Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date

Age of smoking initiation and risk of breast cancer in a sample of Ontario women

<p>Abstract</p> <p>Objectives</p> <p>To examine the association between time of smoking initiation and both the independent and joint effects of active and passive tobacco smoke exposure and the risk of breast cancer in a sample of Ontario women.</p> <p>Methods</p> <p>Data from two large population-based case-control studies conducted among Ontario women aged 25–75 years were combined for analysis (n = 12,768).</p> <p>Results</p> <p>Women who had ever smoked and were exposed to passive smoke had a significant increased risk of breast cancer (OR 1.13, 95%CI 1.01–1.25). A significant increased risk was also observed among women who initiated smoking: at age 26 or older (OR 1.26, 95%CI 1.03–1.55); more than five years from menarche (OR 1.26, 95%CI 1.12–1.42); and, after their first live birth (OR 1.25, 95%CI 1.02–1.52).</p> <p>Conclusion</p> <p>The results suggest that women who initiate smoking at an older age are at an increased risk of breast cancer.</p

Shifts in Practice Based on Rapid Re-Housing for Rural Homelessness: An Exploratory Study of Micropolitan Homeless Service Provision

Based on interviews with rural homeless service providers, the authors examine in this practice note how policy has created shifts in practice for organizations serving homeless populations. Homeless individuals find a decreasing opportunity for assistance while awaiting Rapid Re-Housing. Some organizations, dependent on Rapid Re-Housing monies, are facing a lack of funding to pay for general homeless care provision. Organizations are creating care networks to address requirements of the new policy in addition to pooling resources in underserved areas

Shifts in Practice Based on Rapid Re-Housing for Rural Homelessness: An Exploratory Study of Micropolitan Homeless Service Provision

Based on interviews with rural homeless service providers, the authors examine in this practice note how policy has created shifts in practice for organizations serving homeless populations. Homeless individuals find a decreasing opportunity for assistance while awaiting Rapid Re-Housing. Some organizations, dependent on Rapid Re-Housing monies, are facing a lack of funding to pay for general homeless care provision. Organizations are creating care networks to address requirements of the new policy in addition to pooling resources in underserved areas

The Mayo Clinic Manuscript Series Relative to the Discussion, Dissemination, and Operationalization of the Food and Drug Administration Guidance on Patient-Reported Outcomes

AbstractPatient-reported outcomes (PROs) have become increasingly prevalent in clinical research and practice. On February 2, 2006, the Food and Drug Administration (FDA) released a draft guidance document with respect to incorporating PROs into clinical research endeavors which include FDA involvement. Researchers at the Mayo Clinic worked with FDA personnel and experts from academia, industry, clinical research, and clinical practice to facilitate discussion, dissemination, and operationalization of the FDA guidance document. This article introduces a manuscript series that resulted from this collective effort. Basic terms are definedand a précis of each article in the manuscript series is given. The ultimate conclusion to be drawn from this series is that, while the goals of assessing and analyzing PRO elements of clinical practice and research are challenging, there now exists a scientific foundation that makes achieving these goals feasible and the results credible. This is vitally important because after all, at the heart of all healthcare endeavors is the patient

Genetic Population Structure Analysis in New Hampshire Reveals Eastern European Ancestry

Genetic structure due to ancestry has been well documented among many divergent human populations. However, the ability to associate ancestry with genetic substructure without using supervised clustering has not been explored in more presumably homogeneous and admixed US populations. The goal of this study was to determine if genetic structure could be detected in a United States population from a single state where the individuals have mixed European ancestry. Using Bayesian clustering with a set of 960 single nucleotide polymorphisms (SNPs) we found evidence of population stratification in 864 individuals from New Hampshire that can be used to differentiate the population into six distinct genetic subgroups. We then correlated self-reported ancestry of the individuals with the Bayesian clustering results. Finnish and Russian/Polish/ Lithuanian ancestries were most notably found to be associated with genetic substructure. The ancestral results were further explained and substantiated using New Hampshire census data from 1870 to 1930 when the largest waves of European immigrants came to the area. We also discerned distinct patterns of linkage disequilibrium (LD) between the genetic groups in the growth hormone receptor gene (GHR). To our knowledge, this is the first time such an investigation has uncovered a strong link between genetic structure and ancestry in what would otherwise be considered a homogenous US population

Research-Practice Partnerships as Community-Engaged Learning: Lessons Learned from a Collaborative Project with Youth Development Programs

To bridge the gap between community-engaged learning and research-practice partnerships, we describe our experiences in a project jointly conceptualized and implemented by undergraduate students and youth development practitioners over the course of two academic semesters. The project offered students the opportunity to apply the skills they learned through coursework in a way that also supported the needs of community practitioners, providing both groups with opportunities to learn from each other. In this paper we describe the collaborative project, our process, the challenges we faced, and the impact of the project on the student researchers and the youth development practitioners. Written by representatives of both the student researchers and the practitioner collaborators, we hope this paper will inspire others to incorporate students in research-practice partnerships and that our reflections on the strengths and challenges of this process will facilitate more effective implementation of community-engaged scholarship in the future

Experiences of remote teaching and learning in Ireland during the Covid-19 pandemic (March–May 2020)

Initiated in 2018, Children’s School Lives is an exciting, longitudinal study following 4,000 children in 189 schools through their primary school years. Children’s lived experiences and voices are at the heart of this research. The report, Experiences of Remote Teaching and Learning in Ireland During the Covid-19 Pandemic (March – May 2020), is the second publication arising from the study and focuses on children’s experiences and those of their teachers, principals and families, during the period of school closures earlier this year. The report highlights the important role of education and primary schools in children’s and families’ lives. It also spotlights the centrality of relationships in primary education, those between children and their teacher, between teachers and parents, and relationships between teachers and school leaders. The rich, authentic voices throughout the report give us insights into the many challenges that emerged out of the need to reconfigure and reconceptualise teaching and learning in the context of a global pandemic. This saw primary schooling being relocated from a shared physical space, the classroom, to an online environment, necessitating enormous work, engagement and commitment by study participants—children, parents, teachers and school leaders—to enable teaching and learning to continue. The report also affords us glimpses of how this changed learning environment impacted, positively and negatively, on children, their families, teachers and school leaders.University College DublinNational Council for Curriculum and Assessment (NCCA

Kant, race, and natural history

This article presents a new argument concerning the relation between Kant’s theory of race and aspects of the critical philosophy. It argues that Kant’s treatment of the problem of the systematic unity of nature and knowledge in the Critique of Pure Reason and the Critique of the Power of Judgment can be traced back a methodological problem in the natural history of the period – that of the possibility of a natural system of nature. Kant’s transformation of the methodological problem from natural history into a set of philosophical (and specifically epistemological) problems proceeds by way of the working out of his own problem in natural history – the problem of the natural history of the human races – and specifically the problem of the unity in diversity of the human species, in response to which he develops a theory of race. This theory of race is, further, the first developed model of the use of teleological judgment in Kant’s work. The article thus argues that Kant’s philosophical position on the systematic unity of nature and of knowledge in the first and third Critiques, and his account and defense of teleological judgment, are developed out of problems first articulated in his solution to the problem of the unity in diversity of the human species – that is, in his theory of race. The article does not seek to establish that these aspects of the critical philosophy are therefore racialised. But it does demonstrate, against those who deny its salience to his philosophy, how the problem of the unity in diversity of the human species and Kant’s theory of race is significant for the development of aspects of the critical philosophy and thus contributes to their philosophical problematics