Background: Secreted PCSK9 regulates LDL levels in plasma by mediating degradation of hepatic LDL receptors.Results: LDL binds to PCSK9 in human plasma and in vitro and inhibits PCSK9 binding to cell surface LDL receptors.Conclusion: A large proportion of circulating PCSK9 is bound to LDL in humans.Significance: Regulatory mechanisms that affect activity of secreted PCSK9 represent novel targets for cholesterol-lowering therapies.

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Background-The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition. Methods and Results-We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, PՅ0.05), and urinary 11-dehydrothromboxane B 2 was dose-related (81 mg versus 325 mg, Pϭ0.003). No carryover effects were observed. Conclusions-The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation. (Circulation. 2007;115:3156-3164.)

appears concerned about the uniform inhibition of arachidonic acid-induced aggregation observed in the AspirinInduced Platelet Effect (ASPECT) trial. We would like to reassure Dr Klein that the compliance of the patients in ASPECT was meticulously recorded and, as reported in the manuscript, was overall 98%. Dr Klein should also be aware of the significance of results determined by double crossover studies such as the ASPECT study and the robust statistical analyses performed. 1 Why were we not surprised by the results of the ASPECT study? In a previous study of 223 patients undergoing stenting who were treated with long-term aspirin therapy, only 1 compliant patient was resistant as determined by cyclooxygenase-1 (COX-1)-specific assays and arachidonic acid-induced aggregation in plasma and in whole blood. Interestingly, all of the noncompliant patients (3%) had high arachidonic acid-induced aggregation, suggesting the presence of "resistance," but exhibited low arachidonic acid-induced aggregation after in-hospital treatment. 2 Therefore, the message of the study Tantry et al 2 and of the ASPECT trial is that aspirin responsiveness is very high when assessed by arachidonic acidbased assays in compliant patients. Moreover, the ASPECT study demonstrates the uniformity of this property irrespective of the aspirin dose. Therefore, the our data are not "overshot." Rather, they demonstrate an important physiological effect of aspirin, that is, near uniform and potent inhibition of COX-1. A recent study by others has demonstrated concordant findings. 3 We agree that noncompliance is an important issue with any pharmacological therapy. On the basis of our data, arachidonic acid-induced platelet aggregation is a good barometer of patient compliance with aspirin and probably other drugs, as patients who are noncompliant with aspirin may also be more likely to be noncompliant with their other prescribed medications.The second important message from the ASPECT study relates to the potential antiplatelet effects of aspirin mediated by non-COX-1 pathways assessed by stimulating platelets with agonists other than arachidonic acid. We are glad that Dr Klein has also raised this issue. This is indeed a novel idea with potential clinical implications, as recent studies have demonstrated the association of adverse clinical events with "aspirin resistance" measured by a method that is not solely dependent on COX-1 activity. 4 In our article, we state that "The observation of dose-related effects despite near-complete inhibition of arachidonic acid-induced aggregation suggests that aspirin may also exert antiplatelet effects through non-COX-1 pathways" (p 3163). Clearly, we are hypothesizing a novel antiplatelet effect of aspirin that should be the focus of future research, especially in diabetic patients where the dose-dependent antiplatelet effects of aspirin may be more pronounced. 5 It took at least 70 years to determine that aspirin inhibits platelet function by acetylating COX-1 and that aspirin can be used as an effective a...

Point-of-care ultrasound (POCUS) is an important tool for diagnosis and management across medical specialties. This scoping review consolidates POCUS education literature, examining how curricula are developed, implemented, and assessed. We identify literature gaps, explore directions for further research, and provide recommendations for curriculum development, implementation, and improvement. MethodsWe conducted a scoping review per the framework outlined by Arksey & O’Malley. A systematic search of the MEDLINE, EMBASE, Cochrane, ERIC, Web of Science, and Scopus databases was conducted to identify published, English language literature, on POCUS education in undergraduate or graduate medical training.ResultsOf 6,164 articles identified, 421 were analyzed in depth. Curricular content included diverse diagnostic and therapeutic applications, varying significantly by specialty. Teaching modalities included in-person didactics (74%), human models (58%), simulation (33%), and web-based didactics (18%). Several studies showed better outcomes for structured vs. apprenticeship curricula, hands-on teaching vs. didactic lectures, and human models vs. simulators. Web-based didactics were as effective as in-person didactics and conveyed benefits in reusability, cost, and instructor time. Dedicated electives and boot-camps were identified as effective. Few curricula assessed knowledge retention (5%), clinical decision making (3%), learner behavior (12%), or patient outcomes (6%). ConclusionScholarly POCUS education literature is expanding. Curricular content varies and should be tailored to specialty needs. Structured curricula utilizing hands-on learning, electives, and boot-camps can enhance educational outcomes. Higher-level outcomes such as knowledge retention, clinical decision making, learner behavior, and patient outcomes, are lacking and should be a focus of further researchResumeL’échographie au point de service (POCUS) est un outil important pour le diagnostic et la gestion dans toutes les spécialités médicales. Cette étude de portée consolide la littérature éducative POCUS, en examinant comment les programmes d’enseignement sont élaborés, mis en œuvre et évalués. Nous identifions les lacunes de la littérature, explorons les directions à prendre pour des recherches plus approfondies et fournissons des recommandations pour le développement, la mise en œuvre et l’amélioration des programmes d’enseignement. MéthodesNous avons procédé à un examen de portée conformément au cadre défini par Arksey & O’Malley. Une recherche systématique dans les bases de données MEDLINE, EMBASE, Cochrane, ERIC, Web of Science et Scopus a été effectuée afin d’identifier les publications en langue anglaise sur l’enseignement POCUS dans le cadre de la formation médicale de premier ou de deuxième cycle. RésultatsSur les 6 164 articles identifiés, 421 ont fait l’objet d’une analyse approfondie. Le contenu des programmes d’études comprenait diverses applications diagnostiques et thérapeutiques, variant considérablement selon les spécialités. Les modalités d’enseignement comprenaient la didactique en personne (74 %), les modèles humains (58 %), la simulation (33 %) et la didactique basée sur le web (18 %). Plusieurs études ont montré de meilleurs résultats pour les programmes structurés par rapport aux programmes d’apprentissage, l’enseignement pratique par rapport aux cours magistraux didactiques, et les modèles humains par rapport aux simulateurs. La didactique basée sur le web était aussi efficace que la didactique en personne et présentait des avantages en termes de réutilisation, de coût et de temps de l’instructeur. Les cours optionnels et les camps d’entraînement ont été jugés efficaces. Peu de programmes ont évalué la rétention des connaissances (5 %), la prise de décision clinique (3 %), le comportement des apprenants (12 %) ou les résultats pour les patients (6 %). ConclusionLa littérature éducative POCUS est en pleine expansion. Le contenu des programmes d’études varie et doit être adapté aux besoins spécifiques. Des programmes structurés utilisant un apprentissage pratique, des cours optionnels et des camps d’entraînement peuvent améliorer les résultats scolaires. Des résultats de plus haut niveau, tels que la rétention des connaissances, la prise de décision clinique, le comportement de l’apprenant et les résultats pour le patient, font défaut et devraient faire l’objet de recherches plus approfondies.