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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 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.

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 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.

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 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

An amendment to this paper has been published and can be accessed via the original article.

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: 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.