Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Pre- and early-postnatal nutrition modify gene and protein expressions of muscle energy metabolism markers and phospholipid fatty acid composition in a muscle type specific manner in sheep.

We previously reported that undernutrition in late fetal life reduced whole-body insulin sensitivity in adult sheep, irrespective of dietary exposure in early postnatal life. Skeletal muscle may play an important role in control of insulin action. We therefore studied a range of putative key muscle determinants of insulin signalling in two types of skeletal muscles (longissimus dorsi (LD) and biceps femoris (BF)) and in the cardiac muscle (ventriculus sinister cordis (VSC)) of sheep from the same experiment. Twin-bearing ewes were fed either 100% (NORM) or 50% (LOW) of their energy and protein requirements during the last trimester of gestation. From day-3 postpartum to 6-months of age (around puberty), twin offspring received a high-carbohydrate-high-fat (HCHF) or a moderate-conventional (CONV) diet, whereafter all males were slaughtered. Females were subsequently raised on a moderate diet and slaughtered at 2-years of age (young adults). The only long-term consequences of fetal undernutrition observed in adult offspring were lower expressions of the insulin responsive glucose transporter 4 (GLUT4) protein and peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC1α) mRNA in BF, but increased PGC1α expression in VSC. Interestingly, the HCHF diet in early postnatal life was associated with somewhat paradoxically increased expressions in LD of a range of genes (but not proteins) related to glucose uptake, insulin signalling and fatty acid oxidation. Except for fatty acid oxidation genes, these changes persisted into adulthood. No persistent expression changes were observed in BF and VSC. The HCHF diet increased phospholipid ratios of n-6/n-3 polyunsaturated fatty acids in all muscles, even in adults fed identical diets for 1½ years. In conclusion, early postnatal, but not late gestation, nutrition had long-term consequences for a number of determinants of insulin action and metabolism in LD. Tissues other than muscle may account for reduced whole body insulin sensitivity in adult LOW sheep

Framing the Issues: Moral Distress in Health Care

Moral distress in health care has been identified as a growing concern and a focus of research in nursing and health care for almost three decades. Researchers and theorists have argued that moral distress has both short and long-term consequences. Moral distress has implications for satisfaction, recruitment and retention of health care providers and implications for the delivery of safe and competent quality patient care. In over a decade of research on ethical practice, registered nurses and other health care practitioners have repeatedly identified moral distress as a concern and called for action. However, research and action on moral distress has been constrained by lack of conceptual clarity and theoretical confusion as to the meaning and underpinnings of moral distress. To further examine these issues and foster action on moral distress, three members of the University of Victoria/University of British Columbia (UVIC/UVIC) nursing ethics research team initiated the development and delivery of a multi-faceted and interdisciplinary symposium on Moral Distress with international experts, researchers, and practitioners. The goal of the symposium was to develop an agenda for action on moral distress in health care. We sought to develop a plan of action that would encompass recommendations for education, practice, research and policy. The papers in this special issue of HEC Forum arose from that symposium. In this first paper, we provide an introduction to moral distress; make explicit some of the challenges associated with theoretical and conceptual constructions of moral distress; and discuss the barriers to the development of research, education, and policy that could, if addressed, foster action on moral distress in health care practice. The following three papers were written by key international experts on moral distress, who explore in-depth the issues in three arenas: education, practice, research. In the fifth and last paper in the series, we highlight key insights from the symposium and the papers in the series, propose to redefine moral distress, and outline directions for an agenda for action on moral distress in health care

Exchange hazards, relational reliability, and contracts in China: The contingent role of legal enforceability

Building on institutional and transaction cost economics, this article proposes that legal enforceability increases the use of contract over relational reliability (e.g., beliefs that the other party acts in a non-opportunistic manner) to safeguard market exchanges characterized by non-trivial hazards. The results of 399 buyer-supplier exchanges in China show that: (1) when managers perceive that the legal system can protect their firm's interests, they tend to use explicit contracts rather than relational reliability to safeguard transactions involving risks (i.e., asset specificity, environmental uncertainty, and behavioral uncertainty); and (2) when managers do not perceive the legal system as credible, they are less likely to use contracts, and instead rely on relational reliability to safeguard transactions associated with specialized assets and environmental uncertainty, but not those involving behavioral uncertainty. We further find that legal enforceability does not moderate the effect of relational reliability on contracts, but does weaken the effect of contracts on relational reliability. These results endorse the importance of prior experience (e.g., relational reliability) in supporting the use of explicit contracts, and alternatively suggest that, under conditions of greater legal enforceability, the contract signals less regarding one's intention to be trustworthy but more about the efficacy of sanctions. © 2010 Academy of International Business All rights reserved.postprin

Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Comparing the Functional Independence Measure and the interRAI/MDS for use in the functional assessment of older adults: a review of the literature

<p>Abstract</p> <p>Background</p> <p>The rehabilitation of older persons is often complicated by increased frailty and medical complexity - these in turn present challenges for the development of health information systems. Objective investigation and comparison of the effectiveness of geriatric rehabilitation services requires information systems that are comprehensive, reliable, valid, and sensitive to clinically relevant changes in older persons. The Functional Independence Measure is widely used in rehabilitation settings - in Canada this is used as the central component of the National Rehabilitation Reporting System of the Canadian Institute of Health Information. An alternative system has been developed by the interRAI consortium. We conducted a literature review to compare the development and measurement properties of these two systems.</p> <p>Methods</p> <p>English language literature published between 1983 (initial development of the FIM) and 2008 was searched using Medline and CINAHL databases, and the reference lists of retrieved articles. Relevant articles were summarized and charted using the criteria proposed by Streiner. Additionally, attention was paid to the ability of the two systems to address issues particularly relevant to older rehabilitation clients, such as medical complexity, comorbidity, and responsiveness to small but clinically meaningful improvements.</p> <p>Results</p> <p>In total, 66 articles were found that met the inclusion criteria. The majority of FIM articles studied inpatient rehabilitation settings; while the majority of interRAI/MDS articles focused on nursing home settings. There is evidence supporting the reliability of both instruments. There were few articles that investigated the construct validity of the interRAI/MDS.</p> <p>Conclusion</p> <p><b>A</b>dditional psychometric research is needed on both the FIM and MDS, especially with regard to their use in different settings and with different client groups.</p

Marking their own homework: The pragmatic and moral legitimacy of industry self-regulation

When is industry self-regulation (ISR) a legitimate form of governance? In principle, ISR can serve the interests of participating companies, regulators and other stakeholders. However, in practice, empirical evidence shows that ISR schemes often under-perform, leading to criticism that such schemes are tantamount to firms marking their own homework. In response, this paper explains how current management theory on ISR has failed to separate the pragmatic legitimacy of ISR based on self-interested calculations, from moral legitimacy based on normative approval. The paper traces three families of management theory on ISR and uses these to map the pragmatic and moral legitimacy of ISR schemes. It identifies tensions between the pragmatic and moral legitimacy of ISR schemes, which the current ISR literature does not address, and draws implications for the future theory and practice of ISR

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis