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Abstract Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen. Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Abstract Aims Carbohydrate antigen 125 (CA125), a mucin produced by serosal cells in response to mechanical and inflammatory stimuli, has emerged as an important biomarker to guide risk stratification in heart failure (HF). The prognostic value of CA125 in acute coronary syndrome (ACS) patients is less explored. Methods In a cohort of 524 ACS patients (73% males, mean age 67 ± 12 years), we assessed the associations between CA125 and the risk for HF and death during a median follow‐up period of 27.3 months for incident HF and 39.5 months for mortality. Plasma CA125 was measured within 24 h after admission in the entire cohort and after 6 weeks in a subgroup of 115 elderly patients (>75 years of age). We also assessed the relationships between baseline CA125 and echocardiographic parameters of cardiac structure and function at 1 year post‐ACS in this subgroup. Results Baseline CA125 was associated with incident HF in the entire cohort in a Cox proportional hazards model adjusted for age, sex, cardiovascular (CV) risk factors (diabetes, smoking, hypertension, previous HF, previous ACS and previous stroke), renal function and revascularization {hazard ratio [HR] 1.46 [95% confidence interval (CI) 1.10–1.93] per 1‐standard deviation [SD] CA125 increase; P = 0.009}. In the detailed follow‐up subgroup, elevated baseline CA125 predicted subsequent deterioration of left ventricular (LV) ejection fraction (LVEF), defined as a >5% absolute LVEF decrease in patients with LVEF ≥ 50% at discharge [odds ratio (OR) 3.31 (95% CI 1.15–9.54) per 1‐SD baseline CA125 increase; P = 0.027]. We also found significant correlations between high baseline CA125 and larger LV volumes (LV end‐diastolic volume index, Spearman's r = 0.329, P

Abstract Introduction The role of the complement inhibitory proteins CD46 and CD59 in the immune response to an acute coronary syndrome (ACS) is unknown. We investigated the relationships between the shedding of CD46 and CD59 into the circulation, reflected by plasma levels of soluble CD46 and CD59, and the risk for post-ACS complications. Methods We measured plasma sCD46 and sCD59 in a cohort of 546 ACS patients within 24 h after hospital admission, and after 6-weeks in a subgroup of 114 patients. Study outcomes were incident heart failure (HF), major adverse cardiovascular events (MACE) and mortality during a median follow-up period of up to 3.3 years. Echocardiography at 1-year was performed in the follow-up subgroup. Results Elevated sCD46 and sCD59 were correlated with increased levels of inflammatory mediators and metalloproteinases in plasma, and were associated with increased risk for MACE in Cox proportional hazard models adjusted for cardiovascular risk factors and revascularization [HR 95% CI 1.24 (1.02–1.52), p = 0.034 for sCD46 and 1.18 (1.00–1.38), p = 0.049 for sCD59]. Elevated sCD59 was also associated with higher incidence of HF [HR 95% CI 1.41 (1.15–1.74), p = 0.001], and with lower left ventricular ejection fraction at 1-year post-ACS (Spearman r = − 0.234, p = 0.020). We found no associations between plasma levels of the proteins at 6 weeks and outcomes. Conclusions Shedding of the complement regulators CD46 and CD59 in plasma in the acute phase of ACS is associated with a negative prognosis. Plasma sCD46 and sCD59 could reflect the degree of local immune activation and serve as prognostic biomarkers in ACS patients.

Abstract Aims Parameters derived from reservoir‐excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir‐excess pressure parameters could have a detrimental effect on highly‐perfused organs like the heart. We aimed to cross‐sectionally determine whether reservoir‐excess pressure parameters were associated with N‐terminal pro‐brain‐type natriuretic peptide (NT‐proBNP) in older adults. Methods We studied 868 older adults with diverse cardiovascular risk. Reservoir‐excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT‐proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. Results Multivariable linear regression analyses revealed that all reservoir‐excess pressure parameters studied were associated with NT‐proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [β = 0.191 (95% confidence interval, CI: 0.099, 0.283), P

Abstract The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

Abstract Background The molecular pathways linking short and long sleep duration with incident diabetes mellitus (iDM) and incident coronary heart disease (iCHD) are not known. We aimed to identify circulating protein patterns associated with sleep duration and test their impact on incident cardiometabolic disease. Methods We assessed sleep duration and measured 78 plasma proteins among 3336 participants aged 46–68 years, free from DM and CHD at baseline, and identified cases of iDM and iCHD using national registers. Incident events occurring in the first 3 years of follow-up were excluded from analyses. Tenfold cross-fit partialing-out lasso logistic regression adjusted for age and sex was used to identify proteins that significantly predicted sleep duration quintiles when compared with the referent quintile 3 (Q3). Predictive proteins were weighted and combined into proteomic scores (PS) for sleep duration Q1, Q2, Q4, and Q5. Combinations of PS were included in a linear regression model to identify the best predictors of habitual sleep duration. Cox proportional hazards regression models with sleep duration quintiles and sleep-predictive PS as the main exposures were related to iDM and iCHD after adjustment for known covariates. Results Sixteen unique proteomic markers, predominantly reflecting inflammation and apoptosis, predicted sleep duration quintiles. The combination of PSQ1 and PSQ5 best predicted sleep duration. Mean follow-up times for iDM (n = 522) and iCHD (n = 411) were 21.8 and 22.4 years, respectively. Compared with sleep duration Q3, all sleep duration quintiles were positively and significantly associated with iDM. Only sleep duration Q1 was positively and significantly associated with iCHD. Inclusion of PSQ1 and PSQ5 abrogated the association between sleep duration Q1 and iDM. Moreover, PSQ1 was significantly associated with iDM (HR = 1.27, 95% CI: 1.06–1.53). PSQ1 and PSQ5 were not associated with iCHD and did not markedly attenuate the association between sleep duration Q1 with iCHD. Conclusions We here identify plasma proteomic fingerprints of sleep duration and suggest that PSQ1 could explain the association between very short sleep duration and incident DM.

Based on disappointing results of stem cell-based application in clinical trials for patients with critical limb ischemia, we hypothesized that the acidic environment might be the key factor limiting cell survival and function. In the present study, we used microdialysis to determine presence of acidosis and metabolic imbalance in critical ischemia. Moreover, we explored the effect of extracellular acidosis on adipose-derived stem cells (ADSCs) at molecular and transcriptional level. Our data demonstrate that low pH negatively regulates cell proliferation and survival, also, it results in cell cycle arrest, mitochondrial dynamics disorder, DNA damage as well as the impairment of proangiogenic function in a pH-dependent manner. Further transcriptome profiling identified the pivotal signaling pathways and hub genes in response to acidosis. Collectively, these findings provide strong evidences for a critical role of acidosis in ADSCs impairment with ischemic condition and suggest treatments focus on tissue pH balance and acidosis-mediated hub genes may have therapeutic potential in stem cell-based application.

The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.

Abstract Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract

Abstract Aim The aim of the study was to translate, adapt and validate the instrument Basel Extent of Rationing of Nursing Care for Nursing Homes and Home Care for use in the Swedish community health care context. Design A cross‐sectional study. Data were collected from October 2019 to January 2020, and the questionnaire was sent to Registered Nurses, Enrolled Nurses and assistant nurses. Methods The study was performed in four phases: (1) translation, (2) adaptation of the Basel Extent of Rationing of Nursing Care for Nursing Homes and Home Care to the Swedish context, (3) content validity testing, and (4) evaluation of psychometric properties. The collected data resulted in 611 responses. Explorative factor analysis was performed to explore the interrelationship, and Cronbach's alpha was used to evaluate the internal consistency. Results Explorative factor analysis presented six factors/subscales: (1) fundamental care, (2) timely needed‐based care, (3) dignity and support, (4) ensuring respectful treatment, (5) social activities, and (6) documentation, planning and reporting. The Cronbach's alpha for the components showed values between 0.7 and 0.9. Conclusion The analyses indicate an instrument to be usable for Enrolled Nurses and nurse assistants in community health care. Additional tests, can contribute to refining the content of the items and further test reliability and validity of the instrument. No patient or public contribution As this is a study of translation and validation of the instrument Basel Extent of Rationing of Nursing Care for Nursing Homes and Home Care.

AbstractBackground There is an unmet clinical need for novel therapies addressing the residual risk in patients receiving guideline preventive therapy for coronary heart disease. Experimental studies have identified a pro-atherogenic role of the oxidized LDL receptor LOX-1. We investigated the association between circulating soluble LOX-1 (sLOX-1) and the risk for development of myocardial infarction.Methods The study subjects (n = 4658) were part of the Malmö Diet and Cancer study. The baseline investigation was carried out 1991-1994 and the incidence of cardiovascular events monitored through national registers during a of 19.5 ± 4.9 years follow-up. sLOX-1 and other biomarkers were analyzed by proximity extension assay and ELISA in baseline plasma.Results Subjects in the highest tertile of sLOX-1 had an increased risk of myocardial infarction (hazard ratio (95% CI) 1.76 (1.40-2.21) as compared with those in the lowest tertile. The presence of cardiovascular risk factors was related to elevated sLOX-1, but the association between sLOX-1 and risk of myocardial infarction remained significant when adjusting for risk factors.Conclusions In this prospective population study we found an association between elevated sLOX-1, the presence of carotid disease and the risk for first-time myocardial infarction. Taken together with previous experimental findings of a pro-atherogenic role of LOX-1, this observation supports LOX-1 inhibition as a possible target for prevention of myocardial infarction.

Background: Nursing students should develop sufficient professional competence during their nursing education as a prerequisite for providing safe care of high quality utilizing a holistic approach that suits the caring context of their patients. Despite the abundance of studies on professional competence in international literature such as the Scandinavian countries, there are no studies conducted in the Middle East in general and in Saudi Arabia in particular. Aim: The current report is part of a larger study that assessed the self-reported professional competence of newly graduated nursing students in Saudi Arabia. Setting and Design: A cross-sectional correlational study was carried out with a convenience sample of 317 senior Saudi students at the point of graduation from a nursing college affiliated with a public university in Saudi Arabia. Materials and Methods: Data was collected using the Nurse Professional Competence (NPC) Scale – a short version consisting of 35 items and the 10-item General Self-Efficacy (GSE) Scale. Statistical Analysis: The mean scores were calculated for the competency areas, and the median score and interquartile were used for nonparametric variables that were not normally distributed (Shapiro–test). The Chi-square test for data between groups, the Kruskal–Wallis test for comparing more than two independent groups, and Mann–Whitney U-test for comparing two independent groups. In addition, Spearman correlation coefficients to test correlations between groups and the NPC Scale. Results: Students scored highest in the competence areas of nursing care, value-based nursing care, and care pedagogics and lowest scores in the areas of documentation and administration of nursing care, development, leadership and organization of nursing care, and medical and technical care. Professional competence was significantly associated with students' quality of health and GSE. Conclusion: It is important to incorporate competencies in the nursing program and to assess newly graduated students' competence upon graduation. We suggest a follow-up study of these graduates to assess the development of professional competencies and self-efficacy across their internship years.

Abstract Aim To examine the extent and nature of missed nursing care in elderly care in community healthcare contexts from the perspective of healthcare staff, and to identify instruments used to measure missed nursing care and the content of these instruments. Design Scoping review. Methods Searches were conducted in the CINAHL, PubMed, Scopus and Google Scholar databases in March 2020. The selection process followed the PRISMA flow diagram. Results Sixteen research papers were found from nine countries. The instruments used in the studies were Basel Extent of Rationing of Nursing Care for nursing homes (BERNCA‐NH), modified MISSCARE survey and study‐specific instruments or items. The item content differed, as did the number of items, which was between one and 44. The studies reported values for missed nursing care, as well as described reasons for and/or the relation between missed nursing care and organization, working climate and patient outcomes.

Abstract Background Individually designed interventions delivered through mobile health applications (mHealth apps) may be able to effectively support diabetes self-care. Our aim was to review and synthesize available evidence in the literature regarding perception of adults with type 1 diabetes on the features of mHealth apps that help promote diabetes self-care, as well as facilitators and barriers to their use. An additional aim was to review literature on changes in patient reported outcome measures (PROMs) in the same population while using mHealth apps for diabetes self-care. Methods Quantitative and qualitative studies focusing on adults aged 18 years and over with type 1 diabetes in any context were included. A systematic literature search using selected databases was conducted. Data was synthesised using narrative synthesis. Results We found that features of mHealth apps designed to help promote and maintain diabetes self-care could be categorized into self-care data monitoring, app display, feedback & reminders, data entry, data sharing, and additional features. Factors affecting the use of mHealth apps reported in the literature were personal factors, app design or usability factors, privacy and safety factors, or socioeconomic factors. Quality of life and diabetes distress were the most commonly reported PROMs in the included studies. Conclusion We are unable to reach a conclusive result due to the heterogeneity of the included studies as well as the limited number of studies reporting on these areas among adults with type 1 diabetes. We therefore recommend further large-scale studies looking into these areas that can ultimately improve mHealth app use in type 1 diabetes self-care. Systematic review registration Prospero CRD42020157620 .

