Body Image in Primary Schools: A pilot evaluation of a primary school intervention program designed by teachers to improve children's body satisfaction

© 2016 Body Image in the Primary School (Hutchinson & Calland, 2011) is a body image curriculum that is widely available but has not yet been evaluated. This study evaluates a set of 6 of the 49 available lessons from this curriculum. Seventy-four girls and 70 boys aged 9–10 were recruited from four primary schools in the UK. Schools were randomly allocated into the intervention condition, where students received 6hours of body image lessons, or to lessons as normal. Body esteem was significantly higher among girls in the intervention group, compared to the control group, immediately post intervention, and at 3-month follow-up. Moreover, girls with lowest levels of body esteem at baseline reported the largest gains. Internalization was significantly lower among boys in the control group compared to the intervention group at 3-month follow-up. The pattern of results among the control group raises interesting issues for intervention evaluation

Optimising psoriatic arthritis therapy with immunological methods to increase standard evaluation: the protocol of an open-label multicentre, parallel-group, two-arm randomised controlled study evaluation precision medicine approach in the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response. This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care. Methods and analysis: Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques. Ethics and dissemination: Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines. Trial registration number ISRCTN17228602

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

Funder: Kennedy Trust studentshipFunder: Oxford-UCB Prize FellowshipFunder: National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University and Versus Arthritis Research into Inflammatory Arthritis Centre; ref. 22072).Funder: NIHR Birmingham BRC at the University Hospitals Birmingham NHS Foundation Trust and the University of BirminghamFunder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: National Institute for Health Research (NIHR) Oxford Biomedical Research CentreFunder: St Baldrick’s FoundationAbstract: Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis

“Horror, guilt and shame” – Uncomfortable Experiences in Digital Games

Gameplay frequently involves a combination of positive and negative emotions, where there is increasing interest in how to design for more complex forms of player experience. However, despite the risk that some of these experiences may be uncomfortable, there has been little empirical investigation into how discomfort manifests during play and its impact on engagement. We conducted a qualitative investigation using an online survey (N=95), that focused on uncomfortable interactions across three games: Darkest Dungeon, Fallout 4 and Papers, Please. The findings suggest games create discomfort in a variety of ways; through providing high-pressure environments with uncertain outcomes and difficult decisions to make, to the experience of loss and exposing players to disturbing themes. However, while excessive discomfort can jeopardize player engagement, the findings also indicate that discomfort can provide another facet to gameplay, leading to richer forms of experience and stimulating wider reflections on societal issues and concerns

Natural and therapy-induced immune control of HIV-1

The human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response is important in the control of HIV-1 infection. Due to the virus having a high rate of mutation, immune pressure can select for variants that are no longer recognised by CTLs to dominate the viral quasispecies. This is similar to how antiretroviral resistance emerges. HIV-1 is therefore adapting to both human leukocyte antigen (HLA)-restricted immune responses and antiretroviral therapy. This thesis initially focused on the natural CTL response to an HLA-B*51-restricted epitope in integrase. This HLA class I allele is associated with slow progression to AIDS; however, as no CTL-driven escape mutation has been fully defined within this integrase epitope, we cannot determine what contributes to the association of HLA-B*51 and natural control of infection. By longitudinally studying a cohort of early HIV-infected individuals, we observed the emergence of polymorphisms that abrogate a CTL response to this epitope. CTL escape may also prove to be the downfall of current immunotherapy strategies attempting to combat HIV infection. T cell receptors (TCRs) have been genetically modified to enhance their binding affinity to an HLA-A*02-peptide complex and transduced into CD8+ cells to create an HIV adoptive therapy. We demonstrate through in vitro selection pressure assays that escape from these cells may be a difficult task for the virus given that the TCR is able to recognise the majority of variants of this epitope. Antigen processing mutations may represent the only option for escape. How this may translate clinically will only be determined through in vivo studies, which must be meticulously monitored. Finally, when this high affinity TCR was fused to an anti-CD3 single chain variable fragment to create proteins capable of redirecting non-HIV-specific CTLs to HIV-infected cells, we found that the result was specific lysis. These proteins may supersede the use of TCR-transduced cells when used in synergy with antiretroviral therapy

Natural and therapy-induced immune control of HIV-1

The human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response is important in the control of HIV-1 infection. Due to the virus having a high rate of mutation, immune pressure can select for variants that are no longer recognised by CTLs to dominate the viral quasispecies. This is similar to how antiretroviral resistance emerges. HIV-1 is therefore adapting to both human leukocyte antigen (HLA)-restricted immune responses and antiretroviral therapy. This thesis initially focused on the natural CTL response to an HLA-B*51-restricted epitope in integrase. This HLA class I allele is associated with slow progression to AIDS; however, as no CTL-driven escape mutation has been fully defined within this integrase epitope, we cannot determine what contributes to the association of HLA-B*51 and natural control of infection. By longitudinally studying a cohort of early HIV-infected individuals, we observed the emergence of polymorphisms that abrogate a CTL response to this epitope. CTL escape may also prove to be the downfall of current immunotherapy strategies attempting to combat HIV infection. T cell receptors (TCRs) have been genetically modified to enhance their binding affinity to an HLA-A*02-peptide complex and transduced into CD8+ cells to create an HIV adoptive therapy. We demonstrate through in vitro selection pressure assays that escape from these cells may be a difficult task for the virus given that the TCR is able to recognise the majority of variants of this epitope. Antigen processing mutations may represent the only option for escape. How this may translate clinically will only be determined through in vivo studies, which must be meticulously monitored. Finally, when this high affinity TCR was fused to an anti-CD3 single chain variable fragment to create proteins capable of redirecting non-HIV-specific CTLs to HIV-infected cells, we found that the result was specific lysis. These proteins may supersede the use of TCR-transduced cells when used in synergy with antiretroviral therapy.This thesis is not currently available via ORA

Expression of PI3K signaling associated with T cells in psoriasis is inhibited by seletalisib, a PI3Kδ inhibitor, and is required for functional activity

The phosphoinositide 3-kinase (PI3K) pathway plays a key role in many cellular processes, including cell proliferation, survival, and protein synthesis, with the PI3K isoform, PI3Kδ, involved in normal T-cell development and function (Jarmin et al., 2008, Lucas et al., 2016, Vanhaesebroeck et al., 2012). Evidence to suggest that PI3K signaling might play a role in psoriasis comes from reports of increased expression of phosphorylated protein kinase B, mammalian target of rapamycin, and ribosomal protein S6 (pS6), which are downstream in the PI3K signaling pathway, in lesional psoriatic skin compared with nonlesional skin and healthy controls (Buerger et al., 2013, Madonna et al., 2012, Rosenberger et al., 2007). In addition, PI3Kδ knock-in mice, expressing a catalytically inactive form of PI3Kδ (p110δD910A/D910A), and PI3Kγ knockout mice are greatly protected from imiquimod-induced psoriasis-like skin inflammation compared with wild-type mice (Roller et al., 2012)

(2010 -2011) Assembly Resolution 23: In Support of the Existing Handgun Ban on Texas College Campuses

Governmen

(2010 -2011) Assembly Resolution 24: In Support of Closing Loopholes in the Brady Background Check System

Governmen