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Abstract Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5–5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 –0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 –0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07–3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.

Summary: Background: The Canadian National Vaccine Safety Network conducted active safety surveillance for COVID-19 vaccines. This study aimed to characterize the short-to-medium term safety of mRNA COVID-19 vaccines across the pediatric age spectrum. Methods: In this cohort study, vaccinated and unvaccinated children and adolescents aged 6 months to 19 years from eight Canadian provinces and territories were invited to participate. The outcome was a health event preventing daily activities, resulting in school absenteeism, or requiring medical consultation. Age-stratified multivariable regression models were used to examine health events associated with first and second doses of mRNA COVID-19 vaccines across different age groups: children under 5, children aged 5–11 years and adolescents aged 12–19 years. Findings: From January 2021 through February 2023, a total of 259,361 individuals from the dose one survey, 131,032 from the dose 2 survey, and 1179 from the control survey were included. In the week following dose two, vaccinated adolescents showed a higher proportion of health events [794 (4.6%) of 17,218 BNT162b2 recipients, 98 (8.5%) of 1153 mRNA-1273 recipients, 49 of (10.6%) of 464 heterologous schedule recipients] than unvaccinated adolescents [9 (3.7%) of 242 controls], but most events were self-limited and resolved within 7 days. No significant differences in proportion of health events following mRNA COVID-19 vaccines were observed between vaccinated and unvaccinated groups among adolescents after dose 1, or among children under 5 or those aged 5–11 years after any dose. Reported myocarditis/pericarditis cases within 0–28 days peaked among male adolescents following dose 2, in three of (0.037%) 8088 homologous BNT162b2 recipients, and two of (0.529%) 378 homologous mRNA-1273 recipients. Interpretation: Our findings suggest that reported health events, including myocarditis/pericarditis, vary by pediatric age group. Vaccinated adolescents reported health events more frequently following the second mRNA COVID-19 vaccine dose, while younger age groups did not report events more frequently than their unvaccinated counterparts. Funding: Canadian Immunization Research Network, Canadian Institutes of Health Research; Public Health Agency of Canada; COVID-19 Immunity Task Force.

Abstract Background Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI). Methods Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21. Results Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p 50% (p

BackgroundThe Canadian National Vaccine Safety (CANVAS) network conducted a multi-center, prospective vaccine safety study to collect safety data after dose 1 and 2 of COVID-19 vaccines and follow up safety information 7 months after dose 1.ObjectiveThis study aimed to describe and evaluate the recruitment methods used by CANVAS and the retention of participants by each modality.MethodsCANVAS deployed a multi-pronged recruitment approach to reach a larger sample, without in-person recruitment. Three primary recruitment strategies were used: passive recruitment, technology-assisted electronic invitation through the vaccine booking system (auto-invitation), or auto-registration through the vaccine registries (auto-enrollment).ResultsBetween December 2020 and April 2022, approximately 1.3 million vaccinated adults either self-enrolled or were auto-enrolled in CANVAS, representing about 5% of the vaccinated adult Canadian population. Approximately 1 million participants were auto-enrolled, 300,000 were recruited by auto-invitation, and 5,000 via passive recruitment. Overall survey completion rates for dose 1, dose 2 and the 7-month follow-up surveys were 51.7% (681,198 of 1,318,838), 54.3% (369,552 of 681,198), and 66.4% (452,076 of 681,198), respectively. Completion rates were lower among auto-enrolled participants compared to passively recruited or auto-invited participants who self-enrolled. However, auto-enrolled samples were much larger, which offset the lower completion rates.ConclusionOur data suggest that auto-enrollment provided an opportunity to reach and retain a larger number of individuals in the study compared to other recruitment modalities.

BackgroundPeripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD.ObjectiveWe sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise.MethodsEleven PAD patients (52–80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1–2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured.ResultsAlthough peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen’s d = 0.56).ConclusionOverall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.