Developing novel molecular contrast agents for imaging vulnerable plaques

This thesis describes the design, synthesis, and testing of novel MRI contrast agents based on iron oxide nanoparticles for the specific detection and identification of vulnerable plaque. Cardiovascular disease remains the leading cause of death worldwide, primarily due to heart attacks and strokes resulting from vulnerable plaque rupture. Vulnerable plaque occurs in atherosclerosis, when plaque is deposited in the walls of blood vessels and can take on vulnerable or stable phenotypes. There is an urgent need for an imaging biomarker to enable the specific detection of vulnerable plaque to facilitate treatment and prevent future heart attacks and strokes. MRI is a non-ionising, non-invasive imaging modality with the potential for highly customisable contrast agents. Chapter 2 discusses the design and synthesis of a library of superparamagnetic iron oxide nanoparticle-based contrast agents through thermal decomposition and coating with different surface ligands, including poly (maleic anhydride-alt-1-octadecene), alendronate, and poly (ethyleneimine). The agents were characterised through transmission electron microscopy, dynamic light scattering, zeta potential and relaxivity measurements. Chapter 3 presents the results of biological tests performed using the lead candidate from the synthesis carried out in chapter 2, including the coupling of a targeting antibody to the contrast agent, in vitro testing, and MR imaging in a preclinical model with histological verification of the results. Chapter 4 builds on the initial design and synthetic work of Chapter 2 with the introduction of a gold shell, moving towards multi-modality imaging. Several synthetic routes for the introduction of the gold shell and a selection of surface ligands including poly (maleic anhydride-alt-1-octadecene), homocysteine, and citrate were studied, and characterised through transmission electron microscopy, dynamic light scattering, and zeta potential measurements. Chapter 5 summarises the conclusions of the project, presents potential areas for future work and concludes the thesis. Open Acces

The role of schools in children and young people’s self-harm and suicide: systematic review and meta-ethnography of qualitative research

Background Evidence reports that schools influence children and young people’s health behaviours across a range of outcomes. However there remains limited understanding of the mechanisms through which institutional features may structure self-harm and suicide. This paper reports on a systematic review and meta-ethnography of qualitative research exploring how schools influence self-harm and suicide in students. Methods Systematic searches were conducted of nineteen databases from inception to June 2015. English language, primary research studies, utilising any qualitative research design to report on the influence of primary or secondary educational settings (or international equivalents) on children and young people’s self-harm and suicide were included. Two reviewers independently appraised studies against the inclusion criteria, assessed quality, and abstracted data. Data synthesis was conducted in adherence with Noblit and Hare’s meta-ethnographic approach. Of 6744 unique articles identified, six articles reporting on five studies were included in the meta-ethnography. Results Five meta-themes emerged from the studies. First, self-harm is often rendered invisible within educational settings, meaning it is not prioritised within the curriculum despite students’ expressed need. Second, where self-harm transgresses institutional rules it may be treated as ‘bad behaviour’, meaning adequate support is denied. Third, schools’ informal management strategy of escalating incidents of self-harm to external ‘experts’ serves to contribute to non-help seeking behaviour amongst students who desire confidential support from teachers. Fourth, anxiety and stress associated with school performance may escalate self-harm and suicide. Fifth, bullying within the school context can contribute to self-harm, whilst some young people may engage in these practices as initiation into a social group. Conclusions Schools may influence children and young people’s self-harm, although evidence of their impact on suicide remains limited. Prevention and intervention needs to acknowledge and accommodate these institutional-level factors. Studies included in this review are limited by their lack of conceptual richness, restricting the process of interpretative synthesis. Further qualitative research should focus on the continued development of theoretical and empirical insight into the relationship between institutional features and students’ self-harm and suicide

Survival, signaling, and security: Foster carers’ and residential carers’ accounts of self-harming practices among children and young people in care

Research on clinicians’ interpretations of self-harming practices has shown that they can often be negative. To date there has been limited consideration of other professionals’ narratives, notably those working in social care. This article presents focus group and interview data generated with foster carers (n = 15) and residential carers (n = 15) to explore the symbolic meanings ascribed to self-harm among the children and young people they care for. Three repertoires of interpretation are presented: survival, which conceives self-harm as a mechanism for redefining the identity of “looked-after”; signaling, which understands self-harm as a communicative tool for the expression of emotion; and security, which sees self-harming practices as testing the authenticity and safety of the caring relationship. Through their focus on sociocultural narratives, carers position themselves as experts on self-harm due to their intimacy with young people’s social worlds. This construction potentially creates distance from health professionals, which is problematic given the current privileging of interprofessional working

Gender, relationship breakdown, and suicide risk: a review of research in western countries

An association between divorce and suicide risk has been noted in numerous studies, but the gender profile of this risk has not been clearly established. This article reviews the evidence on gender differentials in suicide risk following the breakdown of an intimate relationship (including divorce and separation). Nineteen published articles that included individuallevel data were identified. Twelve reported a greater risk of suicide in men following relationship breakdown, two indicated a greater risk in women, and a further five showed no clear gender differential. Although there are possible indications of increased risk for men, no definitive conclusion about gender differential can be drawn. Furthermore, research is required that directly compares men with women for suicide risk following relationship breakdown

Emotional pedagogy and the gendering of social and emotional learning

Social and emotional learning (SEL) has predominantly been conceptualised as a neurological process, which has precluded understanding of how social, cultural and material discourses inform the expression of emotional experiences. Gender remains a notable omission. This article explores the micro-practices through which gender structures the development of young people’s emotional subjectivities within the context of a school-based SEL intervention. Particular emphasis is placed on the gendering strategies utilised by educational professionals during the course of their emotional pedagogy. Three strategies are considered: the overt coercion of girls to demonstrate their learning; the permission of boys’ passivity, with their docile bodies being indicated as a signifier of participation; and the restricting of occasions for emotional expression in accordance with perceived gender norms. Efforts to inculcate students with a gendered emotional subjectivity mean that differential learning opportunities are on offer, raising concerns about the introduction of new forms of gendered educational inequalities

From ‘Techniums’ to ‘emptiums’: the failure of a flagship innovation policy in Wales

This paper examines the use of European Union Structural Funds to support the development of innovation policy within Wales during the period 2000–06. Drawing on data from the Welsh government and interviews with key stakeholders, it focuses specifically on the Technium programme, a high-profile technology-based innovation intervention that took a predominantly supply-side approach to supporting innovation, resulting in its eventual failure. Consistent within this is an analysis of the efficacy of supply-side policies using European Union funds to support research and development activities to aid economic growth in peripheral, weaker regions

Systematic review of educational interventions for looked-after children and young people: recommendations for intervention development and evaluation

Looked-after children and young people (LACYP) are educationally disadvantaged compared to the general population. A systematic review was conducted of randomised controlled trials evaluating interventions aimed at LACYP aged ≤18 years. Restrictions were not placed on delivery setting or delivery agent. Intervention outcomes were: academic skills; academic achievement and grade completion; special education status; homework completion; school attendance, suspension, and drop-out; number of school placements; teacher-student relationships; school behaviour; and academic attitudes. Fifteen studies reporting on 12 interventions met the inclusion criteria. Nine interventions demonstrated tentative impacts. However, evidence of effectiveness could not be ascertained due to variable methodological quality, as appraised by the Cochrane risk of bias tool. Theoretical and methodological recommendations are provided to enhance the development and evaluation of educational interventions

How can we adapt complex population health interventions for new contexts? Progressing debates and research priorities

Introduction: The UK Medical Research Council and National Institute for Health Research have funded the ADAPT study (2018–2020), to develop methodological guidance for the adaptation of complex population health interventions for new contexts. While there have been advances in frameworks, there are key theoretical and methodological debates to progress. The ADAPT study convened a panel meeting to identify and enrich these debates. This paper presents the panel’s discussions and suggests directions for future research. Methods: Sixteen researchers and one policymaker convened for a 1-day meeting in July 2019. The aim was to reflect on emerging study findings (systematic review of adaptation guidance; scoping review of case examples; and qualitative interviews with funders, journal editors, researchers and policymakers), progress theoretical and methodological debates, and consider where innovation may be required to address research gaps. Discussion: Despite the proliferation of adaptation frameworks, questions remain over the definition of basic concepts (eg, adaptation). The rationale for adaptation, which often focuses on differences between contexts, may lead to adaptation hyperactivity. Equal emphasis should be placed on similarities. Decision-making about intervention modification currently privileges the concept of ‘core components’, and work is needed to progress the use and operationalisation of ‘functional fidelity’. Language and methods must advance to ensure meaningful engagement with diverse stakeholders in adaptation processes. Further guidance is required to assess the extent of re-evaluation required in the new context. A better understanding of different theoretical perspectives, notably complex systems thinking, implementation science and realist evaluation may help in enhancing research on adaptation

Care and reciprocity: a conversation between Rhiannon Armstrong and Mel Evans

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