BACKGROUND & AIMS: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.

• MeSH
• alpha 1-Antitrypsin * genetics   blood   MeSH
• Biomarkers blood   MeSH
• Time Factors MeSH
• alpha 1-Antitrypsin Deficiency * genetics   diagnosis   complications   MeSH
• Adult MeSH
• Elasticity Imaging Techniques MeSH
• Genotype MeSH
• Homozygote MeSH
• Liver Cirrhosis * genetics   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Mutation MeSH
• Lung physiopathology   pathology   diagnostic imaging   MeSH
• Lung Diseases genetics   etiology   diagnosis   MeSH
• Disease Progression * MeSH
• Risk Factors MeSH
• Severity of Illness Index MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

• MeSH
• Aspirin * administration & dosage   therapeutic use   adverse effects   MeSH
• Double-Blind Method MeSH
• Extracellular Vesicles * metabolism   drug effects   MeSH
• Platelet Aggregation Inhibitors * administration & dosage   adverse effects   therapeutic use   MeSH
• Factor Xa Inhibitors * administration & dosage   adverse effects   therapeutic use   MeSH
• Cardiovascular Diseases * blood   prevention & control   drug therapy   MeSH
• Drug Therapy, Combination * MeSH
• Middle Aged MeSH
• Humans MeSH
• Inflammation Mediators blood   MeSH
• Prospective Studies MeSH
• Proteomics methods   MeSH
• Rivaroxaban * administration & dosage   MeSH
• Aged MeSH
• Thrombosis blood   prevention & control   drug therapy   MeSH
• Treatment Outcome MeSH
• Inflammation blood   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Unfractionated heparin is used as the most common anticoagulation for venovenous extracorporeal membrane oxygenation (VV ECMO) patients. However, it is accompanied by frequent bleeding and thrombotic complications. The aim of the study was to demonstrate the feasibility of Enoxaparin anticoagulation for VV ECMO patients. METHODS: This study is a retrospective analysis of VV ECMO patients on continuous intravenous Enoxaparin anticoagulation. The primary outcome was the incidence of bleeding, thrombotic, and neurological complications during ECMO support. The secondary outcome was an analysis of secondary and primary hemostasis profiles. RESULTS: Data from 38 patients were analyzed in this study. The incidence of bleeding complications was 5.3%, for thrombotic complications it was 2.6% and for neurological (bleeding/ischemic events) complications it was 10.5%. The targeted anti-Xa activity of 0.4-0.6 IU/mL was achieved and maintained during whole ECMO period in 28 patients (73.8%), not affecting the hemocoagulation profile represented by APTT-r 1.15 ± 0.2, TT 18.67 ± 3.35 s, PT/INR 1.21 ± 0.19, fibrinogen 5.39 ± 1.49 g/L, antithrombin, and platelet count. Primary hemostasis pathology was diagnosed in all patients by PFA 200 tests Col/EPI 279 ± 38 s and Col/ADP 249 ± 66 s. The running time of ECMO was 7.8 ± 3.4 days. CONCLUSIONS: Enoxaparin anticoagulation appears to be feasible for VV ECMO patients without an increase in adverse events. Further larger-sampled and comparative studies are needed in the future to support our findings.

• MeSH
• Anticoagulants administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Enoxaparin * administration & dosage   therapeutic use   adverse effects   MeSH
• Factor Xa Inhibitors administration & dosage   therapeutic use   MeSH
• Administration, Intravenous MeSH
• Hemorrhage * prevention & control   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * adverse effects   methods   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Feasibility Studies MeSH
• Thrombosis prevention & control   etiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro-inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro-inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL-C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti-inflammatory, alternatively activated macrophages (CD14 + CD16-CD163+) correlated negatively with HDL-C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro-inflammatory response, activating the TNF-α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.

• MeSH
• Macrophage Activation MeSH
• CD36 Antigens metabolism   MeSH
• Atherosclerosis metabolism   MeSH
• Antigens, CD metabolism   MeSH
• Cholesterol * metabolism   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Macrophages * metabolism   immunology   drug effects   MeSH
• Intra-Abdominal Fat metabolism   MeSH
• Tumor Necrosis Factor-alpha metabolism   genetics   MeSH
• Inflammation * metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

There is growing interest in the role of extracellular vesicles (EVs) in neonatal pathology. This study aimed to characterise circulating EVs following preterm birth. This single-centre prospective observational study included cord and postnatal plasma from preterm (n = 101) and full-term infants (n = 66). EVs were analysed using nanoparticle tracking analysis, flow cytometry, proteomics and procoagulant activity assay. We found changes in the concentration, size, cellular origin and proteomic content of circulating EVs in preterm infants during perinatal adaptation. To understand if these changes were related to prematurity or normal adaptation to extrauterine life, they were also investigated in term infants. There was a dramatic increase in the concentration of small and large EVs on Day 3 in the preterm group; specific subsets of platelet (CD42b+ and CD62P+), endothelial (VEGFR2) and tissue factor EVs were elevated. Differentially expressed proteins relating to haemostasis, pulmonary physiology and immunity were identified between Day 1 and 3 in preterm infants. These changes have never previously been described in a large cohort of preterm infants and differ from healthy term infants. These findings have major implications for future neonatal EV studies, particularly the timing of sample collection. Further work is required to understand the clinical implications of this unique EV profile following preterm birth.

• MeSH
• Extracellular Vesicles * metabolism   MeSH
• Adaptation, Physiological * MeSH
• Humans MeSH
• Infant, Premature * blood   MeSH
• Infant, Newborn MeSH
• Prospective Studies MeSH
• Proteomics methods   MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH

With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5183 patients with MF who underwent first allo-HCT between 2005 and 2020 at European Society for Blood and Marrow Transplantation centers, we examined different machine learning (ML) models to predict overall survival after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A random survival forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a 4-level Cox regression-based score and other ML-based models derived from the same data set, and with the Center for International Blood and Marrow Transplant Research score. The RSF outperformed all comparators, achieving better concordance indices across both primary and postessential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike information criterion and time-dependent receiver operating characteristic area under the curve metrics in both sets. Although all models were prognostic for nonrelapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in patients with MF undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Primary Myelofibrosis * therapy   mortality   MeSH
• Prognosis MeSH
• Aged MeSH
• Machine Learning * MeSH
• Hematopoietic Stem Cell Transplantation * mortality   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.

• MeSH
• Epithelial-Mesenchymal Transition physiology   MeSH
• Humans MeSH
• Prostatic Neoplasms * pathology   metabolism   therapy   drug therapy   MeSH
• NF-kappa B metabolism   MeSH
• Hedgehog Proteins metabolism   MeSH
• Signal Transduction * physiology   MeSH
• Transforming Growth Factor beta metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Monotherapy with a potent P2Y12 receptor antagonist after 1 month of dual antiplatelet therapy (DAPT) may reduce bleeding in the absence of increased ischaemic events compared to 12-month DAPT in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). PCI guidance with optical coherence tomography (OCT) may enhance stent expansion. COMPARE STEMI ONE is an international, multicentre, open-label, randomised controlled trial. In 1,656 ST-segment elevation myocardial infarction (STEMI) patients, prasugrel monotherapy after 1 month of DAPT, as compared to standard 12-month prasugrel-based DAPT, will be tested for non-inferiority for the primary composite endpoint of net adverse clinical events - defined as all-cause death, myocardial infarction, stroke, or Bleeding Academic Research Consortium Type 3 or 5 bleeding events - at 11 months after randomisation. Furthermore, an ancillary substudy will test the superiority of OCT-guided versus angiography-guided staged complete revascularisation in achieving a larger minimal stent area (MSA) in non-culprit lesions during staged procedures. COMPARE STEMI ONE is the first randomised controlled trial assessing an abbreviated 1-month DAPT regimen followed by prasugrel monotherapy in the context of STEMI. The trial will also study the value of OCT-guided PCI in terms of the MSA of non-culprit lesions and may elucidate potential synergies between intravascular imaging-guided PCI and abbreviated DAPT regimens. (ClinicalTrials.gov: NCT05491200).

• MeSH
• Purinergic P2Y Receptor Antagonists * therapeutic use   MeSH
• ST Elevation Myocardial Infarction * therapy   drug therapy   diagnostic imaging   surgery   MeSH
• Platelet Aggregation Inhibitors * therapeutic use   MeSH
• Coronary Angiography methods   MeSH
• Percutaneous Coronary Intervention * methods   MeSH
• Humans MeSH
• Tomography, Optical Coherence * methods   MeSH
• Prasugrel Hydrochloride * therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Clinical Trial Protocol MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

• Keywords
• studie COMPASS,
• MeSH
• Platelet Aggregation Inhibitors MeSH
• Factor Xa Inhibitors MeSH
• Myocardial Ischemia drug therapy   prevention & control   MeSH
• Cardiovascular Diseases prevention & control   MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Rivaroxaban * administration & dosage   therapeutic use   MeSH
• Thromboembolism * drug therapy   prevention & control   MeSH
• Thrombosis * drug therapy   prevention & control   MeSH
• Check Tag
• Humans MeSH

• MeSH
• Aspirin * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Diabetes Mellitus * drug therapy   pathology   MeSH
• Platelet Aggregation Inhibitors MeSH
• Diabetes Complications MeSH
• Humans MeSH
• Megakaryocytes pathology   MeSH
• Blood Platelets pathology   drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH