Search Results for: L’eparina inibisce la proteina spike del virus SARS-Cov-2

Oncologi, ‘subito un piano di recupero per la prevenzione’

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

Introduction
Janus kinase (JAK) inhibitors are an important therapeutic option in the treatment of rheumatoid arthritis, but increase the risk of developing herpes zoster. Although a dry recombinant zoster vaccine (RZV) that can be used under immunosuppressive conditions has recently been developed, its optimal use and appropriate timing in patients scheduled to start JAK inhibitors is still unclear. The present study is designed to clarify the appropriate timing of JAK inhibitor initiation to measure varicella zoster virus (VZV)-specific IgG titers and VZV-specific T cell response in patients with rheumatoid arthritis who start tofacitinib at the first RZV vaccination or at the second one.

Methods and analysis
STOP HZ (Effectiveness and S afe T y O f P rophylactic Recombinant H erpes Z oster Virus Vaccination for Rheumatoid Arthritis Patients with Tofacitinib Treatment) study is a multicentre, open-label, randomised, comparative study in patients with rheumatoid arthritis who are scheduled to start tofacitinib. This study enrols 60 study subjects in 12 sites. Enrolled subjects receive RZV two times on day 1 and week 8 and initiate tofacitinib 5 mg two times a day at the time of their first RZV (day 1, group A) or second RZV (week 8, group B) based on randomisation. The random assignment is performed centrally in a 1:1 ratio. Patients in Group B continue the same treatment until the start of tofacitinib treatment. Primary endpoint is VZV-specific IgG antibody titers at week 12 compared with those at baseline in each group. Secondary endpoints include comparison of VZV-specific IgG antibody between the groups, changes in disease activity of rheumatoid arthritis, VZV-specific T cell response and adverse events.

Ethics and dissemination
The study has been approved by the Certified Review Board of Keio (No. 2022008), and conforms to the Declaration of Helsinki and good clinical practice guidelines. Written informed consent is obtained from participants prior to enrolment. The results of this study are planned to be submitted for publishment in relevant peer-review journals.

Trial registration number
jRCTs031230329.

Introduction
Healthcare workers (HCWs) have been of particular relevance for overcoming the SARS-CoV-2 pandemic. At the same time they have been affected by SARS-CoV-2 infections with above average probability. Around 6.5% of the overall infected persons are likely to develop persistent symptoms resulting from the infection, known as long-COVID or post-COVID syndrome (PCS). The aim of this study is (1) to investigate the prevalence, course and characteristics of PCS in German HCWs, (2) to examine its effects on psychosocial variables, (3) to identify rehabilitation and healthcare needs and (4) to analyse treatment experiences.

Methods and analysis
In a cohort study with a randomised selection of participants (N=20 000) from the Employer’s Liability Insurance Association for Health and Welfare Care, the health status of HCWs, who had COVID-19 in their professional context will be examined. There will be two measurement points: baseline (T1) and a 12-month follow-up (T2). The outcome measures are the health status with a particular focus on persistent or newly occurring symptoms after a SARS-CoV-2 infection, health-related quality of life, functional capacity, the subjective need for and utilisation of healthcare services. Pre-existing conditions, the course of the acute infection and sociodemographic factors are considered as predictors. An advisory board made up of affected HCWs supports the study by contributing to the surveys’ contents.

Ethics and dissemination
The study has been approved by the Local Ethics Committee of the Center for Psychosocial Medicine at the University Hospital Hamburg-Eppendorf (LPEK-0518). For dissemination, the results will be published in peer-reviewed journals, presented at conferences and communicated to relevant stakeholders in general and rehabilitation medicine.

Trail registration number
https://drks.de/search/de/trial/DRKS00029314

New England Journal of Medicine, Volume 391, Issue 19, Page 1863-1864, November 14, 2024.

New England Journal of Medicine, Ahead of Print.

The US Centers for Disease Control and Prevention (CDC) issued an updated advisory outlining prevention strategies for people visiting countries with widespread clade I mpox virus outbreaks. These strategies include getting the modified vaccinia Ankara–Bavarian Nordic (JYNNEOS) vaccine, which the World Health Organization recently prequalified.

