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Effects of anticoagulation in patients with device-detected atrial fibrillation and multiple stroke risk factors:a win ratio analysis of the NOAH-AFNET 6 trial
No full textAims Patients with device-detected atrial fibrillation (DDAF) have a lower stroke risk than those with ECG-diagnosed AF, requiring careful evaluation of oral anticoagulation benefits vs. its inherent bleeding risk.Methods and results An unmatched win ratio analysis was performed of the NOAH-AFNET 6 trial dataset, using components of the primary efficacy and safety outcomes of the trial. The primary analysis used this hierarchical order: (1) all-cause death, (2) stroke, (3) systemic or pulmonary embolism/myocardial infarction, and (4) major bleeding. Two additional analyses replaced all-cause death with cardiovascular death or included patient-reported outcomes. Win odds were calculated to account for undecided comparisons. Among 2534 patients 77 +/- 7 years old, 947 (37%) women, median CHA2DS2-VA score 3 [interquartile range (IQR), 3-4], median follow-up 21 months (IQR, 10-38) 1 605 280 win ratio pairs were analyzed. The win ratio comparing edoxaban to no anticoagulation was 0.87 (95% CI: 0.68-1.10; P = 0.23). Most comparisons resulted in no clear winner (undecided pairs 84.9%). In the remaining comparisons, edoxaban won in 46% of the cases, placebo in 54%. Death and major bleeding were the most common events. The win odds was 0.98 (95% CI: 0.94-1.01; P = 0.23).Conclusions This hypothesis-generating win ratio analysis, integrating death, thrombotic events, and major bleeds with and without quality of life, did not find an advantage of anticoagulation with edoxaban over no anticoagulation in patients with DDAF. The most common events were death and major bleeding
Artificial intelligence adoption and workplace training
No full textAs artificial intelligence (AI) reshapes business processes, firms must adapt their training strategies to cultivate a skilled workforce. Using German establishment-level panel data from 2019 to 2023, this study analyzes how firms adjust their training strategies following AI adoption. Staggered difference-in-differences analysis shows that sustained AI adoption is associated with a 14% increase in new apprenticeships among training firms (intensive margin), but is not linked to the training decision (extensive margin). AI adoption is also associated with a modest increase in continuing training, with resources shifting toward high-skilled employees. The results align with AI as an automation innovation that reduces demand for simple skills as well as an augmentation innovation that increases demand for more advanced skills. The German dual apprenticeship system appears critical for firms aiming to build a future-ready workforce in the age of AI
Replication of blood DNA methylomic signatures associated with cerebrospinal fluid levels of YKL-40 and NfL biomarkers
No full textHow to make an app-based program work and show how it works
No full textFor digital health interventions, the "gold standard" of evaluating effectiveness is the randomized control trial (RCT). Yet, RCT methodology presents issues such as precluding changes to the technology during the study period as well as the use of study settings that do not reflect "real world" contexts. In this paper, we draw on empirical material from our ethnographic research on an app-based program called HIVSmart!, which is a digital strategy designed to support people in the process of HIV self-testing. We explore how this digital health approach was made to work in different contexts, and what this means for monitoring and evaluation of digital health interventions. Our analysis reveals that making technology which is "ease to use" depends on various user practices developed over time and the multiple, shifting users who define this ease of use. Furthermore, it shows that asking whether an app is "working" provides different answers at different moments, as the technology, as well as the human and physical supports around it, change and adapt over time. Therefore, questions around the feasibility of the technology, as well as ongoing monitoring efforts, need to be developed in a way that capture this fluctuation in the technology and its surroundings. Based on our insights, we contribute to implementation science approaches in the field of digital health by putting forward recommendations regarding how we can assess the effectiveness of digital health tools
Microvascular Occlusion and Postrecanalization Hyperperfusion in a Swine Model of Acute Ischemic Stroke
No full textBACKGROUND: Despite successful recanalization after endovascular thrombectomy, more than half of patients with acute ischemic stroke with large-vessel occlusions experience an unsatisfactory outcome. Incomplete microvascular reperfusion may contribute to it, but its occurrence remains debated, partly due to clinical observations of hyperperfusion after recanalization. This study investigates the relationship between ischemia duration, infarct development, microclot presence, and cerebral perfusion in a swine model of focal cerebral ischemia and reperfusion. METHODS: Twenty-three swine underwent craniectomy and were randomized into 5 groups: 1-hour, 2-hour, or 4-hour occlusion followed by 4-hour recanalization, 8-hour occlusion without recanalization (positive control), or without occlusion (sham). Middle cerebral artery occlusion was induced using aneurysm clips, with 3-dimensional digital subtraction angiography confirming occlusion and recanalization. Three-dimensional digital subtraction angiography was used for quantification of area at risk and tissue perfusion. Infarct size was measured using 2,3,5-triphenyl-2H-tetrazolium chloride staining. The presence of microclots was quantified using CD61+ platelet immunostaining (number/mm2). Plasma markers of coagulation activation were measured before and during middle cerebral artery occlusion and after recanalization. RESULTS: Area at risk-normalized infarct size increased significantly with ischemia duration (r=0.8, P<0.001). Compared with the noninfarcted hemisphere, microclots in the infarcted hemisphere increased in middle cerebral artery occlusion groups (0.07 [0.04-0.13] versus 0.33 [0.16-0.71], P=0.003). Microclot density in area at risk region showed a positive correlation with ischemia duration (r=0.7, P=0.007), while no such correlation was observed in remote region. Simultaneously, higher perfusion levels were observed at both 2 hours (1.27±0.19, P<0.001) and 4 hours (1.23±0.16, P<0.001) following recanalization, irrespective of the duration of ischemia. No activation of coagulation was detected in systemic plasma. CONCLUSIONS: Focal cerebral ischemia and reperfusion result in a substantial presence of microclots, which occurs alongside hyperperfusion in this swine model of recanalized acute ischemic stroke. These platelet microclots extend beyond the ischemic area. The density of microclots within the ischemic region increased with prolonged ischemia.</p
