The risk of stroke recurrence in patients with atrial fibrillation and reduced ejection fraction

Abstract Background: Atrial fibrillation (AF) and congestive heart failure often coexist due to their shared risk factors leading to potential worse outcome, particularly cerebrovascular events. The aims of this study were to calculate the rates of ischemic and severe bleeding events in ischemic stroke patients having both AF and reduced ejection fraction (rEF) (⩽40%), compared to ischemic stroke patients with AF but without rEF. Methods: We performed a retrospective analysis that drew data from prospective studies. The primary outcome was the composite of either ischemic (stroke or systemic embolism), or hemorrhagic events (symptomatic intracranial bleeding and severe extracranial bleeding). Results: The cohort for this analysis comprised 3477 patients with ischemic stroke and AF, of which, 643 (18.3%) had also rEF. After a mean follow-up of 7.5 ± 9.1 months, 375 (10.8%) patients had 382 recorded outcome events, for an annual rate of 18.0%. While the number of primary outcome events in patients with rEF was 86 (13.4%), compared to 289 (10.2%) for the patients without rEF; on multivariable analysis rEF was not associated with the primary outcome (OR 1.25; 95% CI 0.84–1.88). At the end of follow-up, 321 (49.9%) patients with rEF were deceased or disabled (mRS ⩾3), compared with 1145 (40.4%) of those without rEF; on multivariable analysis, rEF was correlated with mortality or disability (OR 1.35; 95% CI 1.03–1.77). Conclusions: In patients with ischemic stroke and AF, the presence of rEF was not associated with the composite outcome of ischemic or hemorrhagic events over short-term follow-up but was associated with increased mortality or disability

Hemorrhagic Transformation in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Time to Initiation of Oral Anticoagulant Therapy and Outcomes.

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with  HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability

P2Y12 inhibitors plus aspirin for acute treatment and secondary prevention in minor stroke and high-risk transient ischemic attack: A systematic review and meta-analysis

Background: Aspirin is a cornerstone of preventive treatment for stroke recurrence, but during the last few years the role of dual antiplatelet therapy (DAPT) is much more emerging.Objective: This systematic review aimed to compare early use of P2Y12 inhibitors (clopidogrel/ticagrelor) plus aspirin to aspirin alone for acute treatment and secondary prevention in acute non-cardioembolic minor ischemic stroke or TIA.Methods: A systematic search on MEDLINE and EMBASE was performed. Treatment effects were estimated with RRs and 95% CI. We used RevMan 5.4 for data analyses. We assessed methodological quality of selected studies according to Rob2 tools and quality of evidence with GRADE approach.Results: Four RCTs were included, enrolling 21,459 patients. Compared to aspirin alone, DAPT was superior in reducing stroke recurrence (RR 0.74, 95% CI 0.67-0.82, P<0.00001, absolute risk difference by 2%, NNT 50) and disabling stroke defined as mRS>2 (RR 0.84, 95% CI 0.75-0.95, P=0.004), with no impact on all causes of mortality (RR 1.30, 95% CI 0.90-1.89, P=0.16). An increased risk of major bleeding was emerged (RR 2.54, 95% CI 1.65-3.92, P<0.0001, absolute risk difference by 0,4%, NNH 250), in particular with ticagrelor, but there was no correlation between therapy duration and bleeding risk, as appeared from one-month (RR 3.06, 95% CI 1.64 to 5.69) and three-month (RR 2.09, 95% CI 1.18 to 3.69) follow-up analysis.Conclusions: Early administration of P2Y12 inhibitors plus aspirin in patients with acute non-cardioembolic minor ischemic stroke or TIA reduced the incidence of ischemic stroke recurrence, impacting more significantly than the increased bleeding risk and influencing patients' quality of life by reducing disabling stroke

Drug\u2013Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review

Background: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug\u2013drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. Methods: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. Results: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration\u2013time curve (AUC) by 138%, 103%, and 161%, respectively. Conclusions: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs

Drug\u2013Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review

Background: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug\u2013drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. Methods: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. Results: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration\u2013time curve (AUC) by 138%, 103%, and 161%, respectively. Conclusions: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs

Flexibility - Enabling technologies using electric vehicles

Electric car usage has been growing rapidly over the past ten years, cars stock in 2018 exceeded 5 millions, +63% from 2019, Europe is accounting for 24% of the global fleet. The request of fast, rapid and ultra rapid charge is, on the other side, posing electric power network challenges. In this scenario the DSO is interested in exploiting EV charges in terms of flexibility that can be planned in optimized way, especially when it is combined with high penetration of RES. This paper provides evidence that EVs charging sessions, planned using a dedicated forecasting module, can contribute to balance the distribution power network; for this purpose suitable flexibility-enabling technologies developed under the H2020 project SOFIE have been used. Data analysis has pointed out that a proper program of charging sessions could significantly increase self-consumption index; moreover, an optimal scheduling has been validated taking into account realistic constraints for its actual implementation. Finally, the paper shows how the enabling technologies for flexibility exploitation have been implemented and validated; notably, a rescheduling of the charging sessions is allowed through the usage of forecasting techniques as well as the implementation of blockchain technologies for enabling a flexibility marketplace

Combining a joint health supplement with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture. An exploratory controlled trial

Canine cranial cruciate ligament rupture (CrCLR) is a very common pathology. Surgical stabilization is the first choice treatment, although it does not fully eliminate the increased risk of osteoarthritis. This preliminary study was carried out to explore whether a newly formulated joint health supplement would benefit metabolic, clinical and radiographic changes in dogs with CrCLR surgically treated with tibial plateau leveling osteotomy (TPLO). Besides chondroitin sulfate and glucosamine hydrochloride, the studied supplement contained anti-inflammatory and antioxidant ingredients, the main ones being N-palmitoylD-glucosamine (Glupamid) and quercetin. It was thus intended to target not only chondrodegenerative components of osteoarthritis, but also post-injury inflammatory response and oxidative stress of joint tissues. Thirteen dogs underwent TPLO and were randomly allocated to treatment (n = 6) and control groups (n = 7), the former receiving the joint supplement for 90 days. Lameness and radiographic osteoarthritis changes were scored before (i.e., baseline) and at 30 and 90 days post-surgery. Synovial fluid samples were collected from injured stifles at the same time points. Levels of representative metabolites were measured by proton nuclear magnetic resonance spectroscopy in a blinded fashion. In the metabolomic analysis, special attention was paid to lactate, due to its emerging recognition as a key marker of inflammation. In the last time period (from the 30th to the 90th day), lameness improved by a factor of 2.3 compared to control dogs. No significant difference was observed in the radiographic osteoarthritis score between groups. In the first postoperative month, lactate and creatine levels significantly dropped in treated compared to control dogs. Compared to surgery alone, combining the joint supplement with TPLO resulted in a trend to a better clinical outcome in the later time interval but did not influence osteoarthritis radiographic progression. A significantly better rebalance of joint microenvironment in the early time interval (baseline - 30 days) was shown by metabolomic analysis, thus suggesting that the study supplement could limit ongoing inflammatory responses. (C) 2017 Faculty of Veterinary Medicine, Cairo University. Production and hosting by Elsevier B.V

Hedgehog signaling and osteoblast gene expression are regulated by purmorphamine in human mesenchymal stem cells

Several biological events are controlled by Hedgehog (Hh) signaling, including osteoblast phenotype development. This study aimed at evaluating the gene expression profile of human mesenchymal stem cells (hMSCs) treated with the Hh agonist, purmorphamine, focusing on Hh signaling and osteoblast differentiation. hMSCs from bone marrow were cultured in non-osteogenic medium with or without purmorphamine (2 mu M) for periods of up to 14 days. Purmorphamine up-regulated gene expression of the mediators of Hh pathway, SMO, PTCH1, GLI1, and GLI2. The activation of Hh pathway by purmorphamine increased the expression of several genes (e.g., RUNX2 and BMPs) related to osteogenesis. Our results indicated that purmorphamine triggers Hh signaling pathway in hMSCs, inducing an increase in the expression of a set of genes involved in the osteoblast differentiation program. Thus, we conclude that Hh is a crucial pathway in the commitment of undifferentiated cells to the osteoblast lineage. J. Cell. Biochem. 113: 204208, 2012. (C) 2011 Wiley Periodicals, Inc.State of Sao Paulo Research Foundation (FAPESP, Brazil)State of Sao Paulo Research Foundation (FAPESP), Brazi

In Vitro Proliferation and Osteoblastic Phenotype Expression of Cells Derived From Human Vertebral Lamina and Iliac Crest

Study Design. Osteoblastic cells derived from vertebral lamina and iliac crest were isolated and cultured under the same conditions (osteogenic medium, pH, temperature, and CO(2) levels). Objective. To compare proliferation and expression of osteoblastic phenotype of cells derived from vertebral lamina and iliac grafting. Summary of Background Data. Many factors play a role in the success of bone graft in spinal fusion including osteoblastic cell population. Two common sources of graft are vertebral lamina and iliac crest, however, differences in proliferation and osteoblastic phenotype expression between cells from these sites have not been investigated. Methods. Cells obtained from cancellous bone of both vertebral lamina and iliac crest were cultured and proliferation was evaluated by direct cell counting and viability detected by Trypan blue. Alkaline phosphatase (ALP) activity was evaluated by thymolphthalein release from thymolphthalein monophosphate and matrix mineralization by staining with alizarin red S. Gene expression of ALP, osteocalcin, runt-related transcription factor 2, Msh homeobox 2, bone morphogenetic protein 7, intercellular adhesion molecule 1 precursor, osteoprotegerin, and receptor activator of NF-kB ligand was analyzed by real-time PCR. All comparisons were donor-matched. Results. Proliferation was greater at days 7 and 10 in cells from vertebral lamina compared with ones from iliac crest without difference in cell viability. ALP activity was higher in cells from vertebral lamina compared with cells from iliac crest at days 7 and 10. At 21 days, mineralized matrix was higher in cells derived from vertebral lamina than from iliac crest. At day 7, gene expression of ALP, osteocalcin, runt-related transcription factor 2, Msh homeobox 2, bone morphogenetic protein 7, intercellular adhesion molecule 1 precursor, receptor activator of NF-kB ligand, and osteoprotegerin was higher in cells derived from vertebral lamina compared with iliac crest. Conclusion. Cell proliferation and osteoblastic phenotype development in cells derived from cancellous bone were more exuberant in cultures of vertebral lamina than of iliac crest

The Effect of TAK-778 on Gene Expression of Osteoblastic Cells Is Mediated Through Estrogen Receptor

This study evaluated the effect of TAK-778 [(2R, 4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide)] on in vitro osteogenic events and on gene expression of osteoblastic cells derived from human alveolar bone and the participation of estrogen receptors (ERs) on such effect. Osteoblastic cells were subcultured, with or without TAK-778 (10(-5) M), to evaluate cell growth and viability, total protein content, and alkaline phosphatase (ALP) activity at 7, 14, and 21 days; bone-like formation at 21 days; and gene expression, using cDNA microarray, at 7 days. Also, osteoblastic cells were exposed to TAK-778 (10-5 M) combined to ICI182,780, a nonspecific ER antagonist (10(-6) M), and gene expression was evaluated by real-time polymerase chain reaction (PCR) at 7 days. TAK-778 induced a reduction in culture growth and an increase in cell synthesis, ALP activity, and bone-like formation. The cDNA microarray showed genes associated with cell adhesion and differentiation, skeletal development, ossification, and transforming growth factor-P receptor signaling pathway, with a tendency to be higher expressed in cells exposed to TAK-778. The gene expression of ALP, osteocalcin, Msh homeobox 2, receptor activator of NF-kappa B ligand, and intercellular adhesion molecule 1 was increased by TAK-778 as demonstrated by real-time PCR, and this effect was antagonized by ICI182,780. The present results demonstrated that TAK-778 acts at a transcriptional level to enhance the in vitro osteogenic process and that its effect on gene expression of osteoblastic cells is mediated, at least partially, through ERs. Based on these findings, TAK-778 could be considered in the treatment of bone metabolic disorders. Exp Biol Med 234:190-199, 2009State of Sao Paulo Research Foundation (FAPESP)National Council for Scientific and Technological Development (CNPq