Distinguishing between knowledge gaps and misconceptions of Alzheimer’s disease among caregivers in the UK

A popular scale for assessing knowledge about Alzheimer‘s disease is the Alzheimer‘s Disease Knowledge Scale (ADKS). The aim of the study was to investigate the effect of adding ‗don‘t know‘ to the original ‗true‘ or ‗false‘ response option. It was assumed that this modification would provide insight into the reasons underlying incorrect responses and could distinguish between misconceptions and knowledge gaps. To investigate this, carers (care home carers and informal carers) and members of the general population were recruited. The results showed that percentage correct responses was lower than previously reported, suggesting potential inflation of knowledge by guesses without the ‗don‘t know‘ option. Moreover, care-home workers were more likely to select the incorrect response than ‗don‘t know‘ compared to informal carers for several items related to the earlier stages of AD, suggesting a higher level of misconceptions around this topic and highlighting potential training needs for care home carers

A study of the civilisational aspects of Russian soft power in contemporary Ukraine

This thesis contributes to an in-depth understanding of the concept of soft power, which according to Joseph Nye indicates the ability to achieve foreign policy goals through cultural attraction. For the purposes of this study of Russian cultural influence in Ukraine, soft power is rearticulated to highlight the ability to engage in mean-making and cultural-ideational leadership on the international stage. A critique of Nye justifies a reframing of soft power, which is supplied by drawing on the analytical power of post-Marxist hegemony and discourse theory. The methodology through which this concept is operationalised empirically emphasises outcomes over inputs, thus appraisals of soft power must account for whether the discourses promoted by mean-making initiatives resonate favourably with target audiences. Desk-based and field research supports an argument that Moscow acknowledges the need for soft power, understood here in terms of ‘sovereignty of spirit’. This civilisational approach is explored further, and the target narratives advanced by significant proponents of the discourse, namely the Russkiy Mir Foundation, the Russian Orthodox Church and foreign policy officials, are identified. Insights into the activities of the Ukrainian Orthodox Church of the Moscow Patriarchate to promote spiritually-infused discourses are provided, and new developments observed. Finally, the extent of Russian ‘civilisational’ soft power is estimated through surveys and focus groups gauging audience reception to the ideational narratives promoted

Investigating the Intrinsic Role of Programmed Death-Ligand 1 in Human Cancers.

Programmed death-ligand 1 (PD-L1) expression is a survival mechanism employed by tumours to mediate immune evasion and tumour progression. PD-1/PD-L1-targeted therapies have revolutionised the cancer therapy landscape due to their ability to promote durable anti-tumour immune responses in select patients with advanced cancers. However, some patients are unresponsive, hyperprogressive or develop resistance. The exact mechanisms for this are still unclear. Recently, a pro-tumorigenic role of PD-L1 to send pro-survival signals in cancer cells is becoming apparent in some cancers. Better characterisation of the three-dimensional (3D) architecture of solid tumours by utilising 3D cell culture could provide an environment that more closely recapitulates in vivo human tumours for investigating tumour-intrinsic PD-L1 signalling and immunotherapy responses. The role of PD-L1 and how approved immunotherapies may influence its role needs to be fully explored in all cancer types using in vitro cell culture systems that better model tumour heterogeneity compared to standard monolayer cell culture. Within this thesis, human breast prostate and colorectal cancer cell lines were firstly characterised for their expression of immune-inhibitory proteins (PD-L1, PD-1 and PD-L2), immunological proteins (DR4, DR5 and Fas) and tumorigenic proteins (CD44 and HIF1α) at basal level in two-dimensional (2D) monolayer cell culture, before being investigated in two different 3D cell culture models (hanging drop and alginate hydrogel beads) of varying in vitro complexity. In doing this, we were able to demonstrate that cancer cells alter their gene and protein expression levels and develop hypoxia in a 3D environment that more closely mimics human in vivo solid tumours. Cancer cells in 3D reduced their expression of death receptors and antigen presenting machinery which would reduce their susceptibility to immune-mediated cell death and could ultimately hinder their response to immunotherapy. Thereafter, we investigated the biological effects of therapeutically approved anti-PD-L1 monoclonal antibody Atezolizumab, before comparing PD-L1 blockade with PD-L1 knockdown in high PD-L1 expressing breast cancer cells cultured in 2D monolayer and 3D cell culture models. PD-L1 blockade using Atezolizumab demonstrated modest effects on breast cancer cell growth, proliferation, viability, and metabolism in our functional assays, but did reduce the phosphorylation of molecules involved in the PI3K/AKT and MAPK/ERK signalling pathways. PD-L1 knockdown, on the other hand, revealed the importance of PD-L1 expression for the spheroid-forming capabilities of breast cancer cells in our 3D cell culture models. PD-L1 knockdown also potentiated the modest biological effects on breast cancer cell growth, proliferation, viability, and metabolism observed by Atezolizumab treatment. Additionally, cytokine modulation of PD-L1 expression was investigated in combination with PD-L1 blockade and PD-L1 knockdown in our studies. Utilising the 3D alginate model for the culture of breast cancer cells revealed a potential benefit of combining cytokines with PD-L1 targeting for the treatment of breast cancer which warrants further investigation. Altogether this thesis provides new insights into: (1) the expression of immunological and tumorigenic proteins by diverse human cancer cells; (2) how PD-L1 blockade with Atezolizumab may influence PD-L1 intrinsic signalling in breast cancer cells; and (3) how PD-L1 may exhibit a pro-tumour role in breast cancer cells, not only in 2D monolayer but for the first time in two different 3D cell culture models

Management of massive splenomegaly.

A case demonstrating diagnostic and therapeutic rational for surgical management of massive splenomegaly

Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial) : pragmatic, multicentre randomised controlled trial

Acknowledgments This project will be published in full in the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme series. Data monitoring committee: Catherine Hewitt (University of York), Jonathan Lund (University of Nottingham), Tim McAdam (Belfast Health and Social Care Trust), and Amir Nisar (Maidstone and Tunbridge Wells NHS Trust). Trial steering group: David Beard (University of Oxford), Ian Beckingham (Nottingham University Hospitals NHS Trust), John Leeds (Newcastle Hospitals NHS Foundation Trust), and Dee McDonald (patient representative). Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (project No 14/192/71). The Health Services Research Unit of the University of Aberdeen is funded in part by the chief scientist’s office of the Scottish government’s health and social care directorates. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the chief scientist’s office, HTA programme, NIHR, NHS, or Department of Health. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.Peer reviewedPublisher PD

Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease

Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen–specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen–specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma