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1.	Skelton, Alasdair, et al. (författare) Sveriges utsläpp måste minska nu, regeringen : 531 forskare: Annars är sveket monumentalt – ni kan inte säga att ni inte visste 2023 Ingår i: Aftonbladet. - 1103-9000. Tidskriftsartikel (populärvet., debatt m.m.)
2.	Wahlin, Bengt, et al. (författare) Osteoprotegerin and osteocalcin are associated with atherosclerosis in patients with rheumatoid arthritis : a prospective cohort study 2021 Ingår i: Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 39:6, s. 1402-1409 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES:Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA.METHODS:Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11.RESULTS:In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease.CONCLUSIONS:Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.
3.	Agca, R., et al. (författare) EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update 2017 Ingår i: Ann Rheum Dis. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:1, s. 17-28 Tidskriftsartikel (refereegranskat)abstract Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.
4.	Agca, Rabia, et al. (författare) Response to : "Influence of changes in cholesterol levels and disease activity on the 10-year cardiovascular risk estimated with different algorithms in rheumatoid arthritis patients" by Fornaro et al 2020 Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:9 Tidskriftsartikel (refereegranskat)
5.	Berglund, S, et al. (författare) Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine : a six-year follow-up study 2009 Ingår i: Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 27:5, s. 822-825 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: The aim of this study was to investigate whether homocysteine is linked to atherothrombotic (AT) events in patients with rheumatoid arthritis (RA). METHODS: Analysis of homocysteine (Hcy) levels was carried out in 235 consecutive RA patients. They were followed-up for 6.5 years or until death, with analysis of AT risk factors and the type and length of DMARD and corticosteroid treatment. The disease history before inclusion was collected. Six categories of AT events were defined. In addition, the diagnosis of the patients at follow-up was co-analyzed with the nationwide population-based Swedish Inpatient Register and Death Register to certify all events. RESULTS: The Hcy level was found to be higher in males (p<0.05) and increased with age (p<0.001). Patients with folic acid supplementation had significantly lower levels, while those on corticosteroids had higher levels. High Hcy levels predicted AT events (n=48) during a 6.5-year follow-up adjusted for age and male sex in a logistic regression analysis. CONCLUSION: In this study, RA patients on folic acid had lower Hcy levels. High Hcy levels (in addition to age, sex and diabetes) predicted AT event prospectively.
6.	Bjorsenius, I., et al. (författare) Increased progression of atherosclerosis in patients with rheumatoid arthritis is partially reflected by disease severity at the time of diagnosis : 11-year prospective follow-up 2018 Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis. - 0300-9742 .- 1502-7732. ; 47, s. 20-21 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
7.	Björsenius, I, et al. (författare) Extent of atherosclerosis after 11-year prospective follow-up in patients with early rheumatoid arthritis was affected by disease severity at diagnosis 2020 Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis. - 0300-9742 .- 1502-7732. ; 49:6, s. 443-451 Tidskriftsartikel (refereegranskat)abstract Objective: Cardiovascular disease (CVD) is increased among patients with rheumatoid arthritis (RA). The underlying cause is not clear. In this prospective study, patients with early RA were investigated for associations between subclinical atherosclerosis and CVD risk factors as well as inflammation.Method: At diagnosis, RA patients were recruited into a prospective study. A subgroup was included (n = 55) for ultrasound measurements of intima–media thickness (IMT) at inclusion (T0), and after 5 years (T5) and 11 years (T11). Thirty-one age and gender-matched controls were also included for comparison.Results: IMT increased significantly between T0 and T11 among patients and controls (p < 0.0001). No statistically significant differences in IMT between patients and controls were detected at T11, T5, or T0 (p > 0.05 for all). In simple regression models, IMT at T11 was significantly associated with age (p < 0.0001), as well as systolic blood pressure at T0 (p < 0.01) and T11 (p < 0.01) among RA patients. Furthermore, the composite Systematic COronary Risk Evaluation (SCORE) measurements (p < 0.0001) and Reynolds risk score (p < 0.01) and the radiographic Larsen score (p < 0.05) at T0 were all significantly associated with IMT at T11. Results from conditional logistic regression analysis showed an increased progression rate between T0 and T11 in the RA group compared with controls (p < 0.05).Conclusion: We found increased atherosclerotic development among patients with RA compared with controls 11 years after diagnosis. The atherosclerotic burden was associated with disease severity at baseline.
8.	Boknäs, Niklas, 1979-, et al. (författare) Platelet function testing at low platelet counts : When can you trust your analysis? 2019 Ingår i: Research and Practice in Thrombosis and Haemostasis. - : Wiley-Blackwell. - 2475-0379. ; 3:2, s. 285-290 Tidskriftsartikel (refereegranskat)abstract Background: Although flow cytometry is often brought forward as a preferable method in the setting of thrombocytopenia, the relative effects of low sample counts on results from flow cytometry-based platelet function testing (FC-PFT) in comparison with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) has not been reported.Objectives: To compare the effects of different sample platelet counts (10, 50, 100, and 200x10(9)L(-1)) on platelet activation measured with FC-PFT, LTA, and MEA using the same anticoagulant and agonist concentrations as for the commercial MEA test.Methods: Platelets were stimulated with two commonly used platelet agonists (ADP [6.5 mu molL(-1)] and PAR1-AP [TRAP, 32 mu molL(-1)]). The specified sample platelet counts were obtained by combining platelet-rich and platelet poor hirudinized plasma in different proportions with or without red blood cells.Results: For FC, P-selectin exposure and PAC-1 binding was reduced at 10x10(9)L(-1) after stimulation with PAR1-AP (by approximately 20% and 50%, respectively), but remained relatively unchanged when ADP was used as agonist (n=9). The platelet count-dependent effects observed with PAR1-AP were eliminated when samples were pre-incubated with apyrase, implying that reduced purinergic signaling was the main underlying factor (n=5). Both aggregometry-based PFTs showed a 50% reduction at 50x10(9)L(-1) and more than 80% reduction at 10x10(9)L(-1), irrespective of agonist used (n=7).Conclusions: Although FC-PFT is generally preferable to aggregometry-based PFTs in situations with low sample platelet counts, a careful optimization of experimental parameters is still required in order to eliminate platelet count-related effects.
9.	Erelund, Sofia, et al. (författare) Heart rate variability and cardiovascular risk factors in patients with rheumatoid arthritis : a longitudinal study 2023 Ingår i: Autonomic Neuroscience. - : Elsevier. - 1566-0702 .- 1872-7484. ; 249 Tidskriftsartikel (refereegranskat)abstract Background: It is established that the risk of cardiovascular disease (CVD) is increased in patients with Rheumatoid Arthritis (RA). Heart rate variability (HRV) is a method for evaluating the activity in the cardiac autonomic nervous system. Our aim was to assess the longitudinal development of HRV in patients with RA and compare with healthy controls. Furthermore, we wanted to investigate associations between HRV, inflammatory disease activity and cardiovascular complications in patients with RA over time.Method: HRV was assessed with frequency-domain analysis at baseline and after five years in 50 patients with early RA, all being younger than 60 years. HRV indices were age-adjusted based on the estimated age-dependency in 100 age and sex matched healthy controls. Additionally, clinical data including serological markers, disease activity, and blood pressure were collected from the patients. Eleven years after inclusion CVD was assessed.Results: At baseline, patients with RA presented with lower HRV compared to controls during deep breathing (6 breaths/min), paced normal breathing (12 breaths/min) and after passive tilt to the upright position. No significant change in HRV was observed at the five-year follow-up. A significant negative correlation was found between HRV parameters and systolic blood pressure (SBP) at baseline. A significant positive correlation was found between heart rate and inflammatory markers at baseline but not after five years. Nine patients had developed CVD after 11 years, but no significant association was found with baseline HRV data.Conclusion: This study showed that patients with RA have autonomic imbalance both at an early stage of the disease and after five years, despite anti-rheumatic medication, but no correlation between HRV and inflammation markers were observed. Reduced HRV was also significantly negatively correlated with increased SBP. Hypertension is a common finding in patients with RA. Thus, significant decline of HRV could be a useful early marker for development of hypertension in patients with RA.
10.	Frodlund, Martina, et al. (författare) The impact of immunomodulating treatment on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases compared to healthy controls. : A Swedish nationwide study (COVID19-REUMA) 2023 Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 41:20, s. 3247-3257 Tidskriftsartikel (refereegranskat)abstract Objectives: To elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying anti-rheumatic drugs (b/ts DMARDs).Methods: Antibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2-12 weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or >= 4-fold increase in antibodies in individuals seropositive for both spike proteins.Results: Patients (n = 414) receiving b/ts DMARDs (283 had arthritis, 75 systemic vasculitis and 56 other autoimmune diseases) and controls (n = 61) from five Swedish regions participated. Treatments groups were: rituximab (n = 145); abatacept (n = 22); Interleukin 6 receptor inhibitors [IL6i (n = 79)]; JAnus Kinase Inhibitors [JAKi (n = 58)], Tumour Necrosis Factor inhibitor [TNFi (n = 68)] and Interleukin12/23/17 inhibitors [IL12/23/17i (n = 42)]. Percentage of patients with positive antibody response after two doses was significantly lower in rituximab (33,8%) and abatacept (40,9%) (p < 0,001) but not in IL12/23/17i, TNFi or JAKi groups compared to controls (80,3%). Higher age, ritux-imab treatment and shorter time between last rituximab course and vaccination predicted impaired anti-body response. Antibody levels collected 21-40 weeks after second dose decreased significantly (IL6i: p = 0,02; other groups: p < 0,001) compared to levels at 2-12 week but most participants remained seropositive. Proportion of patients with positive antibody response increased after third dose but was still significantly lower in rituximab (p < 0,001).Conclusions: Older individuals and patients on maintenance rituximab have an impaired response after two doses of COVID-19 vaccine which improves if the time between last rituximab course and vaccina-tion extends and also after an additional vaccine dose. Rituximab patients should be prioritized for (2023) booster vaccine doses. TNFi, JAKi and IL12/23/17i does not diminished humoral response to primary and an additional vaccination.
11.	Frodlund, Martina, et al. (författare) The serological immunogenicity of the third and fourth doses of COVID-19 vaccine in patients with inflammatory rheumatic diseases on different biologic or targeted DMARDs : a Swedish nationwide study (COVID-19-REUMA) 2024 Ingår i: Microbiology Spectrum. - : AMER SOC MICROBIOLOGY. - 2165-0497. ; 12:4 Tidskriftsartikel (refereegranskat)abstract Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or ≥fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases (n = 414), and controls (n = 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab (n = 133), abatacept (n = 22), IL6r inhibitors (n = 71), JAnus Kinase inhibitors (JAK-inhibitors) (n = 56), tumor necrosis factor inhibitor (TNF-inhibitors) (n = 61), IL12/23/17 inhibitors (n = 27), and controls (n = 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) (P < 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses.
12.	Frodlund, Martina, et al. (författare) The serological immunogenicity of the third and fourth doses of COVID-19 vaccine in patients with inflammatory rheumatic diseases on different biologic or targeted DMARDs: a Swedish nationwide study (COVID-19-REUMA) 2024 Ingår i: MICROBIOLOGY SPECTRUM. - : AMER SOC MICROBIOLOGY. - 2165-0497. ; 12:4 Tidskriftsartikel (refereegranskat)abstract Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or >= fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases (n = 414), and controls (n = 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab (n = 133), abatacept (n = 22), IL6r inhibitors (n = 71), JAnus Kinase inhibitors (JAK-inhibitors) (n = 56), tumor necrosis factor inhibitor (TNF-inhibitors) (n = 61), IL12/23/17 inhibitors (n = 27), and controls (n = 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) (P < 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses. IMPORTANCE Results from this study provide further evidence that additional doses of COVID-19 vaccines are immunogenic and result in satisfactory antibody response in a majority of patients with inflammatory rheumatic diseases (IRD) receiving potent immunomodulating treatments such as biological or targeted disease-modifying anti-rheumatic drugs (DMARDs) given as monotherapy or combined with traditional DMARDs. We observed that rituximab treatment, both as monotherapy and combined with csDMARDs, impaired antibody response, and only roughly 50% of patients developed a satisfactory antibody response including response to omicron subvariants after the third vaccine. In addition, higher IgG levels at the last rituximab course before the third vaccine dose and a longer time after the last rituximab treatment increased the chance of a satisfactory antibody response. These results indicate that rituximab-treated patients should be prioritized for additional vaccine doses. CLINICAL TRIALS EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with number 2021-000880-63.
13.	Hofstedt, Oscar E., et al. (författare) Associations between serological biomarkers and subclinical atherosclerosis in patients with rheumatoid arthritis after 11 years of follow-up 2024 Ingår i: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 42:5, s. 967-973 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: To investigate the relationship between biomarkers known to be involved in both chronic inflammation and subclinical atherosclerosis, as measured by carotid intima media thickness (cIMT), in patients with RA compared to controls.METHODS: Between 2000 and 2004, all patients under 60 years of age with newly diagnosed RA in the northern region of Sweden were invited to participate in this study. Measurements of cIMT were undertaken at inclusion (T0), after five years of follow-up (T5) and after eleven years of follow-up (T11). Patients were clinically assessed and blood was drawn for analysis of biomarkers.RESULTS: In patients with RA (n=54), linear regression models showed that cIMT at T11 was associated with levels of GDF-15 at T5 and T11, but not with baseline levels. GDF-15 was strongly associated with age. At T11, mean level of GDF-15 was elevated compared to controls. Levels of adiponectin, MCP-1, cathepsin S, endoglin and IL-6 were higher in patients with RA compared to controls, but showed no association with cIMT. In multivariable linear regression models with cIMT at T11 as dependent variable, change in GDF-15 from T0 to T11 was associated to an increase in cIMT at T11. Adjusting for systolic blood pressure and age respectively rendered this association statistically non-significant,CONCLUSIONS: Among these patients with RA GDF-15 was associated to cIMT after 11 years of follow-up. GDF-15 should be a biomarker of interest in future research, to further understand its role in the accelerated atherogenesis in patients with RA.
14.	Hörnberg, Kristina, et al. (författare) Individual regression modelling of spinal mobility measurements in long-term ankylosing spondylitis : In-depth analyses with comparison to norm data 2023 Ingår i: Arthritis care & research. - : John Wiley & Sons. - 2151-464X .- 2151-4658. ; 75:4, s. 793-800 Tidskriftsartikel (refereegranskat)abstract Objectives: Normal age-related decline and temporary restrictions in mobility complicate the understanding of spinal mobility deterioration over time in patients with ankylosing spondylitis (AS). In this study, we aimed to determine whether spinal mobility deterioration occurred linearly in patients with AS. We also aimed to compare patterns of change with corresponding age-related normal values and analyze variations in temporary fluctuations in mobility measurements over time.Methods: We included 111 men and 30 women (median age 20.9 years at symptom onset), who were followed for median 34 years since symptom onset. This resulted in 9 697 spinal mobility measurements for analysis. Individual linear regression models for development of lateral spinal flexion (LSF), 10 cm Schober test (ST10), chest expansion (CE), and cervical rotation (CR) were analyzed and compared with normal age-related decline over time.Results: The median values for the constants of all measurements were significantly lower than the norm data. However, LSF, ST10, and CE followed a yearly linear decline comparable to the norm data, whereas CR declined about twice as fast as expected from the norm data (beta median [25th-75th percentile]: -0.62° [-1.16°, -0.22°] and -0.35° [-0.35°, -0.35°]), respectively. Temporary fluctuations in LSF and CE were significantly higher during the early phase of the disease, with decreasing residuals over time.Conclusion: Based on median constants of our data, mobility restrictions related to AS seem to mainly occur during the first years of disease, indicating a narrow window of opportunity for prevention.
15.	Hörnberg, Kristina, et al. (författare) Isotemporal Substitution of Time Between Sleep and Physical Activity : Associations With Cardiovascular Risk Factors in Early Rheumatoid Arthritis 2021 Ingår i: ACR Open Rheumatology. - : John Wiley & Sons. - 2578-5745. ; 3:3, s. 138-146 Tidskriftsartikel (refereegranskat)abstract Objective: We aimed to determine relationships between objectively measured nightly sleep, sedentary behavior (SB), light physical activity (LPA), and moderate to vigorous physical activity (MVPA) with risk factors for cardiovascular disease (CVD) in patients with early rheumatoid arthritis (RA). Furthermore, we aimed to estimate consequences for these risk factors of theoretical displacements of 30 minutes per day in one behavior with the same duration of time in another.Methods: This cross-sectional study included 78 patients with early RA. Nightly sleep, SB, LPA, and MVPA were assessed by a combined heart rate and accelerometer monitor. Associations with risk factors for CVD were analyzed using linear regression models and consequences of reallocating time between the behaviors by isotemporal substitution modeling.Results: Median (Q1-Q3) nightly sleep duration was 4.6 (3.6-5.8) hours. Adjusted for monitor wear time, age, and sex, 30-minutes-longer sleep duration was associated with favorable changes in the values β (95% confidence interval [CI]) for waist circumference by -2.2 (-3.5, -0.9) cm, body mass index (BMI) by -0.9 (-1.4, -0.4) kg/m2 , body fat by -1.5 (-2.3, -0.8)%, fat-free mass by 1.6 (0.8, 2.3)%, sleeping heart rate by -0.8 (-1.5, -0.1) beats per minute, and systolic blood pressure by -2.5 (-4.0, -1.0) mm Hg. Thirty-minute decreases in SB, LPA, or MVPA replaced with increased sleep was associated with decreased android fat and lower systolic blood pressure levels. Replacement of SB or LPA with MVPA yielded lower BMIs.Conclusion: Shorter sleep during the night is common among patients with early RA and is associated with adverse risk factors for CVD.
16.	Hörnberg, Kristina, et al. (författare) Physical activity in early and long-standing RA : relations to disease activity, cardiovascular risk factors and subclinicalatherosclerosis Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Background: The excess risk for cardiovascular disease (CVD) in Rheumatoid Arthritis (RA), is partly attributable to traditional cardiovascular risk factors for CVD and systemic inflammation, factors known to be modified by physical activity.Objectives: The aim of this cross-sectional study was to objectively measure and compare the level of physical activity in patients with early and long-standing RA, and to investigate its associations with disease activity, risk factors for CVD and measures of subclinical atherosclerosis.Methods: This study included 84 patients with early and 37 with long-standing RA (disease duration, mean [SD] 1.4 [0.4] and 16.3 [2.3] years respectively). Physical activity was measured using a combined accelerometer and heart rate monitor and included total physical activity (counts /min), proportion of moderate to vigorous physical activity (MVPA) and sedentary time. Further assessments were; disease activity (Erythrocyte sedimentation rate [ESR], Disease activity score [DAS28]), functional ability (Health Assessment Questionnaire [HAQ]), risk factors for CVD (blood lipids, i.e., triglycerides, high density lipoprotein [HDL], low density protein [LDL], blood glucose, blood pressure, waist circumference, body mass index [BMI]), body fat and subclinical atherosclerosis (pulse wave velocity [PWV], augmentation index [AIx] and carotid intima-media thickness [cIMT]).Results: Physical activity variables did not differ between patients with early and long-standing RA. Thirty- seven % of the patients with early and 43% of the patients with long-standing RA did not reach WHOs recommended levels of MVPA. Univariate linear regression analyses with the two groups combined, showed associations between total physical activity and younger age, lower values for HAQ and ESR, as well as more beneficial values for blood glucose, triglycerides, waist circumference, BMI, body fat, sleeping heart rate (SHR), systolic and diastolic blood pressure, aortic blood pressure and pulse pressure (PP), AIx, PWV, and cIMT. After adjusting each variable for age, sex, disease duration and Actiheart wear time, associations remained for all variables except triglycerides, aortic PP, PWV, AIx and cIMT. In a final regression model, the association with ESR was no longer evident. More time spent in MVPA was associated with younger age and with favourable values of blood glucose, HDL, LDL, waist circumference, SHR and PWV. After the same adjustments, associations remained for HAQ, HDL, blood glucose and SHR.Conclusions: Physical activity behaviour was similar in patients with early and long-standing RA. Total physical activity as well as more time spent in moderate to vigorous physical activity were associated with more favourable risk factors for CVD and measures of subclinical atherosclerosis. Patients with lower functional ability were less physically active. These results stress the importance of promoting physical activity in patients with RA.
17.	Hörnberg, Kristina, et al. (författare) Physical activity in rheumatoid arthritis : relationship to cardiovascular risk factors, subclinical atherosclerosis, and disease activity 2020 Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis Group. - 0300-9742 .- 1502-7732. ; 49:2, s. 112-121 Tidskriftsartikel (refereegranskat)abstract Objective: To investigate associations between physical activity and risk factors for cardiovascular disease (CVD), subclinical atherosclerosis, and disease activity in patients with early and long-standing rheumatoid arthritis (RA).Method: This cross-sectional study included 84 patients with early and 37 with long-standing RA (disease duration, mean ± sd: 1.4 ± 0.4 and 16.3 ± 2.3 years, respectively). Physical activity was measured using a combined accelerometer and heart-rate monitor. Further assessments were disease activity (erythrocyte sedimentation rate, Disease Activity Score in 28 joints), functional ability (Health Assessment Questionnaire), risk factors for CVD (blood lipids, i.e. triglycerides, high-density lipoprotein, low-density lipoprotein; blood glucose, blood pressure, sleeping heart rate, waist circumference, body mass index, and body fat), and subclinical atherosclerosis (pulse-wave velocity, augmentation index, and carotid intima–media thickness).Results: Physical activity variables did not differ between patients with early and long-standing RA. However, 37% of the patients with early and 43% of those with long-standing RA did not reach the World Health Organization’s recommended levels of moderate to vigorous physical activity (MVPA). In a final multiple regression model, adjusted for age, gender, disease duration, and activity monitor wear time, higher total physical activity was associated with lower body fat and higher functional ability. With the same adjustments, more time spent in MVPA was associated with lower high-density lipoprotein and lower sleeping heart rate.Conclusions: Physical activity was associated with more favourable risk factors for CVD. However, many patients were physically inactive, stressing the importance of promoting physical activity in RA.
18.	Innala, Lena, et al. (författare) Age at onset determines severity and choice of treatment in early rheumatoid arthritis : a prospective study 2014 Ingår i: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362 .- 1478-6354. ; 16:2, s. R94- Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: Disease activity, severity and co-morbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in early disease.METHODS: In this study, 950 RA patients were followed regularly from inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender/swollen joints, visual analogue scale (VAS) pain/global, disease activity score (DAS28)) and function (health assessment questionnaire (HAQ)). Disease severity, measured by radiographs of hands/feet (erosions, Larsen score), extra-articular disease, nodules and co-morbidities and treatment (disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, biologics, nonsteroidal anti-inflammatory drugs (NSAIDs)) were recorded at inclusion and after 5 years. Autoantibodies (rheumatoid factor (RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptides (ACPA)) and genetic markers (human leukocyte antibody (HLA)-shared epitope, protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analyzed at inclusion. Data were stratified as young (YORA) and late (LORA) onset RA, defined as being below/above median age (58 years) at onset.RESULTS: LORA was associated with lower frequency of ACPA (P <0.05) and carriage of PTPN22-T variant (P <0.01), but with greater disease activity at inclusion measured as ESR (P < 0.001), CRP (P <0.01) and accumulated disease activity (area under the curve for DAS28) at 6 (P <0.01), 12 (P <0.01) and 24 months (P <0.05), and a higher HAQ score (P <0.01) compared with YORA. At baseline and 24 months, LORA was more often associated with erosions (P <0.01 for both) and a higher Larsen score (P <0.001 for both). LORA was more often treated with corticosteroids (P <0.01), less often with methotrexate (P <0.001) and biologics (P <0.001). YORA was more often associated with early DMARD treatment (P <0.001). Multiple regression analyses supported our findings regarding impact of age on chosen treatment.CONCLUSION: YORA patients were more frequently ACPA-positive. LORA was more often associated with erosions, higher Larsen scores, disease activity and HAQ at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and with less DMARDs in early disease. This could have implications for development of co-morbidities.
19.	Innala, Lena, et al. (författare) Age at onset determines severity and choice of treatment in early rheumatoid arthritis 2012 Ingår i: Arthritis and Rheumatism. - : John Wiley & Sons. - 0004-3591 .- 1529-0131. ; 64:10, s. S908-S908 Tidskriftsartikel (refereegranskat)
20.	Innala, Lena, et al. (författare) Cardiovascular events in early rheumatoid arthritis (RA) are a result of inflammatory burden and traditional risk factors : a five year prospective study 2011 Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 13:4, s. R131- Tidskriftsartikel (refereegranskat)abstract Introduction Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first 5 years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the 5 year follow-up period and the modulatory effect of pharmacological treatment.Methods All patients from the four northern-most counties of Sweden with early RA are since December 1995 consecutively recruited at diagnsosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the 5-year follow-up (T5).Result Among the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% ( p<0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5%(p<0.01) whilst smoking decreased from 29.8 to 22.4 % ( p<0.001) and the BMI from 26.3 to 25.8( p<0.05) , respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (AUC DAS28), extra-articular disease, corticosteroid use, shorter duration of treatment with DMARDs and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised ESR at inclusion and AUC DAS28 at 6 months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.Conclusion The occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.
21.	Innala, Lena, 1060-, et al. (författare) Co-morbidity in patients with early rheumatoid arthritis - inflammation matters 2016 Ingår i: Arthritis Research & Therapy. - : BioMed Central. - 1478-6362. ; 18 Tidskriftsartikel (refereegranskat)abstract Background: Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA. Methods: Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on comorbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for >= 5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5). Results: Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidism (6.3 %) and malignancy (5.0 %). After 5 years, 41.0 % had developed at least one new co-morbidity, the most common being: hypertension (15.1 %), malignancy (7.6 %), stroke/transient ischemic accident (5.1 %), myocardial infarction (4.3 %) and osteoporosis (3.7 %). Age at disease onset, a raised erythrocyte sedimentation rate (ESR) at inclusion, previous treatment with glucocorticoids (GC; p < 0.001 for all), extra-articular RA (Ex-RA; p < 0.01), DAS28 (area under the curve) at 24 months (p < 0.05), previous smoking at inclusion (p = 0.058) and male gender (p < 0.01) were associated with a new co-morbidity overall at T5. Treatment with biologics (p < 0.05) reduced the risk. In multiple logistic regression modelling, ESR (p = 0.036) at inclusion was associated with a new co-morbidity after 5 years, adjusted for age, sex, smoking and GC treatment. In a similar model, Ex-RA (p < 0.05) was associated with a new co-morbidity at T5. In a third model, adjusted for age and sex, a new pulmonary co-morbidity was associated with a smoking history at inclusion (p < 0.01), but not with ESR. Conclusion: There was substantial co-morbidity among early RA patients already at disease onset, with considerable new co-morbidity being added during the first five years. Measures of disease activity were associated with the occurrence of a new co-morbidity indicating that the inflammation is of importance in this context.
22.	Innala, Lena, et al. (författare) Comorbidity in early rheumatoid arthritis : does inflammation matter? 2013 Ingår i: Arthritis and Rheumatism. - : Wiley-Blackwell. - 0004-3591 .- 1529-0131. ; 65:Special issue, Supplement 10, s. S176-S176, Meeting Abstract: 408 Tidskriftsartikel (refereegranskat)
23.	Innala, Lena, et al. (författare) Comorbidity in early rheumatoid arthritis - which is the role of inflammation? 2014 Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 73, s. 406-406 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
24.	Innala, Lena, et al. (författare) Comorbidity in patients with early rheumatoid arthritis : does inflammation matter? Annan publikation (övrigt vetenskapligt/konstnärligt)
25.	Isaksson, J., et al. (författare) Screening and simple counselling affect traditional cardiovascular risk factors in patients with early rheumatoid arthritis 2014 Ingår i: Scandinavian Journal of Rheumatology. - : Informa Healthcare. - 0300-9742 .- 1502-7732. ; 43:Suppl. 127 Meeting Abstract PP234, s. 76-76 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) and increased mortality in CVD. The cause of this increase has not been completely established, but chronic inflammation is thought to play a role. Traditional cardiovascular risk factors also appear to be important and may be potentiated by this inflammation. The Swedish Society for Rheumatology (SRF) has developed a set of guidelines for screening and primary prevention of CVD in patients with RA. The aim of this study was to evaluate these guidelines in a clinical setting.Method: Forty-seven patients newly diagnosed with RA during 2012 at the Department of Rheumatology, University Hospital of Umeå were recruited. Three months after initial diagnosis of RA, patients were examined physically and blood samples were collected with regard to traditional cardiovascular risk factors according to the guidelines from the SRF. Tests of cardiorespiratory fitness were also performed. Additionally, patients received simple counselling regarding matters of diet, tobacco use and exercise from a nurse and a physiotherapist, respectively. The counselling session, based upon national guidelines from the National Food Agency and the Public Health Agency, was performed once per patient and lasted for approximately 45 minutes. A follow-up was performed 9 months after the first examination. This intervention was integrated into the clinic’s pre-existing early RA follow-up programme. The results were adjusted for disease activity and disability.Results: Among the 47 included patients, 45 reached the 9-month follow-up. Two were excluded because of delayed follow-up. Mean diastolic blood pressure decreased significantly from 80 to 77 mmHg (p < 0.05). Mean S-cholesterol decreased significantly from 5.5 to 5.2 mmol/L (p < 0.05). Mean ApoA1/ApoB decreased significantly from 0.73 to 0.65 (p < 0.05). In all the remaining variables (waist circumference, BMI, systolic blood pressure, LDL, HDL, triglycerides, FP-glucose), a clear decreasing trend could be observed (p > 0.05). Aerobic capacity according to Åstrand remained unchanged (p > 0.05).Conclusions: Several traditional risk factors for CVD were improved at the 9-month follow-up. This suggests that this model of screening according to the SRF guidelines and simple counselling according to national guidelines might be useful in primary prevention of CVD in patients with RA.
26.	Laranjeiro, F., et al. (författare) Comparative assessment of the acute toxicity of commercial bio-based polymer leachates on marine plankton 2024 Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. Tidskriftsartikel (refereegranskat)abstract Conventional plastics have become a major environmental concern due to their persistence and accumulation in marine ecosystems. The development of potential degradable polymers (PBP), such as polyhydroxyalkanoates (PHAs) and polylactic acid (PLA), has gained attention as an alternative to mitigate plastic pollution, since they have the potential to biodegrade under certain conditions, and their production is increasing as replacement of conventional polyolefins. This study aimed to assess and compare the toxicity of leachates of pre-compounding PBP (PLA and the PHA, polyhydroxybutyrate-covalerate (PHBv)) and polypropylene (PP) on five marine planktonic species. A battery of standard bioassays using bacteria, microalgae, sea urchin embryos, mussel embryos and copepod nauplii was conducted to assess the toxicity of leachates from those polymers. Additionally, the presence of chemical additives in the leachates was also verified through GC-MS and LC-HRMS analysis. Results showed that PHBv leachates exhibited higher toxicity compared to other polymers, with the microalgae Rhodomonas salina, being the most sensitive species to the tested leachates. On the other hand, PP and PLA generally displayed minimal to no toxicity in the studied species. Estimated species sensitivity distribution curves (SSD) show that PHBv leachates can be 10 times more hazardous to marine plankton than PP or PLA leachates, as demonstrated by the calculated Hazardous Concentration for 5 % of species (HC5). Qualitative chemical analysis supports the toxicological results, with 80 % of compounds being identified in PHBv leachates of which 2,4,6-trichlorophenol is worth mentioning due to the deleterious effects to aquatic biota described in literature. These findings underscore the fact that whereas environmental persistence can be targeted using PBP, the issue of chemical safety remains unsolved by some alternatives, such as PHBv. Gaining a comprehensive understanding of the toxicity profiles of PBP materials through a priori toxicological risk assessment is vital for their responsible application as alternatives to conventional plastics.
27.	Lindström, Henrik, et al. (författare) A new method for manufacturing nanostructured electrodes on glass substrates 2002 Ingår i: Solar Energy Materials and Solar Cells. - : Elesevier Science B.V.. - 0927-0248 .- 1879-3398. ; 73, s. 91-101 Tidskriftsartikel (refereegranskat)
28.	Makoveichuk, Elena, et al. (författare) High concentrations of Angiopoietin-like Protein 4 detected in serum from patients with rheumatoid arthritis can be explained by non-specific antibody reactivity 2017 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1 Tidskriftsartikel (refereegranskat)abstract Angiopoietin-like protein 4 (ANGPTL4) is suggested to be a master regulator of plasma triglyceride metabolism. Our aim was to study whether the previously reported high levels of ANGPTL4 detected in serum from patients with rheumatoid arthritis (RA) by ELISA was due to any specific molecular form of this protein (oligomers, monomers or fragments). ANGPTL4 levels were first determined in serum from 68 RA patients and 43 age and sex matched control subjects and the mean values differed by a factor of 5.0. Then, ANGPTL4 was analyzed after size exclusion chromatography (SEC) of serum samples. With serum from one of the RA patients with high levels of ANGPTL4, the dominant reactivity was found in fractions corresponding to high-molecular weight proteins. In addition, a minor peak of reactivity eluting late from the column was found both in the patient and in controls. By the use of Hetero-Block r, and by careful selection of antibodies, we documented non-specific reactions for ANGPTL4 in 39% of samples from the RA patients, most likely due to cross-reactivity of the antibodies with rheumatoid factor (RF). The corresponding figure for control subjects was 6.3%. After corrections for non-specific reactions, the mean level of ANGPTL4 in serum from RA patients was still significantly higher than in control individuals (mean levels were 101 +/- 62 and 67 +/- 39 ng/ml respectively, P = 0.02). We re-analyzed samples from our previously published studies on ANGPL4 levels in patients on hemodialysis and patients with diabetes type 2. These samples did not show false positive reactions. The levels of ANGPTL4 were comparable to those detected previously.
29.	Ramström, Sofia, 1973-, et al. (författare) Platelet Function Determined by Flow Cytometry : New Perspectives? 2016 Ingår i: Seminars in Thrombosis and Hemostasis. - : Thieme Medical Publishers. - 0094-6176 .- 1098-9064. ; 42:3, s. 268-281 Forskningsöversikt (refereegranskat)abstract Flow cytometry enables studies of several different aspects of platelet function in response to a variety of platelet agonists. This can be done using only a small volume of whole blood, and also in blood with low platelet counts. These properties, together with the increasing number of flow cytometers available in hospitals worldwide, make flow cytometry an interesting option for laboratories interested in studies of platelet function in different clinical settings. This review focuses on practical issues regarding the use of flow cytometry for platelet function testing. It provides an overview of available activation markers, platelet agonists, and experimental setup issues. The review summarizes previous experience and factors important to consider to perform high-quality platelet function testing by flow cytometry. It also discusses its current use and possibilities and challenges for future use of flow cytometry in clinical settings.
30.	Richtnér, Anders, et al. (författare) Ledning av innovation : Att hantera balansgången mellan effektivitet och kreativitet 2012 Ingår i: Innovationsledning och kreativitet i svenska företag. - : Stiftelsen IMIT - Institute for Management of Innovation and Technology & VINNOVA. - 9789186517571 Bokkapitel (övrigt vetenskapligt/konstnärligt)
31.	Ruge, Toralph, et al. (författare) Circulating plasma levels of cathepsin S and L are not associated with disease severity in patients with rheumatoid arthritis 2014 Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 43:2, s. 371-373 Tidskriftsartikel (refereegranskat)abstract Background: Rheumatoid arthritis (RA) is characterized by chronic synovitis and articular cartilage destruction. Increased activities of cathepsin S and cathepsin L, two potent cysteine proteases, are thought to play a role in the pathogenesis of the irreversible articular cartilage destruction. Nevertheless, data regarding the potential importance of the cathepsins as circulating biomarkers in RA patients are limited.Method: Subjects enrolled in this study are part of a larger study where patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study. In total, 71 patients were included, along with 44 age- and sex-matched control subjects. Plasma levels of cathepsin S and L were analysed. Disease severity was assessed using the 28-joint count Disease Activity Score (DAS28).Results: Plasma levels of cathepsin S and L were significantly increased in patients with RA compared to healthy controls (p < 0.05 for both). However, in the patients with RA, no association between the cathepsins and the severity of the disease, as characterized by DAS28, was observed (p > 0.51).Conclusions: Although circulating levels of cathepsin S and L were significantly increased in patients with recently diagnosed RA, our data do not support the notion that circulating levels of cathepsins are relevant biomarkers for disease severity.
32.	Sandell, Mikael, et al. (författare) A novel noble metal stent coating reduces in vitro platelet activation and acute in vivo thrombosis formation : a blinded study Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Inherent to any stenting procedure is the prescription of dual antiplatelet therapy (DAPT) to reduce the platelet response. Clinical guidelines recommend 6 - 12 months of DAPT, depending on stent type, clinical picture and patient factors. Our hypothesis is that a nanostructured noble metal coating has the potential to reduce protein deposition and platelet activation, which in turn could reduce the need for DAPT. Here, a noble metal nanostructure coating on stents is investigated. Twelve pigs underwent endovascular implantation of coated and non-coated stents for paired comparisons in a double-blinded study design. The non-coated control stent was placed at the contralateral corresponding artery. Volumetric analysis of angiographic data, performed by a treatment blinded assessor, demonstrated a significant thrombus reduction for one of the coatings compared to control. This effect was already seen one hour after implantation. This finding was supported by in vitro data showing a significant reduction of coagulation activation in the coated group. This novel coating shows promise as an implant material addition and could potentially decrease the need for DAPT in the acute clinical setting.
33.	Sandell, Mikael, et al. (författare) A novel noble metal stent coating reduces in vitro platelet activation and acute in vivo thrombosis formation : a blinded study 2023 Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1 Tidskriftsartikel (refereegranskat)abstract Inherent to any stenting procedure is the prescription of dual antiplatelet therapy (DAPT) to reduce the platelet response. Clinical guidelines recommend 6–12 months of DAPT, depending on stent type, clinical picture and patient factors. Our hypothesis is that a nanostructured noble metal coating has the potential to reduce protein deposition and platelet activation. These effects would reduce subsequent thrombo-inflammatory reactions, potentially mitigating the need for an extensive DAPT in the acute phase. Here, a noble metal nanostructure coating on stents is investigated. Twelve pigs underwent endovascular implantation of coated and non-coated stents for paired comparisons in a blinded study design. The non-coated control stent was placed at the contralateral corresponding artery. Volumetric analysis of angiographic data, performed by a treatment blinded assessor, demonstrated a significant thrombus reduction for one of the coatings compared to control. This effect was already seen one hour after implantation. This finding was supported by in vitro data showing a significant reduction of coagulation activation in the coated group. This novel coating shows promise as an implant material addition and could potentially decrease the need for DAPT in the early phases of stent implementation.
34.	Södergren, Anna, et al. (författare) Atherosclerosis in early rheumatoid arthritis : very early endothelial activation and rapid progression of intima media thickness 2010 Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 12:4, s. R158- Tidskriftsartikel (refereegranskat)abstract INTRODUCTION : In this study we aimed to investigate whether there are indications of premature atherosclerosis, as measured by endothelial dependent flow-mediated dilation (ED-FMD) and intima media thickness (IMT), in patients with very early RA, and to analyze its relation to biomarkers of endothelial dysfunction, taking inflammation and traditional cardiovascular disease (CVD) risk factors into account. METHODS : Patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study of CVD co-morbidity. Of these, all patients aged ≤60 years were consecutively included in this survey of CVD risk factors (n = 79). Forty-four age and sex matched controls were included. IMT of common carotid artery and ED-FMD of brachial artery were measured using ultrasonography. Blood was drawn for analysis of lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)-mass, VonWillebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), sE-selectin, sL-selectin and monocyte chemotactic protein-1 (MCP-1). In a subgroup of 27 RA patients and their controls the ultrasound measurements were reanalysed after 18 months. RESULTS : There were no significant differences between RA patients and controls in terms of IMT or ED-FMD at the first evaluation. However after 18 months there was a significant increase in the IMT among the patients with RA (P < 0.05). Patients with RA had higher levels of VWF, sICAM-1 (P < 0.05) and of MCP-1 (P = 0.001) compared with controls. In RA, IMT was related to some of the traditional CVD risk factors, tPA-mass, VWF (P < 0.01) and MCP-1 and inversely to sL-selectin (P < 0.05). In RA, ED-FMD related to sL-selectin (P < 0.01). DAS28 at baseline was related to PAI-1, tPA-mass and inversely to sVCAM-1 (P < 0.05) and sL-selectin (P = 0.001). CONCLUSIONS : We found no signs of atherosclerosis in patients with newly diagnosed RA compared with controls. However, in patients with early RA, IMT and ED-FMD were, to a greater extent than in controls, related to biomarkers known to be associated with endothelial dysfunction and atherosclerosis. After 18 months, IMT had increased significantly in RA patients but not in controls.
35.	Södergren, Anna, 1977-, et al. (författare) Biomarkers associated with cardiovascular disease in patients with early rheumatoid arthritis 2019 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 14:8 Tidskriftsartikel (refereegranskat)abstract Objectives: Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease (CVD). In this prospective 5-year follow up of patients with RA, we analysed several biomarkers, known to be associated with atherosclerosis and/or inflammation in the general population. The aim of this study was to find out whether the RA-disease per se affect these biomarkers and if those could be associated with the progression of atherosclerosis, as measured by intima media thickness (IMT) among patients with early RA.Methods: Patients from northern Sweden diagnosed with early RA, are consecutively recruited into an ongoing prospective study on CVD comorbidity. A subgroup of patients, aged ≤60 years (n = 71) was included for ultrasound measurements of IMT at inclusion (T0) and after 5 years (T5) together with age-sex-matched controls (n = 40). The patients were clinically assessed. Blood was analysed for lipids, ESR and CRP and several biomarkers known to be associated with atherosclerosis in the general population.Results: At T0, the patients with RA had significantly lower levels of MIF and significantly higher levels of interleukin (IL)-18 and MIC-1 compared with controls. At T5, the patients with RA had significantly higher levels of pentraxin3, MIC-1, TNF-R2, ICAM-1, VCAM-1 and endostatin compared with controls. At T0 the levels of MPO correlated with DAS28, sCD40L with CRP and IL-18 with systolic blood pressure and Reynolds risk score. Using PLSR on a CVD-panel analysed with multiplex immunoassay, the patients with RA could be correctly classified into those who had a worsening in their IMT over the five years or not. Here, MMP3 was identified as influential.Conclusions: This study indicates that the RA disease itself could affect several of the biomarkers in this study, and possibly also the processes involved in the development of atherosclerosis.
36.	Södergren, Anna, 1977-, et al. (författare) Case fatality over 365 days after first acute coronary syndrome in patients with ankylosing spondylitis 2018 Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 77, s. 341-341 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
37.	Södergren, Anna, 1977-, et al. (författare) Characteristics and outcome of a first acute myocardial infarction in patients with ankylosing spondylitis 2021 Ingår i: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 0770-3198 .- 1434-9949. ; 40, s. 1321-1329 Tidskriftsartikel (refereegranskat)abstract Objectives To study clinical characteristics, mortality, and secondary prevention, after a first incident acute myocardial infarction (AMI) in patients with ankylosing spondylitis (AS) compared with the general population. Methods In total, 292 subjects with AS and a first AMI between Jan 2006 and Dec 2014 were identified using the Swedish national patient register. Each subject was matched with up to 5 general population comparators per AS-patient (n = 1276). Follow-up started at the date of admission for AMI and extended until death or 365 days of follow-up. Cox regression was used to assess mortality in two time intervals: days 0-30 and days 31-365. For a subgroup with available data, clinical presentation at admission, course, treatment for AMI, and secondary prevention were compared. Results During the 365-day follow-up, 56/292 (19%) AS patients and 184/1276 (14%) comparators died. There were no difference in mortality due to cardiovascular-related causes, although the overall mortality day 31-365 was increased among patients with AS compared with comparators (HR [95% CI] = 2.0 [1.3;3.0]). At admission, AS patients had a higher prevalence of cardiovascular comorbidities compared with comparators. At discharge, patients with AS were less often prescribed lipid-lowering drugs and non-aspirin antiplatelet therapy. Conclusions Patients with AS tend to have a higher comorbidity burden at admission for first AMI. The mortality after a first AMI due to cardiovascular-related causes does not seem to be elevated, despite an increased overall mortality during days 31-365 among patients with AS compared with the general population.
38.	Södergren, Anna, et al. (författare) Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry 2017 Ingår i: Methods in Molecular Biology. - New York, NY : Springer. - 1064-3745 .- 1940-6029. ; 1594, s. 191-203, s. 191-203 Tidskriftsartikel (refereegranskat)abstract Flow cytometry is a method that allows high throughput analysis of individual cells in suspension. By inclusion of fluorescently labelled antibodies, it is possible to analyze the abundance of one or more surface antigens, such as LAMP-1, without prior lysis of cells. Here we describe the special considerations required for the investigation of lysosomal exocytosis from platelets analyzed with flow cytometry.
39.	Södergren, Anna, 1985- (författare) Formation and Relevance of Platelet Subpopulations 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Platelets are important players in the hemostatic system, acting as guardians of vessel integrity. When they come across a breach in the vessel wall, they quickly adhere to the damaged surface, secrete activating and adhesive compounds from their secretory granules, recruit additional platelets into a growing platelet plug and support the action of the coagulation system. In the past decades, it has become clear that platelets form functionally different platelet subpopulations. The aggregatory platelets build the platelet plug, whereas the procoagulant subpopulation support and direct the actions of the coagulation system. The aim of this thesis was to examine the formation and features of the different platelet subpopulations, and elucidate their respective roles in hemostasis.Platelet lysosomal secretion is not well characterized. In Paper I, we found that lysosomal secretion, detected as LAMP-1 surface exposure, occur upon potent platelet stimulation including secondary activation by ADP. This is regulated by the endothelial platelet inhibitors nitric oxide and prostacyclin. As observed in Paper II, lysosomal secretion might also be of clinical relevance as a quality indicator for platelet concentrates used for transfusion, an area were quality control may become increasingly important in the future. Among several evaluated platelet activation markers, platelet LAMP-1 exposure and the ability to form procoagulant platelets may be useful as novel indicators of platelet responsiveness. Moreover, the ability to form procoagulant platelets varies extensively between individuals, something we established in Paper III. Here we also present a novel flow cytometry protocol enabling the simultaneous investigation of 6 different platelet activation markers. Using this protocol we investigate the formation of procoagulant platelets and reveal that only a subpopulation of platelets may become procoagulant. Further we show that this is dependent on the agonist stimulation applied. Finally in Paper IV, we explore the influence of the procoagulant platelet subpopulation on different aspects of hemostasis. While platelet aggregation was not affected, the fraction of procoagulant platelets was found to strongly correlate to peak thrombin generation, and to be associated with plasma cholesterol levels.In conclusion, this thesis presents evidence for the use of LAMP-1 surface exposure and the formation of a procoagulant platelet subpopulation as potential indicators of platelet activation potential. The formation of procoagulant platelets varies extensively between individuals, influence hemostasis and is associated with the known risk factor cholesterol. Thus, the formation of a procoagulant platelet subpopulation may be a candidate biomarker for cardiovascular disease, to be explored in the future.
40.	Södergren, Anna, 1977-, et al. (författare) Increased incidence of and impaired prognosis after acute myocardial infarction among patients with seropositive rheumatoid arthritis. 2007 Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd & European League Against Rheumatism. - 0003-4967 .- 1468-2060. ; 66:2, s. 263-266 Tidskriftsartikel (refereegranskat)abstract Objective: To examine the incidence and outcome of acute myocardial infarction (AMI) in patients with rheumatoid arthritis compared with the general population, and to examine whether care and treatment of an AMI differs between patients and controls. Methods: The Multinational Monitoring of Trends and Determinants of Cardiovascular Disease register for northern Sweden was used to compare those incidences of AMI in a cohort of patients with rheumatoid arthritis with that in the general population. 35 patients with rheumatoid arthritis who had also experienced an AMI were identified. For each patient with rheumatoid arthritis, three controls with a history of AMI but without rheumatoid arthritis were randomly selected from the same register, and matched for age, sex and year of the AMI for evaluation of case fatality and potential differences in treatment of AMI. Results: The standardised incidence ratio for AMI was 2.9 in patients with rheumatoid arthritis compared with the general population (p<0.05). During the first 10 years after an AMI, patients with rheumatoid arthritis had a higher overall case fatality compared with controls (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.02 to 2.71). Survival time was decreased in the rheumatoid arthritis group compared with controls despite the same care and treatment. Conclusion: Both the incidence of and case fatality after an AMI were higher among patients with rheumatoid arthritis than among the general population. The results emphasise the necessity of optimising the preventive, diagnostic and caring strategies for AMI in rheumatoid arthritis.
41.	Södergren, Anna, et al. (författare) Increased incidence of stroke and impaired prognosis after stroke among patients with seropositive rheumatoid arthritis 2009 Ingår i: Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 27:4, s. 641-644 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To examine the incidence of, and outcome after, a stroke in patients with rheumatoid arthritis (RA) compared with the general population. METHODS: The northern Sweden MONICA register was used to compare the incidence of stroke in a cohort of RA patients with the general population. Forty RA patients who had also suffered a stroke were identified. For each patient with RA, three controls with a history of stroke but without RA were randomly collected from the same register, and matched for age and sex. RESULTS: The standardised incidence ratio (SIR) for stroke was 2.7 in RA patients compared with the general population (p<0.05). During the follow-up, RA patients had a higher overall case fatality (CF) following stroke compared with controls (hazard ratio (HR) =1.70, p<0.05). CONCLUSIONS: Both the incidence of a stroke, and the subsequent CF, were higher among RA patients compared with the general population. The results emphasize the necessity of optimising the prevention of stroke and follow-up care after a stroke in RA.
42.	Södergren, Anna, et al. (författare) Is Lipoprotein-Associated Phospholipase A2a Link between Inflammation and Subclinical Atherosclerosis inRheumatoid Arthritis? 2015 Ingår i: BioMed Research International. - : Hindawi Publishing Corporation. - 2314-6133 .- 2314-6141. Tidskriftsartikel (refereegranskat)abstract Objective. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Methods. Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients <= 60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age-and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. Results. There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). Conclusion. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity.
43.	Södergren, Anna, 1977-, et al. (författare) No signs of premature atherosclerosis in early rheumatoid arthritis albeit endothelial biomarkers are upregulated Annan publikation (övrigt vetenskapligt/konstnärligt)
44.	Södergren, Anna, et al. (författare) Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol 2018 Ingår i: Scientific Reports. - London, UK : Nature Publishing Group. - 2045-2322. ; 8:1 Tidskriftsartikel (refereegranskat)abstract It is recognised that platelets respond differently to activation, where a subpopulation of platelets adopt a procoagulant phenotype while others are aggregatory. However, it has not been thoroughly tested whether these subpopulations will remain in maximally activated samples, or if they are merely a result of different platelet sensitivities to agonist activation. Here platelets were activated with gradually increasing concentrations of thrombin and/or the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Platelet activation was investigated using a novel six-colour flow cytometry protocol evaluating exposure of phosphatidylserine, active conformation of the fibrinogen receptor αIIbβ3, α-granule and lysosomal release (P-selectin and LAMP-1 exposure), mitochondrial membrane integrity and platelet fragmentation. Upon activation by CRP-XL or thrombin+CRP-XL, platelets formed three differently sized subpopulations. Normal-sized platelets showed high exposure of aggregatory active αIIbβ3 and intact mitochondria, while the smaller platelets and platelet fragments showed high exposure of procoagulant phosphatidylserine. The distribution of platelets between the differently sized subpopulations remained stable despite high agonist concentrations. All three were still present after 30 and 60 min of activation, showing that all platelets will not have the same characteristics even after maximal stimulation. This suggests that platelet subpopulations with distinct activation patterns exist within the total platelet population.
45.	Södergren, Anna, et al. (författare) Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion 2016 Ingår i: Vox Sanguinis. - : Wiley-Blackwell Publishing Inc.. - 0042-9007 .- 1423-0410. ; 110:2, s. 116-125 Tidskriftsartikel (refereegranskat)abstract Background and ObjectivesStorage lesions may prevent transfused platelets to respond to agonists and arrest bleeding. The aim of this study was to evaluate and quantify the capacity of platelet activation during storage using flow cytometry and new markers of platelet activation. Materials and MethodsActivation responses of platelets prepared by apheresis were measured on days 1, 5, 7 and 12. In addition, comparisons were made for platelet concentrates stored until swirling was affected. Lysosome-associated membrane protein-1 (LAMP-1), P-selectin and phosphatidylserine (PS) exposure were assessed by flow cytometry on platelets in different subpopulations in resting state or following stimulation with platelet agonists (cross-linked collagen-related peptide (CRP-XL), PAR1- and PAR4-activating peptides). ResultsThe ability to form subpopulations upon activation was significantly decreased already at day 5 for some agonist combinations. The agonist-induced exposure of PS and LAMP-1 also gradually decreased with time. Spontaneous exposure of P-selectin and PS increased with time, while spontaneous LAMP-1 exposure was unchanged. In addition, agonist-induced LAMP-1 expression clearly discriminated platelet concentrates with reduced swirling from those with retained swirling. This suggests that LAMP-1 could be a good marker to capture changes in activation capacity in stored platelets. ConclusionThe platelet activation potential seen as LAMP-1 exposure and fragmentation into platelet subpopulations is potential sensitive markers for the platelet storage lesion.
46.	Södergren, Anna, 1977-, et al. (författare) Significant Increase of intima media thickness in eighteen months among patients with newly diagnosed rheumatoid arthritis Annan publikation (övrigt vetenskapligt/konstnärligt)
47.	Södergren, Anna, et al. (författare) The Extent of Subclinical Atherosclerosis Is Partially Predicted by the Inflammatory Load : A Prospective Study over 5 Years in Patients with Rheumatoid Arthritis and Matched Controls 2015 Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:6, s. 935-942 Tidskriftsartikel (refereegranskat)abstract Objective. This prospective followup study investigated subclinical atherosclerosis in relation to traditional cardiovascular disease (CVD) risk factors and inflammation in patients with rheumatoid arthritis (RA) recruited at diagnosis compared with controls. Methods. Patients diagnosed with early RA were consecutively recruited into a prospective study. From these, a subgroup aged <= 60 years (n = 71) was consecutively included for ultrasound measurement of intima-media thickness (IMT) and flow-mediated dilation (FMD) at inclusion (T0) and after 5 years (T5). Age-and sex-matched controls (n = 40) were also included. Results. In the Wilcoxon signed-rank test, both IMT and FMD were significantly aggravated at T5 compared to baseline in patients with RA, whereas only IMT was significantly increased in controls. In univariate linear regression analyses among patients with RA, the IMT at T5 was significantly associated with age, systolic blood pressure (BP), cholesterol, triglycerides, Systematic Coronary Risk Evaluation (SCORE), and Reynolds Risk Score at baseline (p < 0.05). Similarly, FMD at T5 was significantly inversely associated with age, smoking, systolic BP, SCORE, and Reynolds Risk Score (p < 0.05). A model with standardized predictive value from multiple linear regression models including age, smoking, BP, and blood lipids at baseline significantly predicted the observed value of IMT after 5 years. When also including the area under the curve for the 28-joint Disease Activity Score over 5 years, the observed value of IMT was predicted to a large extent. Conclusion. This prospective study identified an increased subclinical atherosclerosis in patients with RA. In the patients with RA, several traditional CVD risk factors at baseline significantly predicted the extent of subclinical atherosclerosis 5 years later. The inflammatory load over time augmented this prediction.
48.	Södergren, Anna, et al. (författare) Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances 2016 Ingår i: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 27:1, s. 86-92 Tidskriftsartikel (refereegranskat)abstract Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.
49.	Södergren, Anna, 1977-, et al. (författare) Time trends of cardiovascular disease in the general population and inflammatory arthritis 2023 Ingår i: Rheumatic Disease Clinics of North America. - : Elsevier. - 0889-857X .- 1558-3163. ; 49:1, s. 1-17 Forskningsöversikt (refereegranskat)
50.	Tynngård, Nahreen, et al. (författare) Platelet adhesion changes during storage studied with a novel method using flow cytometry and protein-coated beads 2015 Ingår i: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 26:2, s. 177-185 Tidskriftsartikel (refereegranskat)abstract The aim of the present study was to set up and evaluate a novel method for studies of platelet adhesion and activation in blood and platelet suspensions such as platelet concentrate (PC) samples using protein-coated polystyrene beads and flow cytometry. To demonstrate its usefulness, we studied PCs during storage. PCs were prepared by aphaeresis technique (n = 7). Metabolic variables and platelet function was measured on day 1, 5, 7 and 12 of storage. Spontaneous and TRAP-6-induced adhesion to fibrinogen-and collagen-coated beads was analyzed by flow cytometry. P-selectin and phosphatidyl serine (PS) expression was assessed on platelets bound to beads as well as on non-adherent platelets. Platelet adhesion to fibrinogen beads had increased by day 12 and adhesion to collagen beads at day 7 of storage (p<0.05). TRAP-6 stimulation significantly increased the platelet adhesion to fibrinogen beads (p<0.05) as well as the P-selectin and PS exposure on platelets bound to beads (p<0.01) during the first 7 days of storage, but by day 12, significant changes were no longer induced by TRAP-6 stimulation. We demonstrate that our adhesion assay using protein-coated polystyrene beads can be used to assess the adhesion properties of platelets during storage without the addition of red blood cells. Therefore it may offer a useful tool for future studies of platelet adhesive capacity in transfusion medicine and other settings.

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