Chronic hepatitis B virus (HBV) infection remains a significant global health burden, affecting over 250 million people worldwide who are at risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Currently available nucleos(t)ide analogues (NAs) are effective in controlling viraemia; however, functional cure, defined as loss of hepatitis B surface antigen (HBsAg), is rare and difficult to achieve and likely requires robust immune responses, reflecting the need for innovative therapeutic strategies.1 Thus, the future of treating chronic HBV infections relies on combination therapies that include both direct-acting antiviral agents and immunomodulatory agents.2 In this context, selgantolimod (SLGN), an agonist of Toll-like receptor 8 (TLR8), could be a promising candidate. Its efficacy in the treatment of chronic HBV infections has been investigated in preclinical models and clinical trials,3–5 but there remains limited understanding of its impact on immune effectors within the…

Circulation, Volume 150, Issue Suppl_1, Page A4144514-A4144514, November 12, 2024. Introduction:Human Immunodeficiency Virus Associated Cardiomyopathy (HIVAC) is characterized by left ventricular (LV) systolic or diastolic dysfunction with or without LV dilatation and heart failure symptoms. The introduction of antiretroviral therapy (ART) has changed the fulminant systolic heart failure presentation of HIV myocarditis to diastolic heart failure. We present a unique case of dilated cardiomyopathy in a young patient without advanced HIV illness which has rarely been documented in the literature. This is a rare presentation of HIVAC in the post-ART era.Case Report:A 32-year-old male with a past medical history (PMH) of the human immunodeficiency virus (HIV) presented with complaints of new onset worsening shortness of breath and lower extremity edema for four weeks. He was diagnosed with HIV seven years ago and was not compliant with ART. Laboratory testing showed a cluster of differentiation 4 (CD4) 823 and HIV load 2550. Myocarditis was ruled out by normal troponin levels and no new changes on the electrocardiogram (ECG). Transthoracic echocardiogram (TTE) showed dilated left ventricle (LV), LV global hypokinesis, LV ejection fraction (LVEF) 10-15%, dilated right ventricle, biatrial dilation, moderate to severe mitral regurgitation, severe tricuspid regurgitation, pulmonary artery (PA) systolic pressure 73 mmHg and no pericardial effusion. Coronary angiography was negative for coronary artery disease (CAD). The patient was started on carvedilol and outpatient evaluation for a left ventricular assistance device.Discussion:Systolic dysfunction in patients with HIVAC carried a poor prognosis in the pre-ART era and was common in patients with elevated c-reactive protein (CRP), tobacco use, and previous myocardial infarction (MI). After the advent of ART, systolic dysfunction is rare and replaced by diastolic cardiomyopathy in the setting of ART use. Diagnosis is usually by excluding other etiologies and biopsy is not necessarily required. Management is usually guideline-directed medical therapy (i.e. beta blocker, renin-angiotensin-aldosterone antagonists, sodium-glucose cotransporter-2) and device-based therapy but there is still data lacking to assess its benefit.

Circulation, Volume 150, Issue Suppl_1, Page A4139176-A4139176, November 12, 2024. Introduction:During natural aging, physiological remodeling of the heart is a critical for the cardiovascular disease and heart failure. miR-30a-5p is related to kidney injury, cancer, and autoimmune diseases. However, whether miR-30a-5p has an effect in cardiac aging has yet to be explored.Hypothesis:This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence.Methods:We established miR-30a-5p knockout/overexpressing mouse model. Natural heart aging (18-months-old) and D-galactose-induced aging mouse model were established. The mechanism was explored in D-galactose- or 10-days-cultured cardiomyocytes.Results:miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpressed mice on natural- or D-galactose-induced heart aging. In vitro, using RNA-sequence and a series of molecular biology, the mechanism of miR-30a-5p-regulated cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice showed effects similar to those observed in knockout mice. Notably, overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Further evidence demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence.Conclusions:This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p–TP53INP1–p53 axis is essential for heart and cardiomyocyte aging.

Circulation, Volume 150, Issue Suppl_1, Page A4122301-A4122301, November 12, 2024. Background:Recent studies in both human genetics and mouse models have highlighted the significance of phosphatidylinositol (PI) in the progression of fatty liver disease (FLD). Despite this, the precise mechanisms underlying PI’s role remain elusive.Aims:This study aimed to elucidate the involvement of PI in FLD by disrupting hepatic PI biosynthesis through modulation of CDP-diacylglycerol synthase 2 (CDS2) expression, the primary enzyme in PI biosynthesis (A).Methods:We generated liver-specific knockouts of CDS2 and SCAP (SREBP cleavage-activating protein) using adeno-associated virus (AAV) expressing sgRNA against each gene. Phospholipid species were analyzed and quantified by LC/MS.Results:CDS2 liver-specific knockout mice (B, C) exhibited a pronounced development of fatty liver, characterized by elevated triglyceride and cholesterol levels (C). Notably, liver PI levels were significantly reduced in CDS2 knockout mice (E), accompanied by dysregulated activation of sterol regulatory element-binding protein (SREBP) even during fasting conditions (F), leading to increased de novo lipogenesis. Intraperitoneal administration of exogenous PI effectively normalized SREBP cleavage (G), highlighting PI’s critical role in SREBP regulation. Furthermore, simultaneous knockout of SCAP with CDS2 restored the normal liver phenotype, implicating SREBP activation as a central mechanism underlying fatty liver development in CDS2 knockout mice (H, I).Conclusion:Deletion of CDS2 in the liver reduced PI levels, subsequently inducing significant fatty liver due to dysregulated SREBP activation. This study underscores the importance of CDS2 in maintaining PI homeostasis, which in turn regulates SREBP activity and lipid metabolism. Our findings provide valuable insights into the pathogenesis of metabolic disorders and offer potential therapeutic strategies for targeting FLD.

Circulation, Volume 150, Issue Suppl_1, Page A4123674-A4123674, November 12, 2024. Background:Transplantation arteriosclerosis is one of the major complications for the mid- and long-term survival of recipients with organ transplantation. Although previous studies suggest that CD34 stem/progenitor cells are involved in this process, the heterogeneity and potential adverse effects of CD34+SPCs have not been fully determined.Methods and Results:A mouse model of transplant arteriosclerosis was established by using Balb/c, C57BL/6J, CD34-CreERT2, R26-tdTomato, Rosa26-iDTR, CD34-Dre, PI16-CreERT2, CAG-LSL-RSR-tdTomato-2A-DTR mice. Using single-cell RNA-seq and the innovative application of genetic lineage tracing with dual recombinases, we identified a subpopulation of fibroblast progenitor cells marked by high CD34 and PI16 expression. Interestingly, this progenitor cell group gave rise to a distinct chemotactic fibroblast subset. Based on chemokine antibody microarray assay and transcriptome analysis, the subgroup with increased CD34 expression and decreased PI16 expression promoted intimal hyperplasia, acting through the paracrine release of a specific chemokine CCL11 (eotaxin-1). Moreover, the binding of CCL11 to its receptor CCR3 triggered the PI3K-AKT signaling pathway in smooth muscle cells, promoting their proliferation and migration to form neointimal lesions. Overexpression of CCL11 by adeno-associated virus can promote neointimal hyperplasia in vivo, while neutralization of CCL11 or inhibition of receptor CCR3 can alleviate neointimal lesions.Conclusion:Our findings identified CD34+/PI16+fibroblast progenitors able to differentiate into specific chemotactic fibroblasts that release chemokines pivotal for neointima formation, implicating a therapeutic potential targeting the chemotactic behavior of these cells.

Circulation, Volume 150, Issue Suppl_1, Page A4143264-A4143264, November 12, 2024. Background:R-on-T phenomenon occurs when an electrical stimulus is delivered at a critical point during ventricular repolarization. This can initiate ventricular arrhythmias like polymorphic ventricular tachycardia (PMVT). We describe a case of ventricular pacemaker spikes delivered on the T wave causing PMVT.Case:A 53-year-old female with CAD s/p stent, postpartum cardiomyopathy s/p Bi-V CRT-D (Boston Scientific G124), and paroxysmal atrial fibrillation presented for elective endoscopy and colonoscopy to evaluate her dysphagia and abdominal pain. Her CRT-D was reprogrammed from DDD pacing with lower rate limit (LRL) 50 bpm to an asynchronous Bi-V DOO mode at 50 bpm (‘electrocautery mode’) for the procedure (tachy therapy disabled). Her LV-RV offset was 40 msec. Prior to receiving sedation or medications, she was found unresponsive. Telemetry showed Spike-on-T phenomenon which initiated PMVT. She was externally defibrillated with 200J and received magnesium and an IV amiodarone bolus. She returned to sinus rhythm, but one minute later had another Spike-on-T event initiating PMVT. She was successfully defibrillated with 360J. Post-shock EKG showed an asynchronous Bi-V paced rhythm at 50 bpm.Decision Making:The patient was admitted to the CCU for post-resuscitation care. Her electrolytes and cardiac enzymes were unremarkable. Her CRT-D was reprogrammed to DDD 80-140 bpm. Transthoracic echocardiogram showed normal biventricular systolic function. Cardiac catheterization did not show obstructive CAD. After reprogramming of her device, she had no further events. After initial treatment with IV amiodarone load, she was discharged home on oral magnesium gluconate.Discussion:The only intervention prior to her procedure was device reprogramming (DDD 50 bpm to DOO 50 bpm). Telemetry showed pacer spikes initiating PMVT. Given the LV-RV offset of 40 msec, she would have received these two tightly coupled pacemaker spikes in an asynchronous mode, in this unfortunate instance during her T wave. While her bowel preparation may have led to electrolytes abnormalities, post-resuscitation electrolytes were normal. Fortunately, she received prompt therapy and was reprogrammed with increased LRL.Conclusion:We described a case of Spike-on-T PMVT prior to colonoscopy without obvious provocation other than asynchronous pacemaker spikes. Reprogramming devices in DOO mode with increased LRL may prevent PVCs and asynchronous pacemaker spikes from triggering PMVT.