Abstract Background With an ageing population, there is an increasing need for care, both as home care and in nursing homes. However, some needed care is not carried out for different reasons, which can affect patient safety. The aim of the study was to describe prevalence, type, and reasons for missed nursing care in home care and nursing homes, from nurses’ perspective. Methods A cross sectional design with quantitative and qualitative approach. A Swedish version of Basel Extent of Rationing of Nursing Care for nursing homes and 15 study specific questions were answered by 624 registered nurses, enrolled nurses, or nurse assistants. Both descriptive and analytical, independent-samples t-test, analyses were used. Qualitative content analysis was used for the open-ended question. Results The care activity most often missed in home care was: ‘set up or update care plans’ (41.8%), and in nursing homes: ‘scheduled group activity’ (22.8%). Reasons for missed nursing care were lack of preparedness for unexpected situations, obstacles in a deficient work environment, unsatisfactory planning in the organisation, and/or shortcomings related to the individual. Conclusion Not all care activities needed are performed, due to reasons such as lack of time or organisational issues. Missed nursing care can lead to adverse events and affect patient safety. It is important to be aware of missed nursing care and the reasons for it, which gives a possibility to initiate quality improvement work to ensure patient safety.

Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.

Abstract Aim The aim of the study was to determine the psychometric properties, construct validity and internal consistency of the Chinese language version of the Nurse Professional Competence scale short form. Design A methodological design was used. Methods Questionnaire data from 260 nursing students nearing graduation from 2 universities in China were analysed using confirmatory factor analysis, known‐group validity and internal consistency. Results The confirmatory factor analysis revealed that the model was acceptable, and the analyses for known‐group validity revealed statistically significant differences in all factors and the total scale of the Nurse Professional Competence scale short form. Internal consistency revealed that Cronbach's alpha values exceeded 0.70 for all factors and the total scale. The Chinese language version of the Nurse Professional Competence scale short form has acceptable construct validity and good internal consistency.

Abstract Background The relationship between growth differentiation factor 15 (GDF-15) and the development of chronic kidney disease (CKD) is still unclear. We sought to examine whether plasma GDF-15 was related to incident CKD and kidney function decline using a large prospective cohort study. Methods 4318 participants of the Malmö Diet and Cancer Study-Cardiovascular Cohort were examined in 1991-1994. Incidence of CKD was followed prospectively by linkage with national patient registers. Estimated glomerular filtration rate (eGFR) was available for all participants at baseline, and was re-measured in a subgroup of 2744 subjects after 16.6 ± 1.49 years. Incidence of CKD was examined in relation to GDF-15 using Cox regression analysis. Logistic regression was used to examine the association of GDF-15 with eGFR change and eGFR-based CKD. Models were carefully corrected for potential confounders including baseline eGFR, N-terminal pro-B-type natriuretic peptide, and competing risk from death. Results 165 patients developed CKD after 19.2 ± 4.04 years of follow-up. The adjusted hazard ratio (95% confidence interval, CI) for CKD in 4th versus 1st quartile of GDF-15 was 2.37 (1.33, 4.24) (p for trend

Abstract Aim To explore and present an overview of scope of practice among registered nurses and paramedics with an advanced level of education in pre‐hospital and in‐hospital emergency care. Design An integrative literature review. Method Studies published between 2006 and 2018 were retrieved by searching the databases CINAHL, PubMed, Scopus and Web of Science. Studies were selected by three independent researchers, and data were synthesized using thematic analysis. Results The 25 studies identified focused on in‐hospital (n = 15) and pre‐hospital emergency care (n = 10) and included 13 professional titles originated from seven countries. The thematic analysis disclosed four themes; “Versatile care,” “Safe care based on precision and accuracy,” “Autonomous performance within boundaries” and “Beneficial towards patients and society.” Advanced paramedics’ and advanced nurses’ services are characterized as safe, of high quality and of public benefit. Their services are being used in everyday practice as well as directed to certain categories of patients.

Background and Purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necrosis factor receptor superfamily and well known for their involvement in inflammatory diseases: atherosclerotic mouse models with disrupted CD40 signalling develop lesions of reduced size with a more stable plaque profile. This study investigated the potential of plasma and intraplaque levels of CD40 and CD40L as markers for cardiovascular disease (CVD) in humans and their association with plaque stability. Methods Soluble CD40 and CD40L (sCD40L) were measured in plasma in 1,437 subjects from The SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort. Intra-plaque levels of sCD40 and sCD40L were measured in atherosclerotic plaque homogenates from 199 subjects of the Carotid Plaque Imaging Project (CPIP) cohort. Results Both plasma sCD40 and sCD40L levels were elevated in individuals with prevalent stroke, while sCD40 levels also were higher in individuals with a prior acute myocardial infarction. Plasma levels of sCD40 correlated with carotid intima-media thickness and total carotid plaque area and were associated with risk of cardiovascular events over a 3-year follow-up period. Intra-plaque levels of sCD40 and sCD40L were associated with plaque components characteristic for plaque vulnerability and extracellular matrix remodelling. Conclusions Higher plasma sCD40 and sCD40L levels are associated with prevalent CVD. Plasma sCD40 levels also correlate with the severity of carotid atherosclerosis and predict future cardiovascular events, while intra-plaque levels correlate with a vulnerable plaque phenotype. Our findings thus demonstrate that elevated levels of sCD40 and sCD40L are markers of CVD.

Major clinical centers in Sweden have witnessed an inflow of patients with chronic symptoms following initial outpatient care for coronavirus disease-2019 (COVID-19) infection, suggestive of postural orthostatic tachycardia syndrome. This report presents the first case series of 3 Swedish patients diagnosed with postural orthostatic tachycardia syndrome more than 3 months after the primary COVID-2019 infections. (Level of Difficulty: Intermediate.)

Abstract Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE-/- mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.

Abstract Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P

Abstract Background Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target. Methods Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers. Results Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p

Abstract Aims Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch‐induced circulating biomarkers for predicting hypertension‐associated HF. Methods and results Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch‐activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1–48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P

Abstract Aim To explore and describe changes in self‐assessed clinical competence and the need for further training among newly graduated Registered Nurses during their first 15 months of professional work in acute care hospital settings. Design Quantitative longitudinal design. Methods The 50‐item Professional Nurse Self‐Assessment Scale of clinical core competencies II was used. A total of 45 newly graduated Registered Nurses answered the questionnaire at four different occasions. Data were collected after 2, 5, 9 and 15 months of working experience. Result The components “ethical decision‐making,” “cooperation and consultation” and “clinical leadership” were rated highest in clinical competence and lowest in need for further training. The components “professional development” and “critical thinking” were rated lowest in clinical competence and “direct clinical practice” rated highest in need for further training. The clinical competence increased significant between 9–15 months, with the exception of “critical thinking” and need for further training decreased significantly between 9–15 months, with the exception of “critical thinking.”

Objectives: This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist. Background: Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist. Methods: PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses. Results: As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease. Conclusions: PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908)

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Summary: Experimental studies have suggested an atheroprotective role of interleukin (IL)-5 through the stimulation of natural immunoglobulin M antibody expression. In the present study we show that there are no associations between baseline levels of IL-5 and risk for development of coronary events or stroke during a 15.7 ± 6.3 years follow-up of 696 subjects randomly sampled from the Malmö Diet and Cancer study. However, presence of a plaque at the carotid bifurcation was associated with lower IL-5 and IL-5 deficiency resulted in increased plaque development at sites of oscillatory blood flow in Apoe−/− mice suggesting a protective role for IL-5 in plaque development. Key Words: interleukin 5, atherosclerosis, myocardial infarction, stroke

Abstract Background Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin−CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE−/−) mice. Results Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE−/− mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE−/− recipients on high fat diet. ApoE−/− mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma. Conclusions With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE−/− mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.

Abstract Background The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the inter-relationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM). Methods In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s′) and early diastolic (e′) longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12. Results T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL (P

Background The balance between stabilizing and destabilizing atherosclerotic plaque components is used in experimental studies and in imaging studies to identify rupture prone plaques. However, we lack the evidence that this balance predicts future cardiovascular events. Here we explore whether a calculated histological ratio, referred to as vulnerability index (VI), can predict patients at higher risk to suffer from future cardiovascular events. Methods and Results Carotid plaques and clinical information from 194 patients were studied. Tissue sections were used for histological analysis to calculate the VI (CD68 [cluster of differentiation 68], alpha‐actin, Oil red O, Movat pentachrome, and glycophorin A). Postoperative cardiovascular events were identified through the Swedish National Inpatient Health Register (2005–2013). During the follow‐up (60 months) 45 postoperative cardiovascular events were registered. Patients with a plaque VI in the fourth quartile compared with the first to third quartiles had significantly higher risk to suffer from a future cardiovascular event (P=0.0002). The VI was an independent predictor and none of the 5 histological variables analyzed separately predicted events. In the 13 patients who underwent bilateral carotid endarterectomy, the VI of the right plaque correlated with the VI of the left plaque and vice versa (r=0.7, P=0.01). Conclusions Our findings demonstrate that subjects with a high plaque VI have an increased risk of future cardiovascular events, independently of symptoms and other known cardiovascular risk factors . This strongly supports that techniques which image such plaques can facilitate risk stratification for subjects in need of more intense treatment.

Background: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). Methods: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. Results: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m 2 . Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). Conclusions: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.

Abstract The mechanisms responsible for macrovascular complications in diabetes remain to be fully understood. Recent studies have identified impaired vascular repair as a possible cause of plaque vulnerability in diabetes. This notion is supported by observations of a reduced content of fibrous proteins and smooth muscle cell mitogens in carotid endarterectomy from diabetic patients along with findings of decreased circulating levels of endothelial progenitor cells. In the present study we used a diabetic mouse model to characterize how hyperglycemia affects arterial repair responses. We induced atherosclerotic plaque formation in ApoE-deficient (ApoE−/−) and heterozygous glucokinase knockout ApoE-deficient mice (ApoE−/− GK+/−) mice with a shear stress-modifying cast. There were no differences in cholesterol or triglyceride levels between the ApoE−/− and ApoE−/− GK+/− mice. Hyperglycemia did not affect the size of the formed atherosclerotic plaques, and no effects were seen on activation of cell proliferation, smooth muscle cell content or on the expression and localization of collagen, elastin and several other extracellular matrix proteins. The present study demonstrates that hyperglycemia per se has no significant effects on tissue repair processes in injured mouse carotid arteries, suggesting that other mechanisms are involved in diabetic plaque vulnerability.

Background: An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods: Fas ligand was used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic β-cells and release of TNFR-1, TRAILR-2 and Fas measured by ELISA. Proximity Extension Assay was used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malmö Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results: Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlated with markers of impaired glucose metabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion: The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors are markers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions.

Abstract Several large-scale genome-wide association studies have identified single-nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype in humans has not been investigated. Carotid plaques (n = 206) from patients with and without cerebrovascular symptoms were analyzed for expression of ADAMTS-7 by immunohistochemistry and correlated to components associated with plaque vulnerability. Plaques from symptomatic patients showed increased levels of ADAMTS-7 compared with lesions from asymptomatic patients. High levels of ADAMTS-7 correlated with high levels of CD68-staining and lipid content, but with low smooth muscle cell and collagen content, which together are characteristics of a vulnerable plaque phenotype. ADAMTS-7 levels above median were associated with increased risk for postoperative cardiovascular events. Our data show that ADAMTS-7 is associated with a vulnerable plaque phenotype in human carotid lesions. These data support previous observations of a potential proatherogenic role of ADAMTS-7.

Background When the lectinlike oxidized low‐density lipoprotein (oxLDL) receptor‐1 (LOX‐1), a scavenger receptor for oxLDL, binds oxLDL, processes leading to endothelial dysfunction and inflammation are promoted. We aimed to study release mechanisms of LOX‐1 and how circulating levels of soluble LOX‐1 (sLOX‐1) relate to plaque inflammation and future risk for ischemic stroke. Methods and Results Endothelial cells and leukocytes were used to study release of sLOX‐1. Plasma levels of sLOX‐1 were determined in 4703 participants in the Malmö Diet and Cancer cohort. Incidence of ischemic stroke was monitored. For 202 patients undergoing carotid endarterectomy, levels of sLOX‐1 were analyzed in plasma and plaque homogenates and related to plaque inflammation factors. Endothelial cells released sLOX‐1 when exposed to oxLDL. A total of 257 subjects experienced stroke during a mean follow‐up of 16.5 years. Subjects in the highest tertile of sLOX‐1 had a stroke hazard ratio of 1.75 (95% CI, 1.28–2.39) compared with those in the lowest tertile after adjusting for age and sex. The patients undergoing carotid endarterectomy had a significant association between plasma sLOX‐1 and the plaque content of sLOX‐1 (r=0.209, P=0.004). Plaques with high levels of sLOX‐1 had more oxLDL, proinflammatory cytokines, and matrix metalloproteinases. Conclusions Our findings demonstrate that oxLDL induces the release of sLOX‐1 from endothelial cells and that circulating levels of sLOX‐1 correlate with carotid plaque inflammation and risk for ischemic stroke. These observations provide clinical support to experimental studies implicating LOX‐1 in atherosclerosis and its possible role as target for cardiovascular intervention.

Background: Central haemodynamic parameters derived from reservoir pressure analysis (RPA-parameters) exhibit prognostic utility. Alterations in reservoir function could have an unfavourable influence on target organs, such as the kidneys. We determined in older adults whether these RPA-parameters would be associated with the reduction in estimated glomerular filtration rate (eGFR) during a 3-year follow-up period. Methods: We studied 544 individuals (69.4 ± 7.9 yrs, 195F, 235CVD) at baseline and after 3 years. RPA-parameters including reservoir pressure integral (INTPR), peak reservoir pressure, excess pressure integral, systolic and diastolic rate constants were obtained by radial artery tonometry. Results: After 3 years, 95 individuals (72.4 ± 7.6 yrs, 26F) had an eGFR reduction of more than 5 ml/min/1.73 m2/year. A multivariate logistic regression analysis revealed that baseline INTPR was independently associated with the eGFR reduction after adjusting for conventional risk factors and baseline renal function [odds ratio 0.975 (95% CI, 0.958–0.993), p < 0.01]. When the eGFR reduction was expressed as a continuous variable, baseline INTPR was also independently associated with changes in eGFR (β = 0.115, p < 0.01; multivariate linear regression with adjustment for conventional risk factors and baseline renal function). These associations remained unchanged after further adjustments for central artery stiffness or traditional central haemodynamic parameters. No other RPA-parameters exhibited significant associations. Conclusions: These findings demonstrate that baseline INTPR is independently associated with the eGFR reduction in older adults, suggesting that INTPR may play a role in the functional decline of the kidneys.

Background Patients with atherosclerosis have a high risk of cardiovascular events and death. Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix proteins in the intima. We hypothesized that dysregulated remodeling of the basement membrane proteins may be associated with clinical outcomes in patients with atherosclerosis. Methods and Results Neoepitope fragments of collagen type IV (C4M) and laminin (LG1M) were assessed by ELISAs in serum from 787 endarterectomy patients. Matrix metalloproteinases were measured using proximity extension assay and correlated to C4M and LG1M levels using Spearman correlations. A total of 473 patients were followed up for 6 years using national registers, medical charts, and telephone interviews. The incidence of cardiovascular events, cardiovascular mortality, and all‐cause mortality were associated to levels of C4M and LG1M using Kaplan–Meier curves and Cox regression analyses. A total of 101 patients had cardiovascular events, 39 died of cardiovascular mortality, and 64 patients died from all‐cause mortality. C4M levels were increased in patients with symptomatic carotid atherosclerotic disease before surgery (P=0.048). High C4M and LG1M levels were associated with increased risk of all‐cause mortality (P=0.020 and 0.031, respectively) and predicted all‐cause death together with glomerular filtration rate and diabetes mellitus. Conclusions High LG1M and C4M levels were associated with all‐cause mortality, together with glomerular filtration rate and diabetes mellitus. These novel biomarkers need further evaluation but might be tools to identify high‐risk patients.

The idea behind care choice is that healthcare providers would be more responsive to patients’ health problems and needs and in doing so compete with increased quality and that patients should be able to choose from this. The question is how patients choose a healthcare provider by themselves. The aim was to describe what affected when patients chose healthcare providers. A literature review was carried out. The results showed that patients’ choice of healthcare providers depended on the following three themes: their own care experiences, caring relationships with staff and service provided by caregivers. The underlying idea of care choice is competition based on quality of care, but the results show that patients make their choices based on other factors as described in the result and therefore improvement can be achieved if focus is placed on being responsive for patient care needs. patient participation; primary care; caring needs; qualtiy of care; care choice; caring science pasientdeltakelse; primæromsorg; omsorgsbehov; kvalitet på omsorg; omsorg valg; omsorgsfull vitenskap

Background: Collagen type IV is the major constituent of basement membranes underlying endothelial cells and is important for endothelial cell attachment and function. Autoantibodies against native collagen type IV have been found in various autoimmune diseases. Oxidation of LDL in the vascular wall results in the formation of reactive aldehydes, which could modify surrounding matrix proteins. Like oxidized LDL, these modified matrix proteins are likely to induce immune responses. We examined whether autoantibodies against native or aldehyde-modified collagen type IV are associated with myocardial infarction. Methods: IgM and IgG against native and aldehyde-modified collagen type IV were measured by ELISA in serum from 387 survivors of a first myocardial infarction and 387 age- and sex-matched controls. Results: Post-infarction patients had significantly increased levels of IgM against native collagen type IV, and IgG against native collagen type IV was present at detectable level in 17% of patients as opposed to 7% of controls (p

This symposium was focused on reviewing androgen deprivation therapy (ADT) in prostate cancer, highlighting the implications of this therapy in clinical practice and including a focus on the cardiovascular (CV) risk associated with ADT therapy.

Background Myeloid cells play a central role in atherosclerosis. We investigated the associations between the plasma levels of growth factors and chemokines that regulate myeloid cell homeostasis and function and the risk of first‐time acute coronary events in middle‐aged persons. Methods and Results We measured baseline plasma levels of macrophage colony‐stimulating factor; monocyte chemotactic protein 1; C‐C motif chemokine ligands 3, 4, and 20; C‐X‐C motif chemokine ligands 1, 6, and 16; and C‐X3‐C motif chemokine ligand 1 in 292 participants who had a coronary event during follow‐up and 366 controls matched for age, sex, and time of inclusion who remained event free. Study participants were recruited from the Malmö Diet and Cancer Study population cohort and had no previous history of coronary artery disease. We found a strong independent negative association between macrophage colony‐stimulating factor and incident coronary events in a forward stepwise Cox proportional hazards model including all biomarkers alongside the classic Framingham risk factors (age, sex, smoking, total cholesterol, high‐density lipoprotein cholesterol, systolic blood pressure), diabetes mellitus, and medication. Conversely, monocyte chemotactic protein 1 had the strongest independent positive association with the outcome. The addition of macrophage colony‐stimulating factor and monocyte chemotactic protein 1 significantly improved the predictive ability of a model including traditional risk factors alone (C statistic 0.81 [95% CI 0.78–0.84] versus 0.67 [95% CI 0.63–0.71]; net reclassification index 0.52 [0.42–0.62]; P

Although cancer promotes inflammation, the role of inflammation in tumor-genesis is less well established. The aim was to examine if low-grade inflammation is related to post-menopausal breast cancer risk, and if obesity modifies this association.In the Malmö Diet and Cancer cohort, a nested case-control study was defined among 8,513 women free of cancer and aged 55-73 years at baseline (1991-96); 459 were diagnosed with invasive breast cancer during follow-up (until December 31st, 2010). In laboratory analyses of blood from 446 cases, and 885 controls (matched on age and date of blood sampling) we examined systemic inflammation markers: oxidized (ox)-LDL, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, white blood cells, lymphocytes and neutrophils. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer risk was calculated using multivariable conditional logistic regression.Inverse associations with breast cancer were seen in fully-adjusted models, for 2nd and 3rd tertiles of ox-LDL, OR (95% CI): 0.65 (0.47-0.90), 0.63 (0.45-0.89) respectively, p-trend = 0.01; and for the 3rd tertile of TNF-α, 0.65 (0.43-0.99), p-trend = 0.04. In contrast, those in the highest IL-1β category had higher risk, 1.71 (1.05-2.79), p-trend = 0.01. Obesity did not modify associations between inflammation biomarkers and breast cancer.Our study does not suggest that low-grade inflammation increase the risk of post-menopausal breast cancer.

The aim of this study was to test the hypothesis that autoantibodies recognize amino acid sequences in the LDL receptor binding region of apolipoprotein B-100 (apoB-100). Autoantibodies against an unmodified or malondialdehyde (MDA)-modified LDL receptor binding site peptide were determined by ELISA in baseline plasma samples of 78 cases with coronary events and 149 matched controls recruited from the prospective Malmö Diet Cancer Study. IgG and IgM recognizing this peptide were detected in all subjects but did not differ between cases and controls. Inverse associations were observed between IgG against the native binding site and plasma oxidized LDL (r = −0.21, P < 0.005), but there were no significant associations with total or LDL cholesterol levels. In univariate analyses, inverse associations were found between baseline carotid intima-media thickness and IgG against the MDA-modified binding site (r = −0.14, P < 0.05), but this association was lost when controlling for other major cardiovascular risk factors. Specificity studies demonstrated that the binding of autoantibodies to these sequences could be inhibited by oxidized but not by native LDL. Autoantibodies recognizing the LDL receptor binding site in apoB-100 are frequently expressed. Their association with plasma oxidized LDL suggests that they have been generated in response to breakdown products of LDL oxidation, but their influence on cholesterol metabolism and the development of atherosclerosis appears limited.

Atherosclerotic plaques with a low content of connective tissue proteins are believed to have an increased risk of rupture and to give rise to clinical events. The aim of the present study was to investigate if the content of elastin, collagen and of the matrix metalloproteinase (MMP) -1, -3, -9 and -12 in plaques removed at surgery can be associated with the occurrence of ipsilateral symptoms.The atherosclerotic plaques of 221 patients undergoing carotid endarterectomy were analyzed and their composition was related to the incidence of preoperative, intraoperative and postoperative neurological events.Elastin, collagen and MMP-12 contents were lower in males and diabetic patients. Elastin (P .010), MMP-3 (P .008) and MMP-9 (P < .0001) were lower, while MMP-1 (P .004) and MMP-9 (P .002) were higher in plaques of patients with preoperative symptoms, even after correction for the time between the occurrence of symptoms and surgery. Elastin and MMP-12 decreased (r = -0.17, P .009 and r = -.288, P

IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s) as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice.Administration of 1 μg IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apo)E deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC) natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 μg IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease.The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.