The renal baroreflex:A systematic review and meta-analysis in healthy and hypertensive animals
No full textThe renal baroreflex describes the dose-dependent relation between renal pressure and renin release. Former studies have approximated this relation through animal experiments, but the exact shape of the response curve and its alteration by hypertension remain unclear. Therefore, we conducted a systematic review and meta-analysis on the renal baroreflex in healthy and hypertensive animals. Studies retrieved from Pubmed and Embase were screened according to predefined criteria. Data regarding study design and outcome data were extracted, and risk of bias was assessed. Dose-response meta-analysis was conducted on the relationship between renal blood pressure and renin release. Subgroup analyses were conducted for species, sex, outcome units, and experimental setup. From 1508 studies, 55 were included in the systematic review, and 30 in the meta-analysis. Risk of bias was high in most studies. Our meta-analysis shows that in healthy animals, renin decreases linearly with increasing renal blood pressure, reaching a plateau above a threshold pressure of 93 ± 2 mmHg. In hypertensive animals, the linear slope is diminished, the threshold is comparable, and the plateau level is slightly decreased as compared to healthy animals. Despite some limitations, our findings suggest that high blood pressure in hypertensive animals blunts the renal baroreflex by resetting and suppression of the renin response to changes in blood pressure
Targeting the Epigenetic Remodeler GCN5 Prevents Vascular Oxidative Stress and Endothelial Dysfunction in Obesity:Insights in Patients with Cardiometabolic Disease
No full textINTRODUCTION: Epigenetic changes are important modulators of gene expression. The histone acetyltransferase gene non-derepressible 5 (Gcn5) is emerging as a pivotal epigenetic player in metabolism and cancer, yet its role in obesity and cardiovascular disease remains elusive. AIMS: To investigate Gcn5 role in obesity-related endothelial dysfunction. METHODS: Human aortic endothelial cells (HAECs) were exposed to vehicle or palmitic acid (200 uM) in the presence or in the absence of the Gcn5 pharmacological inhibitor CPTH2 or gene silencing. Ex-vivo inhibition of Gcn5 was performed in aortic rings from diet-induced obese and control mice. Chromatin immunoprecipitation (ChIP) was performed to investigate the epigenetic regulation of Nox2 promoter. In parallel, Gcn5/Nox2 expression was assessed by real-time PCR in vascular specimens isolated from obese patients and age-matched healthy controls. Endothelial-dependent vasodilation was also assessed in human vessels. RESULTS: PA increased Gcn5 gene expression in HAECs. Gcn5 upregulation was associated with increased expression of the pro-oxidant enzyme Nox2. Interestingly, either Gcn5 inhibition or gene silencing prevented PA-induced Nox2 upregulation and oxidative stress accumulation. ChiP assay showed increased Gcn5 occupancy and enhanced histone 3 acetylation of lysine 14 (H3K14ac) on Nox2 promoter. In aortic rings from obese mice, pharmacological inhibition of Gcn5 by CPTH2 rescued endothelial-dependent vasorelaxation as compared to vehicle. Finally, Gcn5 was increased in vessels from obese patients and correlated with Nox2 expression and endothelial dysfunction. CONCLUSIONS: Our findings shed light on the importance of epigenetic regulation in obesity and pinpoint Gcn5 as a therapeutic target to prevent endothelial dysfunction in cardiometabolic disease
Response to Bissonnette et al. 'Dupilumab treatment restores lesional and nonlesional skin barrier function in adults and adolescents with atopic dermatitis irrespective of the filaggrin genotype:Results from an open-label, healthy-control-matched, phase 4 clinical study (BALISTAD)'
No full textCareers, competences and values of European higher education graduates in 2022:EUROGRADUATE 2022 : comparative synthesis report
No full textBuilding on the first successful EUROGRADUATE 2018 pilot survey, this comparative synthesis report of the EUROGRADUATE 2022 pilot survey provides an analysis on the careers, competences, and citizenship of over 100.000 higher education graduates in 18 EU/EEA countries, covering graduates of the academic years 2020/21 and 2016/17 (one and five years after graduation) on ISCED-2011 levels 6 (Bachelor) and 7 (Master or long degree programs). The project pursues to monitor the educational pathways of graduates, how they evaluate their study experiences, and how this translates into their professional careers and lives as European citizens. The EUROGRADUATE 2022 survey constitutes a significant contribution to the enhancement of the European Education Area, not least through its contribution to the recent Union of Skills initiative. The EUROGRADUATE surveys are part of the European Graduate Tracking Initiative (EGTI), initiated by the European Commission in response to the Council Recommendation on tracking graduates (2017). In order to guide policies for improving employability of graduates and the match of graduates’ education with labour market requirements, the Council requested to improve the availability, comparability and quality of graduate tracking measures, including for mobile graduates, across EU/EEA countries