Twenty years on from the introduction of the high risk strategy for stroke and cardiovascular disease prevention: a systematic scoping review.

BACKGROUND AND PURPOSE: Early this century, the high risk strategy of primary stroke and cardiovascular disease (CVD) prevention for individuals shifted away from identifying (and treating, as appropriate) all at-risk individuals towards identifying and treating individuals who exceed arbitrary thresholds of absolute CVD risk. The public health impact of this strategy is uncertain. METHODS: In our systematic scoping review, the electronic databases (Scopus, MEDLINE, Embase, Google Scholar, Cochrane Library) were searched to identify and appraise publications related to primary CVD/stroke prevention strategies and their effectiveness published in any language from January 1990 to August 2023. RESULTS: No published randomized controlled trial was found on the effectiveness of the high CVD risk strategy for primary stroke/CVD prevention. Targeting high CVD risk individuals excludes a large proportion of the population from effective blood-pressure-lowering and lipid-lowering treatment and effective CVD prevention. There is also evidence that blood pressure lowering and lipid lowering are beneficial irrespective of blood pressure and cholesterol levels and irrespective of absolute CVD risk and that risk-stratified pharmacological management of blood pressure and lipids to only high CVD risk individuals leads to significant underuse of blood-pressure-lowering and lipid-lowering medications in individuals otherwise eligible for such treatment. CONCLUSIONS: Primary stroke and CVD prevention needs to be done in all individuals with increased risk of CVD/stroke. Pharmacological management of blood pressure and blood cholesterol should not be solely based on the high CVD risk treatment thresholds. International guidelines and global strategies for primary CVD/stroke prevention need to be revised.

Endogenous piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic, can still infect populations in many countries around the globe. The Omicron strain is the most mutated variant of SARS-CoV-2. The high transmissibility of the strain and its ability to evade immunity necessitate a priority study of its properties in order to quickly create effective means of preventing its spread. The current research aimed to examine the in silico interaction between PIWI-interacting RNAs (piRNAs) and the SARS-CoV-2 genome (gRNA) to identify endogenous piRNAs and propose synthetic piRNAs with strong antiviral activity for drug development. This study used validated bioinformatic approaches regarding the interaction of more than eight million piRNAs with the SARS-CoV-2 genome. The piRNAs' binding sites (BSs) in the 5'UTR were located with overlapping nucleotide sequences termed clusters of BSs. Several BSs clusters have been found in the nsp3, nsp7, RNA-dependent RNA polymerase, endoRNAse, S surface glycoprotein, ORF7a, and nucleocapsid. Sixteen synthetic piRNAs that interact with gRNA have been proposed with free binding energy ranging from -170 kJ/mol to -175 kJ/mol, which can be used to create drugs that suppress the reproduction of SARS-CoV-2.

Safety and Outcomes of Intravenous Thrombolytic Therapy in Ischemic Stroke Patients with COVID-19: CASCADE Initiative.

BACKGROUND: There is little information regarding the safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke and COVID-19. METHODS: This multicenter study included consecutive stroke patients with and without COVID-19 treated with IV-tPA between February 18, 2019, to December 31, 2020, at 9 centers participating in the CASCADE initiative. Clinical outcomes included modified Rankin Scale (mRS) at hospital discharge, in-hospital mortality, the rate of hemorrhagic transformation. Using Bayesian multiple regression and after adjusting for variables with significant value in univariable analysis, we reported the posterior adjusted odds ratio (OR, with 95% Credible Intervals [CrI]) of the main outcomes. RESULTS: A total of 545 stroke patients, including 101 patients with COVID-19 were evaluated. Patients with COVID-19 had a more severe stroke at admission. In the study cohort, 85 (15.9%) patients had a hemorrhagic transformation, and 72 (13.1%) died in the hospital. After adjustment for confounding variables, discharge mRS score ≥2 (OR: 0.73, 95% CrI: 0.16, 3.05), in-hospital mortality (OR: 2.06, 95% CrI: 0.76, 5.53), and hemorrhagic transformation (OR: 1.514, 95% CrI: 0.66, 3.31) were similar in COVID-19 and non COVID-19 patients. High-sensitivity C reactive protein level was a predictor of hemorrhagic transformation in all cases (OR:1.01, 95%CI: 1.0026, 1.018), including those with COVID-19 (OR:1.024, 95%CI:1.002, 1.054). CONCLUSION: IV-tPA treatment in patients with acute ischemic stroke and COVID-19 was not associated with an increased risk of disability, mortality, and hemorrhagic transformation compared to those without COVID-19. IV-tPA should continue to be considered as the standard of care in patients with hyper acute stroke and COVID-19.

Prediction of miRNA interaction with mRNA of stroke candidate genes.

BACKGROUND: The role of miRNA in tissue affected by stroke is actively studied, but it remains unclear which miRNAs and target genes are involved in the development of stroke. METHODS: The MirTarget program defines the following features of a miRNA binding to a mRNA: the binding start site, the location of the binding site in mRNA, the free energy of a miRNA binding with a mRNA, and the interaction schemes of miRNA and mRNA. RESULTS: The interaction of 6565 miRNAs with mRNAs of stroke candidate genes was determined. The association of the mRNAs of stroke candidate genes with miRNAs depends on the level of gene expression. Some highly expressed candidate genes are targets of miR-619-5p and miR-5095, which have binding sites located on overlapping mRNA nucleotide sequences (clusters). miR-619-5p and miR-5095 bind to mRNA of 15 genes. Clusters for the binding of miR-1273f,d,e are in mRNAs of highly expressed genes. The start sites of miR-1273d and miR-1273e binding in all clusters are in sequences with one and ten nucleotides, respectively. The clusters of multiple miR-574-5p and ID00470.5p-miR binding sites and the clusters of the miR-466, ID01030.3p-miR, and ID00436.3p-miR binding sites are in mRNAs of some genes expressed at low levels. CONCLUSION: The organization of miRNA binding sites into clusters reduces the length of mRNA and creates competition between miRNAs for binding to mRNA of a target gene. The characteristics of miRNA associations with target genes can be used to recommend markers for a diagnosis of stroke.

Stroke Care Trends During COVID-19 Pandemic in Zanjan Province, Iran. From the CASCADE Initiative: Statistical Analysis Plan and Preliminary Results.

BACKGROUND: The emergence of the COVID-19 pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. This study examines the changes in stroke epidemiology and care during the COVID-19 pandemic in Zanjan Province, Iran. METHODS: This study is part of the CASCADE international initiative. From February 18, 2019, to July 18, 2020, we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in Valiasr Hospital, Zanjan, Iran. We used a Bayesian hierarchical model and an interrupted time series analysis (ITS) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the National Institutes of Health Stroke Scale (NIHSS)], disability [measured by the modified Rankin Scale (mRS)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. We compared in-hospital mortality between study periods using Cox-regression model. RESULTS: During the study period, 1,026 stroke patients were hospitalized. Stroke hospitalization rates per 100,000 population decreased from 68.09 before the pandemic to 44.50 during the pandemic, with a significant decline in both Bayesian [Beta: -1.034; Standard Error (SE): 0.22, 95% CrI: -1.48, -0.59] and ITS analysis (estimate: -1.03, SE = 0.24, p < 0.0001). Furthermore, we observed lower admission rates for patients with mild (NIHSS < 5) ischemic stroke (p < 0.0001). Although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (-10.1%; p = 0.004). We did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p < 0.0001). CONCLUSION: In Zanjan, Iran, the COVID-19 pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. Observed lower admission rates for milder stroke may possibly be due to fear of exposure related to COVID-19. The decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. The results of this research will contribute to a similar analysis of the larger CASCADE dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the COVID-19 pandemic.

piRNA and miRNA Can Suppress the Expression of Multiple Sclerosis Candidate Genes.

Multiple sclerosis (MS) is a common inflammatory demyelinating disease with a high mortality rate. MS is caused by many candidate genes whose specific involvement has yet to be established. The aim of our study was to identify endogenous miRNAs and piRNAs involved in the regulation of MS candidate gene expression using bioinformatic methods. A program was used to quantify the interaction of miRNA and piRNA nucleotides with mRNA of the target genes. We used 7310 miRNAs from three databases and 40,000 piRNAs. The mRNAs of the candidate genes revealed miRNA binding sites (BSs), which were located separately or formed clusters of BSs with overlapping nucleotide sequences. The miRNAs from the studied databases were generally bound to mRNAs in different combinations, but miRNAs from only one database were bound to the mRNAs of some genes. For the first time, a direct interaction between the complete sequence of piRNA nucleotides and the nucleotides of their mRNA BSs of target genes was shown. One to several clusters of BSs of miRNA and piRNA were identified in the mRNA of ADAM17, AHI1, CD226, EOMES, EVI5, IL12B, IL2RA, KIF21B, MGAT5, MLANA, SOX8, TNFRSF1A, and ZBTB46 MS candidate genes. These piRNAs form the expression regulation system of the MS candidate genes to coordinate the synthesis of their proteins. Based on these findings, associations of miRNAs, piRNAs, and candidate genes for MS diagnosis are recommended.

Evolutionary Changes in the Interaction of miRNA With mRNA of Candidate Genes for Parkinson's Disease.

Parkinson's disease (PD) exhibits the second-highest rate of mortality among neurodegenerative diseases. PD is difficult to diagnose and treat due to its polygenic nature. In recent years, numerous studies have established a correlation between this disease and miRNA expression; however, it remains necessary to determine the quantitative characteristics of the interactions between miRNAs and their target genes. In this study, using novel bioinformatics approaches, the quantitative characteristics of the interactions between miRNAs and the mRNAs of candidate PD genes were established. Of the 6,756 miRNAs studied, more than one hundred efficiently bound to mRNA of 61 candidate PD genes. The miRNA binding sites (BS) were located in the 5'-untranslated region (5'UTR), coding sequence (CDS) and 3'-untranslated region (3'UTR) of the mRNAs. In the mRNAs of many genes, the locations of miRNA BS with overlapping nucleotide sequences (clusters) were identified. Such clusters substantially reduced the proportion of nucleotide sequences of miRNA BS in the 5'UTRs, CDSs, and 3'UTRs. The organization of miRNA BS into clusters leads to competition among miRNAs to bind mRNAs. Differences in the binding characteristics of miRNAs to the mRNAs of genes expressed at different rates were identified. Single miRNA BS, polysites for the binding for one miRNA, and multiple BS for two or more miRNAs in one mRNA were identified. Evolutionary changes in the BS of miRNAs and their clusters in 5'UTRs, CDSs and 3'UTRs of mRNA of orthologous candidate PD genes were established. Based on the quantitative characteristics of the interactions between miRNAs and mRNAs candidate PD genes, several associations recommended as markers for the diagnosis of PD.

The randomized clinical trial results of the anxiety treatment in patients with somatoform dysfunction and neurotic disorders.

The existing treatments for somatoform dysfunction (SfD), reaction to severe stress (RSS), and adjustment disorders (AjD) are insufficiently effective and safe. Anxiolytic drug Tenoten proved effective in clinical trials (CT). The aim of this multicenter double-blind placebo-controlled randomized CT was to investigate the safety and efficacy of Tenoten in the treatment of anxiety in adults with SfD, RSS, AjD and other neurotic disorders (oNDs). 390 adult patients with SfD, RSS and AjD or oNDs with the Hospital Anxiety and Depression scale-anxiety (HADS-A) score ≥ 11 were randomized into 4 groups (n = 127 in Tenoten group 1 (4 tablets/day); n = 131 in Tenoten group 3 (8 tablets/day), n = 132 in combined Placebo group 2 + 4). The changes from baseline in the mean Hamilton Anxiety Rating Scale (HAM-A) score in groups 1 and 3 after 12 weeks were the primary outcome. The decrease of the HAM-A score from 18.81 ± 5.81 to 7.26 ± 4.63 (in group 1) and from 18.38 ± 4.3 to 6.40 ± 4.02 (in group 3) was observed post-treatment (pgroup 1/placebo = 0.0055, pgroup 3/placebo < 0.0001). Overall, 46 adverse events (28 in the Tenoten groups and 18 in the Placebo) were reported without any difference between the study groups. Tenoten performed significantly more effective than placebo in the anxiety treatment of adults with SfD, RSS, AjD and oNDs (clinicaltrials.gov NCT03036293).