
  • 2021
  • In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 6:6, s. 678-689
  • Journal article (peer-reviewed)abstract
    • Importance: Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men. Objective: To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Design, Setting, and Participants: Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B- type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Results: A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of $>$/=5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of $>$/=5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women. Conclusions and Relevance: Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
  •  
28.
  • Conroy-Beam, Daniel, et al. (author)
  • Assortative mating and the evolution of desirability covariation
  • 2019
  • In: Evolution and human behavior. - : Elsevier. - 1090-5138 .- 1879-0607. ; 40:5, s. 479-491
  • Journal article (peer-reviewed)abstract
    • Mate choice lies dose to differential reproduction, the engine of evolution. Patterns of mate choice consequently have power to direct the course of evolution. Here we provide evidence suggesting one pattern of human mate choice-the tendency for mates to be similar in overall desirability-caused the evolution of a structure of correlations that we call the d factor. We use agent-based models to demonstrate that assortative mating causes the evolution of a positive manifold of desirability, d, such that an individual who is desirable as a mate along any one dimension tends to be desirable across all other dimensions. Further, we use a large cross-cultural sample with n = 14,478 from 45 countries around the world to show that this d-factor emerges in human samples, is a cross-cultural universal, and is patterned in a way consistent with an evolutionary history of assortative mating. Our results suggest that assortative mating can explain the evolution of a broad structure of human trait covariation.
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29.
  • Conroy-Beam, Daniel, et al. (author)
  • Contrasting Computational Models of Mate Preference Integration Across 45 Countries
  • 2019
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
  • Journal article (peer-reviewed)abstract
    • Humans express a wide array of ideal mate preferences. Around the world, people desire romantic partners who are intelligent, healthy, kind, physically attractive, wealthy, and more. In order for these ideal preferences to guide the choice of actual romantic partners, human mating psychology must possess a means to integrate information across these many preference dimensions into summaries of the overall mate value of their potential mates. Here we explore the computational design of this mate preference integration process using a large sample of n = 14,487 people from 45 countries around the world. We combine this large cross-cultural sample with agent-based models to compare eight hypothesized models of human mating markets. Across cultures, people higher in mate value appear to experience greater power of choice on the mating market in that they set higher ideal standards, better fulfill their preferences in choice, and pair with higher mate value partners. Furthermore, we find that this cross-culturally universal pattern of mate choice is most consistent with a Euclidean model of mate preference integration.
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30.
  • Crona, Joakim, et al. (author)
  • Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids
  • 2013
  • In: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 98:2, s. 151-155
  • Journal article (peer-reviewed)abstract
    • Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with tennozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11(52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxcities grade 3-4 were noted in 4 patients, thrombocytopenia (n =3) and leukopenia (n = 1). Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining tennozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients. Copyright (C) 2013 S. Karger AG, Basel
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31.
  • Cunningham, Jonathan W., et al. (author)
  • Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.
  • 2022
  • In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:14, s. 1302-1310
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. OBJECTIVES: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. METHODS: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF $>$40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. RESULTS: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P $<$ 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. CONCLUSIONS: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
  •  
32.
  • Derlén, Mattias, 1976-, et al. (author)
  • You’re Gonna Miss Me When I’m Gone! : The Impact of Brexit on Member States’ Contribution to the Case Law of the CJEU
  • 2019
  • In: Europarättslig tidskrift. - Stockholm : Europarättslig Tidskrift. - 1403-8722 .- 2002-3561. ; :3, s. 381-395
  • Journal article (peer-reviewed)abstract
    • Brexit is scheduled to happen on October 31, 2019, and researchers have previously studied the impact of Brexit on relationships in the EU’s political institutions. This paper studies how Brexit might affect Member States’ interactions with the Court of Justice of the European Union (CJEU) and, more specifically, when they seek to influence the Court by submitting observations. The Untied Kingdom has consistently been a comparatively active Member State, submitting many observations. The paper introduces and employs a novel approach, studying what we call "mentions" in CJEU decisions, to measure position similarity in Member States' observations and to identify the UK's "allies" before the CJEU. The paper concludes the loss of the UK will be felt in particular in Germany, the Netherlands, Ireland and in the Nordic countries. 
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33.
  • Dewan, Pooja, et al. (author)
  • Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease : An Analysis of DAPA-HF.
  • 2021
  • In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:4, s. 632-643
  • Journal article (peer-reviewed)abstract
    • AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. METHODS AND RESULTS: We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N-terminal pro B-type natriuretic peptide, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0-22.2) vs. 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21-1.72); P $<$ 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48-0.93)] and without COPD [0.76 (0.65-0.87); interaction P-value 0.47]. CONCLUSIONS: In DAPA-HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre-specified outcomes was consistent in patients with and without COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03036124.
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34.
  • Docherty, Kieran F., et al. (author)
  • Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.
  • 2022
  • In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:2, s. 104-118
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: The authors sought to examine the effect of dapagliflozin across the spectrum of risk in patients enrolled in DAPA-HF. BACKGROUND: In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction. METHODS: The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) and the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure) risk models were used to categorize patients according to risk score quintiles. The authors analyzed rates of the primary composite outcome of a worsening HF event or cardiovascular death, its components, and all-cause mortality according to risk quintile and whether risk modified the effect of dapagliflozin. RESULTS: The MAGGIC score was available for 4,740 of 4,744 patients in DAPA-HF (median score 22 [IQR: 18-25]). A1-point increase was associated with an 8.2% (95% CI: 6.9%-9.4%) higher relative risk of the primary endpoint (P $<$ 0.001). The benefit of dapagliflozin over placebo for the primary endpoint was similar across the spectrum of MAGGIC risk score (interaction P = 0.71). Applying the overall relative risk reduction (26%) with dapagliflozin added to standard therapy resulted in 7 fewer patients in the highest MAGGIC risk quintile experiencing a primary outcome, compared with 2 in the lowest quintile, per 100 person-years of treatment. The findings with PREDICT-HF were similar, although this model led to better risk discrimination. CONCLUSIONS: The benefits of dapagliflozin were consistent across the broad spectrum of baseline risk in DAPA-HF.
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35.
  • Docherty, Kieran F., et al. (author)
  • Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction : A Prespecified Analysis of DAPA- HF.
  • 2020
  • In: Circulation. ; 142:17, s. 1623-1632
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events. METHODS: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction
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36.
  • Docherty, Kieran F., et al. (author)
  • Efficacy of Dapagliflozin in Black Versus White Patients With Heart Failure and Reduced Ejection Fraction.
  • 2022
  • In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:1, s. 52-64
  • Journal article (peer-reviewed)abstract
    • OBJECTIVES: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). BACKGROUND: Black patients may respond differently to certain treatments for HFrEF than White patients. METHODS: Patients with New York Heart Association functional class II to IV with an ejection fraction of $<$/=40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because $>$99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. RESULTS: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. CONCLUSIONS: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
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37.
  • Docherty, Kieran F., et al. (author)
  • Iron Deficiency in Heart Failure and Effect of Dapagliflozin : Findings From DAPA-HF.
  • 2022
  • In: Circulation. ; 146:13, s. 980-994
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse- Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline. METHODS: Iron deficiency was defined as a ferritin level $<$100 ng/mL or a transferrin saturation $<$20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. RESULTS: Of the 4744 patients randomized in DAPA- HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P$<$0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron- replete patients (hazard ratio, 0.74 [95% CI, 0.58-0.92] versus 0.81 [95% CI, 0.63-1.03]; P-interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo. CONCLUSIONS: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03036124.
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38.
  • Drevinge, Christina, 1983, et al. (author)
  • Intermediate monocytes correlate with CXCR3(+) Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis
  • 2021
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 16:3
  • Journal article (peer-reviewed)abstract
    • Background Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. Methods 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4(+) helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. Results Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3(+) Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3(+) Th17 cells were associated with bone density or bone microarchitecture measurements. Conclusions Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3(+) Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.
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39.
  • Eriksson, Mikael, et al. (author)
  • Identification of Women at High Risk of Breast Cancer Who Need Supplemental Screening
  • 2020
  • In: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 297:2, s. 327-333
  • Journal article (peer-reviewed)abstract
    • Background Mammography screening reduces breast cancer mortality, but a proportion of breast cancers are missed and are detected at later stages or develop during between-screening intervals. Purpose To develop a risk model based on negative mammograms that identifies women likely to be diagnosed with breast cancer before or at the next screening examination. Materials and Methods This study was based on the prospective screening cohort Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA), 2011-2017. An image-based risk model was developed by using the Stratus method and computer-aided detection mammographic features (density, masses, microcalcifications), differences in the left and right breasts, and age. The lifestyle extended model included menopausal status, family history of breast cancer, body mass index, hormone replacement therapy, and use of tobacco and alcohol. The genetic extended model included a polygenic risk score with 313 single nucleotide polymorphisms. Age-adjusted relative risks and tumor subtype specific risks were estimated by using logistic regression, and absolute risks were calculated. Results Of 70 877 participants in the KARMA cohort, 974 incident cancers were sampled from 9376 healthy women (mean age, 54 years ± 10 [standard deviation]). The area under the receiver operating characteristic curve (AUC) for the image-based model was 0.73 (95% confidence interval [CI]: 0.71, 0.74). The AUCs for the lifestyle and genetic extended models were 0.74 (95% CI: 0.72, 0.75) and 0.77 (95% CI: 0.75, 0.79), respectively. There was a relative eightfold difference in risk between women at high risk and those at general risk. High-risk women were more likely to be diagnosed with stage II cancers and with tumors 20 mm or larger and were less likely to have stage I and estrogen receptor-positive tumors. The image-based model was validated in three external cohorts. Conclusion By combining three mammographic features, differences in the left and right breasts, and optionally lifestyle factors and family history and a polygenic risk score, the model identified women at high likelihood of being diagnosed with breast cancer within 2 years of a negative screening examination and in possible need of supplemental screening.
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40.
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41.
  • Fukaya, Eri, et al. (author)
  • Clinical and Genetic Determinants of Varicose Veins Prospective, Community-Based Study of approximate to 500 000 Individuals
  • 2018
  • In: Circulation. - 0009-7322 .- 1524-4539. ; 138:25, s. 2869-2880
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. METHODS: We applied machine learning to agnostically search for risk factors of varicose veins in 493 519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337 536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. RESULTS: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% Cl, 1.51-2.01; P<0.0001). A genomewide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/ limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse -variance weighted: odds ratio, 1.26; P=2.07x10(-16)). CONCLUSIONS: Using data from nearly a half -million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.
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42.
  • Graham, Angus, 1968-, et al. (author)
  • Theban Harbours and Waterscapes Survey, 2015
  • 2015
  • In: Journal of Egyptian Archaeology. - : SAGE Publications. - 0307-5133 .- 2514-0582. ; 101:1, s. 37-49
  • Journal article (peer-reviewed)abstract
    • Report on the 2015 season of the Theban Harbours and Waterscapes Survey (THaWS). The paper discusses the extension of geoarchaeological and geophysical investigations to the east of the Ramesseum, the continuing work in and around the Temple of Millions of Years of Amenhotep III, and the topographic survey and geophysical survey of the western mounds of the Birket Habu.
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43.
  • Hansen, Tomas, et al. (author)
  • Normal radiological lymph node appearance in the thorax
  • 2019
  • In: Diseases of the esophagus. - : OXFORD UNIV PRESS INC. - 1120-8694 .- 1442-2050. ; 32:10, s. 1-6
  • Journal article (peer-reviewed)abstract
    • Modern treatment of esophageal cancer is multimodal and highly dependent on a detailed diagnostic assessment of clinical stage, which includes nodal stage. Clinical appraisal of nodal stage is highly dependent on knowledge of normal radiological appearance, information of which is scarce. We aimed to describe lymph node appearance on computed tomography (CT) investigations in a randomly selected cohort of healthy subjects. In a sample of the Swedish Cardiopulmonary bioimage study, which investigates a sample of the Swedish population aged 50-64 years, the CT scans of 426 subjects were studied in detail concerning intrathoracic node stations relevant in clinical staging of esophageal cancer. With stratification for sex, the short axis of visible lymph nodes was measured and the distribution of lymph node sizes was calculated as well as proportion of patients with visible nodes above 5 and 10 millimeters for each station. Probability of having any lymph node station above 5 and 10 millimeters was calculated with a logistic regression model adjusted for age and sex. In the 214 men (aged: 57.3 +/- 4.1 years) and 212 women (aged: 57.8 +/- 4.4 years) included in this study, a total of 309 (72.5%) had a lymph node with a short axis of 5 mm or above was seen in at least one of the node stations investigated. When using 10 mm as a cutoff, nodes were visible in 29 (6.81%) of the subjects. Men had higher odds of having any lymph node with short axis 5 mm or above (OR 3.03 95% CI 1.89-4.85, P < 0.001) as well as 10 mm or above (OR 2.31 95% CI 1.02-5.23, P = 0.044) compared to women. Higher age was not associated with propensity for lymph nodes above 5 or 10 millimeters in this sample. We conclude that, in a randomly selected cohort of patients between 50 and 64 years, almost 10% of the men and 4% of the women had lymph nodes above 10 millimeters, most frequently in the subcarinal station (station 107). More than half of the patients had nodes above 5 millimeters on CT and men were much more prone to have this finding. The probability of finding lymph nodes in specific stations relevant of esophageal cancer is now described.
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44.
  • Hatlestad, Kailin (author)
  • Exploring Uncertainty and Significance : Analysing Human Response to Environmental Risk with Computational Archaeology
  • 2024
  • Doctoral thesis (other academic/artistic)abstract
    • As humanity confronts the escalating challenges posed by rapid climate change, it becomes increasingly urgent to understand the complex dynamics of human-environment interactions to mitigate its multifaceted impacts. Archaeology, with its long-term perspective, offers the opportunity to examine past societal responses to environmental risks across diverse locations in Northwestern Europe and temporal scales. This dissertation aims to contribute to this critical endeavour by exploring the socio-environmental dynamics and adaptive strategies of past societies, to inform effective responses to climate change challenges in both the present and future. Utilizing computational archaeology, which integrates digital technologies and computational methods to analyse big data, the dissertation employs probabilistic approaches, including Bayesian modelling like summed probability distributions of radiocarbon (14C) data, to confront uncertainties inherent in reconstructing past human-environmental dynamics from interdisciplinary datasets. Additionally, quantitative methods, such as correlation tests and null hypothesis testing of 14C data, are employed to identify significant shifts in these dynamics, translating insights into quantitative terms for enhanced integration with policy-making processes. The primary objective of the dissertation is to illustrate how the integration of archaeological and environmental big data can enrich the understanding of human responses to environmental challenges. The papers in this thesis demonstrate how computational methods can be applied to big data to understand spatiotemporal changes in human-environmental variables, uncovering risk management strategies and societal vulnerabilities. The papers highlight cases where human communities experienced mitigated adverse effects from severe environmental shifts due to diverse socioeconomic strategies. Simultaneously, the results emphasize regional variations in the impacts of climate change, crucial for understanding the effectiveness of human responses. Moreover, the thesis exhibits how big data analytics both complement and challenge existing archaeological interpretations, contributing to the development of new theories. Importantly, it underscores the significance of diverse socioeconomic strategies in mitigating risks, especially in the face of abrupt environmental events.
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45.
  •  
46.
  • Jackson, Alice M., et al. (author)
  • Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.
  • 2020
  • In: Circulation. - 1524-4539. ; 142:11, s. 1040-1054
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide $<$40, 40, and $>$40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on $<$40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking $>$40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow- up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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47.
  • Jernberg, Tomas, et al. (author)
  • Impact of ischaemic heart disease severity and age on risk of cardiovascular outcome in diabetes patients in Sweden : A nationwide observational study
  • 2019
  • In: BMJ Open. - : BMJ. - 2044-6055. ; 9:4
  • Journal article (peer-reviewed)abstract
    • Objectives To compare short-term cardiovascular (CV) outcome in type 2 diabetes (T2D) patients without ischaemic heart disease (IHD), with IHD but no prior myocardial infarction (MI), and those with prior MI; and assess the impact on risk of age when initiating first-time glucose-lowering drug (GLD). Design Cohort study linking morbidity, mortality and medication data from Swedish national registries. Participants First-time users of GLD during 2007-2016. Outcomes Predicted cumulative incidence for the CV outcome (MI, stroke and CV mortality) was estimated. A Cox model was developed where age at GLD start and CV risk was modelled. Results 260 070 first-time GLD users were included, 221 226 (85%) had no IHD, 16 294 (6%) had stable IHD-prior MI and 22 550 (9%) had IHD+MI. T2D patients without IHD had a lower risk of CV outcome compared with the IHD populations (±prior MI), (3-year incidence 4.78% vs 5.85% and 8.04%). The difference in CV outcome was primarily driven by a relative greater MI risk among the IHD patients. For T2D patients without IHD, an almost linear association between age at start of GLD and relative risk was observed, whereas in IHD patients, the younger (<60 years) patients had a relative greater risk compared with older patients. Conclusions T2D patients without IHD had a lower risk of the CV outcome compared with the T2D populations with IHD, primarily driven by a greater risk of MI. For T2D patients without IHD, an almost linear association between age at start of GLD and relative risk was observed, whereas in IHD patients, the younger patients had a relative greater risk compared with older patients. Our findings suggest that intense risk prevention should be the key strategy in the management of T2D patients, especially for younger patients.
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48.
  • Jhund, Pardeep S., et al. (author)
  • Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure : A Patient-Level, Pooled Meta-Analysis of DAPA-HF and DELIVER.
  • 2022
  • In: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:9, s. 1956-1964
  • Journal article (peer-reviewed)abstract
    • Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction ($<$/=40% and $>$40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82-0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65-0.78; P $<$ 0.001) and MACEs (HR 0.90, 95% CI 0.81-1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient- level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).
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49.
  • Johansson, Åsa, et al. (author)
  • Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome
  • 2016
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:7, s. 1447-1456
  • Journal article (peer-reviewed)abstract
    • N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: ; NCT00391872.
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50.
  • Karpefors, Martin, et al. (author)
  • The Maraca Plot : A Novel Visualization of Hierarchical Composite Endpoints.
  • 2023
  • In: Clinical trials (London, England). - : SAGE Publications. - 1740-7745 .- 1740-7753. ; 20:1, s. 84-88
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Hierarchical composite endpoints are complex endpoints combining outcomes of different types and different clinical importance into an ordinal outcome that prioritizes the clinically most important (e.g. most severe) event of a patient. Hierarchical composite endpoint can be analysed with the win odds, an adaptation of win ratio to include ties. One of the difficulties in interpreting hierarchical composite endpoint is the lack of proper tools for visualizing the treatment effect captured by hierarchical composite endpoint, given the complex nature of the endpoint which combines events of different types. METHODS: Hierarchical composite endpoints usually combine time-to-event outcomes and continuous outcomes into a composite; hence, it is important to capture not only the shift from more severe categories to less severe categories in the active group in comparison to the control group (as in any ordinal endpoint), but also changes occurring within each category. We introduce the novel maraca plot which combines violin plots (with nested box plots) to visualize the density of the distribution of the continuous outcome and Kaplan-Meier plots for time-to-event outcomes into a comprehensive visualization. CONCLUSION: The novel maraca plot is suggested for visualization of hierarchical composite endpoints consisting of several time-to-event outcomes and a continuous outcome. It has a very simple structure and therefore easily communicates both the overall treatment effect and the effect on individual components.
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