Clinical utility of remote platelet function measurement using P-selectin: assessment of aspirin, clopidogrel, and prasugrel and bleeding disorders

Vascular diseases such as myocardial infarction and ischemic stroke are associated with increased platelet function whilst the risk of recurrence is reduced by antiplatelet agents such as aspirin, clopidogrel, and prasugrel. However, some patients exhibit high platelet reactivity, especially with clopidogrel. Existing platelet function tests may not be ideal in that they can be expensive, are often time consuming, and measurements must be made near to the patient and within a few hours of blood collection. Platelet activation leads to translocation of P-selectin from alpha-granules to the cell surface. Following activation with arachidonic acid (which is blocked by aspirin) or adenosine diphosphate (inhibited by clopidogrel) and fixation, samples may be stored or posted to a laboratory performing flow cytometric quantification of platelet P-selectin expression. Acute myocardial infarction and ischemic stroke are associated with high platelet reactivity on clopidogrel in 6–58% of patients when assessed with P-selectin expression, and high reactivity was associated with an increased risk of recurrence after myocardial infarction. Use of P-selectin expression tests may also be of relevance to surgical and veterinary practice and the diagnosis of mild bleeding disorders. The present review explores this topic in further detail

Length of stay in asylum centres and mental health in asylum seekers: a retrospective study from Denmark

<p>Abstract</p> <p>Background</p> <p>The length of stay in asylum centres is generally mentioned as a possible health risk to asylum seekers. Medical staff working with asylum seekers has claimed that long lengths of stay in asylum centres might cause or aggravate mental disorders. We used records from a large, multiethnic group of asylum seekers to study if the incidence of mental disorders increased with length of stay.</p> <p>Methods</p> <p>The study population was asylum seekers in Danish asylum centres run by the Danish Red Cross. General medical care was provided by Red Cross staff who could refer selected cases to medical specialists. If an asylum seeker needed more than three specialist consultations for mental illness or five consultations for physical illness the referrals had to be approved by The Danish Immigration Service. Between July 2001 – December 2002 the Red Cross prospectively registered health related data on all new applications (n = 4516) to the Immigration Service regarding referrals to medical specialists. We used these records to analyse the association between length of stay in the asylum centres and overall rate of referral for mental disorders. Data was analysed using weighted linear regression.</p> <p>Results</p> <p>We found that referrals for mental disorders increased with length of stay in asylum centres in a large, multiethnic population of asylum seekers. The association was found in all the categories of psychiatric illness studied and for a majority of the nationality groups studied.</p> <p>Conclusion</p> <p>Length of stay in asylum centres was associated with an increase in referrals for mental disorders in a large, multiethnic group of asylum seekers. The present study supports the view that prolonged length of stay in an asylum centre is a risk factor for mental health. The risk of psychiatric illness among asylum seekers should be addressed by political and humanitarian means, giving prevention of illness the highest priority.</p

Challenges to undertaking randomised trials with looked after children in social care settings.

BACKGROUND: Randomised controlled trials (RCTs) are widely viewed as the gold standard for assessing effectiveness in health research; however many researchers and practitioners believe that RCTs are inappropriate and un-doable in social care settings, particularly in relation to looked after children. The aim of this article is to describe the challenges faced in conducting a pilot study and phase II RCT of a peer mentoring intervention to reduce teenage pregnancy in looked after children in a social care setting. METHODS: Interviews were undertaken with social care professionals and looked after children, and a survey conducted with looked after children, to establish the feasibility and acceptability of the intervention and research design. RESULTS: Barriers to recruitment and in managing the intervention were identified, including social workers acting as informal gatekeepers; social workers concerns and misconceptions about the recruitment criteria and the need for and purpose of randomisation; resource limitations, which made it difficult to prioritise research over other demands on their time and difficulties in engaging and retaining looked after children in the study. CONCLUSIONS: The relative absence of a research infrastructure and culture in social care and the lack of research support funding available for social care agencies, compared to health organisations, has implications for increasing evidence-based practice in social care settings, particularly in this very vulnerable group of young people

Dual Action of lysophosphatidate- functionalised titanium: Interactions with human (MG63) osteoblasts and methicillin resistant staphylococcus aureus

© 2015 Skindersoe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices

Ethical issues, research and vulnerability : gaining the views of children and young people in residential care

Children and young people in residential care are some of the most vulnerable in our society. They may have experienced violence and physical, sexual or emotional abuse. They may be involved in offending or the misuse of drugs and alcohol. They are separated from their families and have to cope with living in a group situation with other young people and staff members. Children and young people in residential care also possess strengths, competencies and resilience. We have much to learn from their experiences and perspectives, both generally and surrounding their time in care. This paper will address the ethical issues which arise from gaining the views of children and young people in residential care, drawing on the experience of carrying out three studies in particular (Kendrick et al. 2004, The development of a residential unit working with sexually aggressive young men. In: H.G. Eriksson and T. Tjelflaat, eds. Residential care: horizons for the new century. Aldershot: Ashgate, 38-55; Docherty et al. 2006, Designing with care: interior design and residential child care. Farm7 and SIRCC. http://www.sircc.strath.ac.uk/publications/Designing_with_Care.pdf; Steckley, L. and Kendrick, A., 2005. Physical restraint in residential child care: the experiences of young people and residential workers. Childhoods 2005: Children and Youth in Emerging and Transforming Societies, University of Oslo, Norway, 29 June-3 July 2005, Steckley and Kendrick 2007, Young people's experiences of physical restraint in residential care: subtlety and complexity in policy and practice. In: M. Nunno, L. Bullard and D. Day, eds. For our own safety: examining the safety of high-risk interventions for children and young people. Washington, DC: Child Welfare League of America, forthcoming). The paper will discuss: information, consent and choice about involvement in the research; confidentiality, privacy and safety. It will also explore some of the more complex issues of ethical good practice which arise from researching children in their own living space. The negotiation of children's time and space must be approached carefully, with consideration of their rights and wishes. Sensitivity to children and young people's priorities and preoccupations must be paramount

The Generationing of Power: A Comparison of Child-Parent and Sibling Relations in Scotland

The paper concentrates on an exploration of power relations within families. The paper discusses parental power in relation to legitimacy, household resources and children’s anticipated reactions of adult discipline. The nature of sibling power is highlighted before exploring the reciprocal expectations of sibling and child-parent interactions. The paper ends by suggesting that the generationing of power relations can lead to differing degrees of backstage and frontstage performances within the home

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

The P2X1 receptor and platelet function

Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1 receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 &lt;200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines