The causative agents in infective endocarditis: a systematic review comprising 33,214 cases.

Infective endocarditis (IE) incidence remains high with considerable fatality rates; guidelines for prophylaxis against IE are currently under review in some settings which highlights the importance of maintaining up-to-date epidemiological estimates about the most common microbial causes. The objective of this systematic review, following PRISMA guidelines, was to identify the most common microbial causes of IE in recent years. Medline was searched from January 1, 2003 to March 31, 2013 for all articles containing the term "infective endocarditis". All relevant studies reporting diagnostic results were included. Special patient subpopulations were assessed separately. A total of 105 studies were included, from 36 countries, with available data on a total of 33,214 cases. Staphylococcus aureus was found to be the most common microorganism, being the most frequent in 54.3 % of studies (N = 57) (and in 55.4 % of studies using Duke's criteria for diagnosis [N = 51]). Viridans group streptococci (VGS), coagulase-negative staphylococci (CoNS), Enterococcus spp and Streptococcus bovis were among the most common causes. S. aureus was the most common pathogen in almost all population subgroups; however, this was not the case in patients with implantable devices, prosthetic valves, or immunocompromised non-HIV, as well as in the sub-group from Asia, emphasizing that a global one-size-fits-all approach to the management of suspected IE is not appropriate. This review provides an evidence-based map of the most common causative agents of IE, highlighting S. aureus as the leading cause in the 21st century. The changing epidemiology of IE in some patient sub-groups in the last decade and the very high number of microbiologically undiagnosed cases (26.6 %) suggest the need to revisit IE prophylaxis and diagnostic strategies

Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture.; The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score.; This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint.; In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction.; Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score

Estimated pulse wave velocity improves risk stratification for all-cause mortality in patients with COVID-19

Accurate risk stratification in COVID-19 patients consists a major clinical need to guide therapeutic strategies. We sought to evaluate the prognostic role of estimated pulse wave velocity (ePWV), a marker of arterial stiffness which reflects overall arterial integrity and aging, in risk stratification of hospitalized patients with COVID-19. This retrospective, longitudinal cohort study, analyzed a total population of 1671 subjects consisting of 737 hospitalized COVID-19 patients consecutively recruited from two tertiary centers (Newcastle cohort: n = 471 and Pisa cohort: n = 266) and a non-COVID control cohort (n = 934). Arterial stiffness was calculated using validated formulae for ePWV. ePWV progressively increased across the control group, COVID-19 survivors and deceased patients (adjusted mean increase per group 1.89 m/s, P &lt; 0.001). Using a machine learning approach, ePWV provided incremental prognostic value and improved reclassification for mortality over the core model including age, sex and comorbidities [AUC (core model + ePWV vs. core model) = 0.864 vs. 0.755]. ePWV provided similar prognostic value when pulse pressure or hs-Troponin were added to the core model or over its components including age and mean blood pressure (p &lt; 0.05 for all). The optimal prognostic ePWV value was 13.0 m/s. ePWV conferred additive discrimination (AUC: 0.817 versus 0.779, P &lt; 0.001) and reclassification value (NRI = 0.381, P &lt; 0.001) over the 4C Mortality score, a validated score for predicting mortality in COVID-19 and the Charlson comorbidity index. We suggest that calculation of ePWV, a readily applicable estimation of arterial stiffness, may serve as an additional clinical tool to refine risk stratification of hospitalized patients with COVID-19 beyond established risk factors and scores

Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis

ObjectivesThe abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA).MethodsDNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of IFIT1, MX1 and IFI44, which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of IL1β, IL6, TNF, IL17A and IL23A was also assessed in PsA and control subgroups.ResultsIn PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean ± SD; 9.42 ± 2.71 vs 4.88 ± 1.98, p&lt;0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and IL6 RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 ± 6.99 vs 4.24 ± 4.26; p&lt;0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher IL1β expression, as well as in those with higher TNF/IL23A PBMCs expression.ConclusionDNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by &gt;2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-alpha, while silencing of NEAT1 profoundly attenuated the TNF-alpha-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-alpha-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD

A Simple Prognostic Score for Critical COVID-19 Derived from Patients without Comorbidities Performs Well in Unselected Patients

We aimed to search for laboratory predictors of critical COVID-19 in consecutive adults admitted in an academic center between 16 September 2020–20 December 2021. Patients were uniformly treated with low-molecular-weight heparin, and dexamethasone plus remdesivir when SpO2 n = 241, 49 year-old median, 71% males), 22 (9.1%) developed critical disease and 2 died (0.8%). White-blood-cell counts, neutrophils, neutrophil-to-lymphocyte ratio, CRP, fibrinogen, ferritin, LDH and γ-GT at admission were each univariably associated with critical disease. ROC-defined cutoffs revealed that CRP > 61.8 mg/L, fibrinogen > 616.5 mg/dL and LDH > 380.5 U/L were each associated with critical disease development, independently of age, sex and days from symptom-onset. A score combining higher-than-cutoff CRP (0/2), LDH (0/1) and fibrinogen (0/1) predicted critical disease (AUC: 0.873, 95% CI: 0.820–0.926). This score performed well in an unselected patient cohort (n = 1228, 100% unvaccinated) predominantly infected by the alpha variant (AUC: 0.718, 95% CI: 0.683–0.753), as well as in a mixed cohort (n = 527, 65% unvaccinated) predominantly infected by the delta variant (AUC: 0.708, 95% CI: 0.656–0.760). Therefore, we propose that a combination of standard biomarkers of acute inflammatory response, cell death and hypercoagulability reflects the severity of COVID-19 per se independently of comorbidities, age and sex, being of value for risk stratification in unselected patients

Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations

Purpose The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study, we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients. Methods Fifty-two consecutive COVID-19 patients-before dexamethasone treatment in cases required-recruited between April 15 to June 15, 2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8 a.m., 12, 6, and 10 p.m.), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients. Results Median CRP and IL-6 measurements were about sixfold higher in patients than controls (both p &lt; 0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391 (0.054, 0663) vs. 0.081 (0.054, 0.243) mu g/dl, p &lt; 0.001 and 0.183 (0.090, 0.834) vs. 0.054 (0.054, 0.332) mu g/dl, p &lt; 0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81 +/- 2.46 vs. 2.75 +/- 0.810, respectively, p &lt; 0.001). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, was strongly correlated with nocturnal cortisol salivary levels (rho = 0.555, p &lt; 0.001) in patients. Conclusions Increased evening and nocturnal but not morning cortisol secretion may occur in even clinically mild COVID-19. In the context of acute viral infection (COVID-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoidsecreting adrenal zonafasciculata without influencing the secretion of DHEA and aldosterone

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system

AIMS Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. METHODS AND RESULTS Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. CONCLUSIONS SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events. TRANSLATIONAL PERSPECTIVES This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting