Improving support for older people looking after someone with advanced cancer

The briefing paper is about the findings and recommendations from a research project conducted at the University of Nottingham, with funding awarded by Macmillan Cancer Support. The project was set up to study the experiences and main support needs of older carers looking after someone with advanced cancer and to facilitate the active involvement of carers in the research process. Looking after someone with advanced cancer approaching the end of their life has a substantial and enduring impact on older carers. Various factors contribute to the diverse quality and impact of end of life care experiences for both the person with advanced cancer and their caregiver. These include factors relating to the care giver and care recipient, such as the communication style and quality of relationship between them; the availability, provision and quality of informal support, and the duration of the end of life care phase. They also include factors external to the care giver and care recipient such as the availability, provision and quality of formal health and social care services for both the care giver and the person with advanced cancer. The study participants main support needs and recommendations for improving support for older carers are provided

Synthesis and Transition Metal-Catalysed Reactivity of Vinyl and Allenyl Benzoxazinanones

Transition metal-catalysed reactions represent a valuable tool for the construction of sp3-rich, stereodefined molecular scaffolds in a single synthetic step. Though these reactions have garnered considerable attention over the last few decades, recent literature indicates that the fractional sp3 character of drug-like molecules has gradually decreased over the last twenty years. This is in part, due to the increased use of transition metal-catalysed cross-coupling reactions such as the Heck and Suzuki–Miyaura reactions, which allow for the preparation of flat, aromatic molecules in a single synthetic step. It was therefore the aim of this dissertation to synthesise novel sp3-rich molecular scaffolds in a single synthetic step via transition metal-catalysed reactions. This has been achieved in two sections: Part I which details the use of vinyl benzoxazinanones as 1,4-dipole precursors in (4 + 2) dipolar cycloaddition reactions, and Part II which proposes a synthetic route towards novel allenyl benzoxazinanones and investigates the reactivity of these systems under nickel catalysis. The synthesis of sp3-rich tetrahydro-5H-indolo[2,3-b]quinolines was achieved in Part I of this dissertation via the palladium-catalysed decarboxylative, dearomative (4 + 2) cycloaddition of vinyl benzoxazinanones with 3-nitroindoles. While initial attempts to react N-tosyl protected vinyl benzoxazinanones with 3-nitroindole in the presence of a palladium(0) catalyst were unsuccessful, replacing this substrate with the unprotected vinyl benzoxazinanone led to the formation of tetrahydro-5H-indolo[2,3-b]quinolines in moderate to excellent yields (42–94%), with excellent diastereoselectivity (up to \u3e98:2). The relative stereochemistry of these tetrahydro-5H-indolo[2,3-b]quinolines was determined as trans through a combination of nuclear magnetic resonance (1-D NOE and 2-D NOESY) analysis and X-ray crystallographic analysis. The scope of this reaction was shown to accommodate a wide range of electron-donating and electron-withdrawing substituents on the benzene portion of the indole ring. This was in contrast to indoles which contained electron-donating groups at N-1 or groups that were less electron-withdrawing than tosyl (such as Bz, Ac, Me), and indoles containing C-3 substituents such as acetyl, cyano and methyl ester which resulted in no reaction. These findings highlight the significance of the C-3 electron-withdrawing nitro-substituent and the strong electron-withdrawing N-substituents in rendering the indole sufficiently electrophilic to participate in the cycloaddition reaction with vinyl benzoxazinanones. A brief asymmetric protocol of this reaction was also demonstrated in the presence of a chiral phosphinooxazoline ligand, generating the corresponding tetrahydro-5H-indolo[2,3-b]quinoline in high NMR yield (90%), moderate dr (46:54 trans:cis) and high enantioselectivity for the trans diastereomer (\u3e98% ee)

Novel areas of crosstalk between the cyclic AMP and PKC signalling pathways

Mediation of biological functions occurs via tightly regulated signal transduction pathways. These complex cascades often employ crosstalk with other signalling pathways to exert strict control to allow for correct cellular responses. The cyclic AMP signalling pathway is involved in a wide range of cellular processes which require tight control, including cell proliferation and differentiation, metabolism and inflammation. Protein Kinase C (PKC) signalling is also involved in the regulation of many biological functions, due to the wide range of PKC isoforms, and there is emerging evidence that there are critical points of crosstalk between these two central signalling pathways. The aims of this research, therefore, are to identify the molecular basis underlying this pivotal cross-communication. The identification of the complex formed by Receptor for activated C Kinase 1 (RACK1), a scaffold protein for PKC, and the cyclic AMP-specific phosphodiesterase PDE4D5 demonstrated a potential area of crosstalk between the cyclic AMP and PKC signalling pathways although the function of the complex remained largely unknown. In this thesis I have outlined a role for RACK1 binding to PDE4D5 to control the enzymatic activity of the phosphodiesterase. Although RACK1 does not affect the intracellular localisation of PDE4D5, it does afford structural stability to PDE4D5, providing protection against denaturation. Furthermore, interaction with RACK1 facilitates high affinity binding of PDE4D5 to cyclic AMP and increases phosphodiesterase sensitivity to inhibition by rolipram, a PDE4-specific inhibitor that is a therapeutic treatment for depression and Alzheimer’s disease. Additionally, RACK1-bound PDE4D5 was found to be activated by PKCα, providing a route of negative regulation by PKC on cyclic AMP in HEK293 cells. The discovery of EPAC (Exchange Protein directly Activated by Cyclic AMP) has opened up the field of cyclic AMP research, providing an alternative route for the cyclic AMP signalling originally thought to occur solely through Protein Kinase A (PKA). Recent investigations have linked cyclic AMP signalling via EPAC to the control of inflammation, through the induction of Suppressor of Cytokine Signalling 3 (SOCS-3) to inhibit IL-6 signalling. Here I have further delineated this pathway in COS1 to show that induction of SOCS-3 by EPAC requires phospholipase C (PLC) ε. Investigation into downstream effectors of PLC action lead to the identification of PKCα and PKCδ as essential components of this pathway, further elucidating a mechanism by which cyclic AMP can affect inflammation and revealing a point of crosstalk between the two signalling pathways. Further elaborating on the identification of PKC isoforms α and δ as crucial components in the control of cytokine signalling by cyclic AMP via EPAC, investigations into the effect of cyclic AMP on PKC α and δ activation and autophosphorylation, and on downstream effectors, were carried out. It was revealed that cyclic AMP had no influence on PKCδ activity, although a role for cyclic AMP signalling through EPAC on the activation and autophosphorylation of PKCα was identified. Additionally, phosphorylation of the downstream kinase ERK was found to occur independently of PKC activation and required the presence of EPAC1 in COS1 cells. The work presented in this thesis therefore begins to delineate a novel pathway in which the cyclic AMP and PKC pathways work together to afford cell regulation, including the regulation of gene expression, through novel areas of crosstalk

Educational resources, control and expenditure:: a local authority study

This study is concerned with the continuing disparity in levels of resources in the British education system. This disparity is examined on a regional and local level by focussing on the North East of England and on one local authority in the region. The imbalance between regions, local authorities and localities within local authorities is related to an interconnecting network of processes that can be seen to influence and reinforce the distribution of educational resources. The study examines the mechanisms of resource and expenditure allocation in the education system and the control mechanisms inherent in these allocation procedures. Analysis of educational provision in one Tyneside local authority shows a clear relationship between levels of resources and the mechanisms, at both national and local level, that control and allocate the finance for educational provision in the local authority. Research for the study was carried out during 1975 - 1977, at a time of economic recession, high inflation and public expenditure cutbacks. The thesis highlights the financial problems that local authorities were experiencing at the time, as they tried to provide an increasingly costly education service with an education budget that was increasing at a much slower rate. As a consequence of these problems, unequal levels of education resources have become reinforced and accentuated by the financial constraints of the 1970s

Structure and dynamics in polystyrene/single-walled carbon nanotube nanocomposites via neutron scattering techniques

Small angle and quasielastic neutron scattering (SANS and QENS) were used to investigate the cause of the minimum in the diffusion coefficient for polystyrene (PS)/single walled carbon nanotube (SWCNT) nancomposites (M. Mu, N. Clarke, R. J. Composto and K. I. Winey, Macromolecules, 2009, 42, 7091–7097). Radius of gyration (Rg) values for PS/SWCNT nanocomposites were obtained by fitting SANS data with the Debye equation, and were found to increase by ~450% (110 kg mol–1) and ~500% (230 kg mol–1), indicating agglomeration or incomplete contrast-matching of the matrix and the nanotubes. Elastic scans recorded via QENS on ring and chain-labelled samples indicated that the PS rings were more mobile in both the polymer and the nanocomposite, and that adding SWCNTs increased the mobility of the chain at SWCNT concentrations above 1 wt%, especially around the glass transition temperature (Tg). Slower motions of the ring also increased, but only at 4 wt% loading. The stiffness values for the chain and ring were isolated for the first time, indicating reduced chain stiffness on addition of increasing levels of SWCNTs. QENS peaks were Fourier transformed and the decay curves fitted with the KWW function. Only the data recorded at 177 °C returned relaxation times that could be resolved, suggesting that the motions at lower temperatures are slower than could be detected. Tg values were extracted calorimetrically and from neutron data. The calorimetric Tg had a minimum at ~1 wt%. The neutron Tg was recorded from data on two spectrometers, IRIS (2-200 ps) and HFBS (100 ps–10 ns); the ring data recorded on IRIS increased relative to the bulk on loading, while the chain data recorded on HFBS decreased, indicating that the chain and rings are affected by SWCNTs on different timescales. The neutron static structure factor was affected at loading levels of 0.1–3 wt%, and the effect was more pronounced for the chain than the ring. This work clearly indicates that adding nanoparticles influences the local structure and fast local dynamics of PS/SWCNTs, and while it does not identify the origin of the minimum in the diffusion coefficient, it does narrow the time window where the origin must lie

General practice referral of ‘at risk’ populations to community leisure services: Applying the RE-AIM framework to evaluate the impact of a community-based physical activity programme for inactive adults with long-term conditions

Background: In the UK a high proportion of adults with long-term conditions do not engage in regular physical activity. General practice (GP) referral to community-based physical activity is one strategy that has gained traction in recent years. However, evidence for the real-world effectiveness and translation of such programmes is limited. This study aimed to evaluate the individual and organisational impacts of the ‘CLICK into Activity’ programme - GP referral of inactive adults living with (or at risk of) long-term conditions to community-based physical activity.Methods: A mixed methods evaluation using the RE-AIM framework was conducted with data obtained from a range of sources: follow-up questionnaires, qualitative interviews, and programme-related documentation, including programme cost data. Triangulation methods were used to analyse data, with findings synthesised across each dimension of the RE-AIM framework.Results: A total of 602 individuals were referred to CLICK into Activity physical activity sessions. Of those referred, 326 individuals participated in at least one session; the programme therefore reached 30.2% of the 1,080 recruitment target. A range of individual-, social-, and environmental-level factors contributed to initial physical activity participation. Positive changes over time in physical activity and other outcomes assessed were observed among participants. Programme adoption at GP surgeries was successful, but the GP referral process was not consistently implemented across sites. Physical activity sessions were successfully implemented, with programme deliverers and group-based delivery identified as having an influential effect on programme outcomes. Changes to physical activity session content were made in response to participant feedback. CLICK into Activity cost £175,000 over three years, with an average cost per person attending at least one programme session of £535.Conclusions: Despite not reaching its recruitment target, CLICK into Activity was successfully adopted. Positive outcomes were associated with participation, although low 6- and 12-month follow-up response rates limit understanding of longer-term programme effects. Contextual and individual factors, which may facilitate successful implementation with the target population, were identified. Findings highlight strategies to be explored in future development and implementation of GP referral to community-based physical activity programmes targeting inactive adults living with (or at risk of) long-term conditions

Facts4Life: Phase II evaluation of the school-based resource. Final evaluation report

In April 2015 members of UWE's Centre for Public Health and Wellbeing were commissioned to undertake an evaluation of a school-based intervention, known as ‘Facts4Life'. The broad aim of the evaluation was to better understand the impact of Facts4Life on Gloucestershire-based pupils and their teachers, and to determine the costs associated with Facts4Life implementation in a school setting. This final evaluation report presents the findings from the research

Wall and the bridge: a spatial history of segregation measures in Scottish prisons

This project explores the contemporary history of segregation in Scottish prisons, focusing on measures of ‘special handling’ particularly the network of small units that was operative between the 1950s and the 1990s. Scotland has a complicated, troubling, idiosyncratic and, to a lesser degree, inspiring tradition of special handling measures, involving generic punishment blocks, anachronistic isolation units, highly innovative specialist units, ‘safe’ and ‘silent’ cells, and more collective segregation spaces such as vulnerable prisoners wings. Such sites have provoked considerable attention across public and political arenas; they have been sources of shame, pride, criticism and confusion; in specific penal moments, they have been experienced by prisoners (and officers) as warzones, sanctuaries, coffins and creative spaces; and, in terms of efficacy, they have both exacerbated and ameliorated the behavioural difficulties of the prisoners contained within them. The objectives of this research are (1) to chronologically map the evolution of key segregation sites, attending to the external pressures that have informed the policies, procedures and rules governing their protean use, (2) to explore the impact of particular environmental factors on the initial design, operation and, subsequently, the closure of these sites, and (3) to reflect on the relationship between space and the ways individuals have understood, coped with, and in various ways ‘acted-out’ their segregated confinement. Deciding who, how and why to segregate prisoners raises questions of a conceptual, operational, political, and moral nature. But deciding where to segregate prisoners situates such questions within the physical constraints and potentialities of space. By adopting a spatial-temporal approach, this research straddles disciplines, utilising the methods of penal history, prison sociology, and – though in a more approximate manner – the steadily burgeoning sub-discipline of carceral geography. Additionally, by marshalling a number of personal testimonies, this history attempts to capture the emotional resonances of segregation – how it feels to actually live and work in ‘prisons within prisons’

Issues, opportunities and concepts in the teaching of programming to novice programmers at the University of Lincoln : three approaches.

This thesis describes three small-scale, computer-based approaches developed and used by the author in her teaching of programming concepts to novice programmers, using Pascal as a first language, within a higher education context. The first approach was the development of a piece of tutorial CAL, the second was the development of an on-line help system and the third the development of a pattern language. For the first two, the author created the product. For the pattern language, she designed the template. These three approaches are described and the results obtained outlined. The work also looks at the kind of research methodologies and tools available to the author and present a rationale for her choices of method and tools. This work also briefly reviews some learning theories that could be used to underpin the design, use and evaluation of CAL. The thesis looks at a range of topics associated with the teaching of programming and the use of CAL. It looks at issues around the psychology and human aspects of learning to program, such as confirmatory bias and vision. It looks at other research efforts aimed at developing software to support inexperienced programmers, including new programming languages specifically designed to teach programming concepts and sophisticated programming support environments. The work briefly reviews various types of CAL and their uses. It also examines some key projects in CAL development from the 1960s onwards, with particular emphasis on UK projects from the early 1970s to the late 1990s. It looks at what conclusions can be drawn from examining some of the many CAL projects in the past. Finally, the work reviews the various strands of the author's research efforts and presents a brief overview and some initial suggestions for the teaching of programming to novice programmers