Circulation, Volume 150, Issue Suppl_1, Page A4133460-A4133460, November 12, 2024. Background and hypothesis:Influenza is a significant public health and economic threat around the world. Although pneumonia is the most common complication associated with influenza, there are several clinical reports demonstrating increased risk for cardiovascular disease. Influenza infection induces interferons, proinflammatory cytokines and chemokines, and recruits’ macrophages and neutrophils to control the virus. However, an excessive influx of innate immune cells and dysregulated production of inflammatory mediators results in pathological responses during influenza infection. Studies have shown that influenza infection correlates with increased incidence of myocardial infarction. Atherosclerosis is the most known cause of ischemic heart diseases and stroke. Vascular cell adhesion molecule-1 (VCAM1) has been shown to promote adhesion of monocytes and promotes atherosclerosis. In this study, we hypothesize that VCAM1 plays a role in exacerbation of atherosclerosis during influenza infection.Methods:High-Fat diet (HFD)-fed Apoe-/-mice were infected with influenza A/PR/8/34 (H1N1) and weight loss, survival rate, and gene expression of vascular endothelial adhesion molecules, inflammatory cytokines and chemokines were measured. HFD-fed Apoe-/-mice were infected with influenza, and treated with anti-VCAM1 antibody, and weight loss and cellular responses were measured.Results and conclusions:Increased weight loss and decreased survival of mice were observed in response to influenza infection in HFD-induced atherosclerosis in Apoe-/-mice. Further, the expression of VCAM1, and the levels of IL-6, CCL2, CCL3, CCL5 were significantly increased in aorta in Apoe-/-mice when compared to PBS-treated controls. Increased survival, decreased weight loss, decreased lesion area, decreased frequency of CD11b+F4/80+Ly6C+, CD4+RORgt+cells and increased frequency of CD4+FoxP3+Treg cells were observed in aorta in response to antibody mediated VCAM1 neutralization. These results suggest that VCAM1 plays a pathological role in influenza-induced exacerbation of atherosclerosis.

Circulation, Volume 150, Issue Suppl_1, Page A4117883-A4117883, November 12, 2024. Introduction/Background:Cardiovascular symptoms appear in a high proportion of patients in the few months following a severe SARS-CoV-2 infection. Non-invasive methods to predict disease severity could help personalizing healthcare and reducing the occurrence of these symptoms.Research Questions/Hypothesis:We hypothesized that blood long noncoding RNAs (lncRNAs) and machine learning (ML) could help predict COVID-19 severity.Goals/Aims:To develop a model based on lncRNAs and ML for predicting COVID-19 severity.Methods/Approach:Expression data of 2906 lncRNAs were obtained by targeted sequencing in plasma samples collected at baseline from four independent cohorts, totaling 564 COVID-19 patients. Patients were aged 18+ and were recruited from 2020 to 2023 in the PrediCOVID cohort (n=162; Luxembourg), the COVID19_OMICS-COVIRNA cohort (n=100, Italy), the TOCOVID cohort (n=233, Spain), and the MiRCOVID cohort (n=69, Germany). The study complied with the Declaration of Helsinki. Cohorts were approved by ethics committees and patients signed an informed consent.Results/Data:After data curation and pre-processing, 463 complete datasets were included in further analysis, representing 101 severe patients (in-hospital death or ICU admission) and 362 stable patients (no hospital admission or hospital admission but not ICU). Feature selection with Boruta, a random forest-based method, identified age and five lncRNAs (LINC01088-201, FGDP-AS1, LINC01088-209, AKAP13, and a novel lncRNA) associated with disease severity, which were used to build predictive models using six ML algorithms. A naïve Bayes model based on age and five lncRNAs predicted disease severity with an AUC of 0.875 [0.868-0.881] and an accuracy of 0.783 [0.775-0.791].Conclusion:We developed a ML model including age and five lncRNAs predicting COVID-19 severity. This model could help improve patients’ management and cardiovascular outcomes.