'It all hinges around background doesn't it?' The experiences of pupils in grammar schools who are considered to be from disadvantaged backgrounds- a mixed methods study.

The present government suggests that grammar schools are a means of achieving upward social mobility (USM) for young people identified as both disadvantaged and high academic achievers (Gorard & Siddiqui, 2018). It appears keen on extending the current grammar school provision based upon this rationale, as evidenced by the creation of the Selective Schools Expansion Fund (DfE, 2018). Existing literature that examines adults who have experienced USM concludes that whilst conferring some benefits it can also result in psychological stress (Friedman, 2014, 2016, Manstead, 2018, Reay, Crozier & Clayton, 2009, 2010). Research thus far around grammar schools has focussed primarily upon whether those identified as disadvantaged have as much chance of attending as ‘non- disadvantaged’ peers, or upon the academic outcomes of attendance. Less has been explored concerning the first-person experiences of disadvantaged students who access grammar schools, and potentially experience USM. Using eligibility for free school meals (eFSM) as a proxy indicator for disadvantage, this research examined the experiences of 6 participants who were either past or present grammar school students who were eFSM. There were two phases of data collection, the first being the completion of a repertory grid (Kelly, 1956), and the second being an individualised semi- structured interview, informed by a Slater (1977) analysis of each participant’s grid. A thematic analysis was then conducted across the interview data of all participants. Five themes and their relationship to each other suggest that grammar schools may offer some benefits upon disadvantaged pupils who attend, such as increasing aspirations via exposure to other, more affluent peers. However, this may come at the price of accepting a stigmatising narrative concerning one’s own more modest background and result in behaviours that seek to conceal and hide this background, as students explore their identity at the boundary of two social fields. The findings raise ethical considerations regarding the potential cost of social mobility for some. Factors which may contribute to pupil resiliency as they navigate life between their home and school environments are also explored, and implications for EP practice at both the school level and at a policy level are considered

TMPRSS2 promoter driven enzyme-prodrug therapy for the treatment of PCa

Prostate cancer (PCa) progression is dependent on transcriptional activation of the androgen receptor (AR) in the majority of cases. Therefore, therapies include anti-androgens, which decrease levels of circulating androgens and inhibit AR activity. However, resistance inevitably develops, resulting in more aggressive, incurable late-stage disease with intact or constitutively active AR signalling. There is currently no cure for castration-resistant metastatic PCa and novel therapies are needed. In this work I aimed to develop a non-replicating adenovirus for delivery of a potent prodrug-converting enzyme expressed at high levels to specifically target and kill PCa cells. TMPRSS2 is a major AR-regulated gene, commonly expressed at higher levels in cancer than normal prostate. In 40-70% of PCa cases the AR-regulated TMPRSS2 promoter is fused to oncogenic ERG. Based on this, we generated TMPRSS2 promoter and enhancer constructs, utilising promoter regions upstream of Exon1 and Exon2 of TMPRSS2 to drive the prodrug-converting chimeric enzyme cytosine deaminase uracil phosphoribosyl transferase (CD/UPRT) to investigate the therapeutic efficacy in various PCa models. Prior work in the lab evaluated the selectivity and transcriptional efficiency of the various promoter and enhancer regions upstream of Exon1 and Exon2 in TMPRSS2 were investigated by Luciferase (Luc) expression. To further improve on promoter activity and transcription, the TMPRSS2 constructs were inserted into an expression cassette derived from the versatile expression vector VISA (VP16-GAL4-WPRE integrated systemic amplifier). When the Luc-gene was replaced with CD/UPRT in the VISA vector, specific and dose-dependent cell killing was observed in 22RV1 (AR+) cells when the non-toxic prodrug 5-flourocytosine (5-FC) was administered. To increase transfection efficiency, I inserted the TMPRSS2-VISA-CD/UPRT expression cassette into a non-replicating adenovirus (Ad5-TV-CU) replacing the E1-genes. Ad5-TV-CU was characterized and protein expression of the CD/UPRT gene was detected at high levels post infection in AR-expressing 22RV1, LNCaP sublines, and VCaP cells, whilst remaining inactive in DU145 and HEK293 cells (AR-negative). Dose-dependent decreases in EC50-values were observed upon infection with Ad5-TV-CU in combination with low doses of 5-FC in a number of cell lines, including 22RV1, LNCaP-104-S, LNCaP-CDXR3 and LNCaP-104R1 cells, whilst demonstrating no cell killing at any concentration in PC3, PNT1a, PNT2 and PrEC cells (AR-). To determine efficacy of the viral vector in vivo, I explored various AR-expressing PCa cell lines grown as xenografts in immunodeficient murine models, including 22RV1 and the LNCaP sublines LNCaP-104-S and LNCaP-CDXR3. However, establishment of the in vivo models was unsuccessful due to variable tumour take and growth (LNCaP) or tumours grew fast and studies had to be terminated prior to efficacy determination (22RV1). Further comparison of the Exon1 TMPRSS2 promoter with the traditional PSA promoter and the chimeric PSA promoter/enhancer demonstrated the Exon1 TMPRSS2 construct to be superior by inducing 3.5-fold and 2.3-fold higher levels of luciferase expression than the PSA constructs, respectively. Investigation of both Exon1 and Exon2 TMPRSS2 promoters revealed that fusion of the two regions to form the chimeric Exon1/Exon2 promoter, drove higher levels of prostate specific expression, that have the potential to drive higher level expression than the SV40 promoter, this higher expression could improve efficacy of the current non-replicating Ad5-TV-CU. In summary, Ad5-TV-CU has demonstrated efficacy in a number of AR expressing cell lines, with limited results in vivo. Further studies that incorporate the optimal LW chimeric promoter into a replicating adenoviral vector could dramatically improve the efficacy of this virus for future studies. Additionally the discovery of a more suitable in vivo model will help to establish the true therapeutic potential of the new optimal Ad5-TV-CU virus

Time-dependent forgetting in visual short-term memory

This is an accepted manuscript of an article published by Routledge, Taylor & Francis in Journal of Cognitive Psychology on 18/05/2020. The published version can be accessed online here: https://doi.org/10.1080/20445911.2020.1767627 The accepted version of the publication may differ from the final published version.Whether visual short-term memory can be lost over an unfilled delay, in line with timedependent forgetting, is controversial. Prior work has yielded mixed results and it is possible that other processes make a bigger contribution to memory loss than the length of the retention interval. The present study explored time-dependent forgetting in visual short-term memory in relation to other factors. In three experiments, participants compared single target and probe objects over a 2 s or 10 s retention interval. The objects across trials were either similar or dissimilar (Experiment 1) and had to be remembered in the presence of an additional distractor (Experiment 2) or under conditions where the amount of time separating trials varied (Experiment 3). In all experiments, the retention interval manipulation made the biggest contribution to performance, with accuracy decreasing as the retention interval was lengthened from 2 s to 10 s. These results pose problems for interference and temporal distinctiveness models of memory but are compatible with temporal forgetting mechanisms such as decay

Comorbidity and polypharmacy in people with dementia:insights from a large, population-based cross-sectional analysis of primary care data

Background: The care of older people with dementia is often complicated by physical comorbidity and polypharmacy, but the extent and patterns of these have not been well described. This paper reports analysis of these factors within a large, cross-sectional Methods: Data were extracted for 291,169 people aged 65 years or older registered with 314 general practices in the UK, of whom 10,258 had an electronically recorded dementia diagnosis. Differences in the number and type of 32 physical conditions and the number of repeat prescriptions in those with and without dementia were examined. Age–gender standardised rates were used to calculate odds ratios (ORs) of physical comorbidity and polypharmacy. Results: People with dementia, after controlling for age and sex, had on average more physical conditions than controls (mean number of conditions 2.9 versus 2.4; P < 0.001) and were on more repeat medication (mean number of repeats 5.4 versus 4.2; P < 0.001). Those with dementia were more likely to have 5 or more physical conditions (age–sex standardised OR [sOR] 1.42, 95% confidence interval (CI) 1.35–1.50; P < 0.001) and were also more likely to be on 5 or more (sOR 1.46; 95% CI 1.40–1.52; P < 0.001) or 10 or more repeat prescriptions (sOR 2.01; 95% CI 1.90–2.12; P < 0.001). Conculsions: People with dementia have a higher burden of comorbid physical disease and polypharmacy than those without dementia, even after accounting for age and sex differences. Such complex needs require an integrated response from general health professionals and multidisciplinary dementia specialists

Preliminary Characterisation of NP339, a Novel Polyarginine Peptide with Broad Antifungal Activity

FUNDING SOURCE The study was funded by NovaBiotics with support from The UK Governments’ Department of Health and Social Care, delivered by Innovate UK. Shane Smith and Carol Munro’s contribution to the project was funded by a Scottish Universities Life Sciences Alliance Bioskape grant award.Peer reviewedPublisher PD

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Community compensation in the context of Carbon Capture and Storage: Current debates and practices

Societal opposition has the potential to slow down the implementation of Carbon Capture and Storage (CCS). One of the difficulties is that the perceived benefits associated with a CCS facility for local communities tend to be low compared to its perceived burdens. As is the case for other low carbon technologies, community compensation (or community benefits) has been suggested as a way to restore this perceived imbalance. A diverse literature has looked into the role of community compensation across various land uses and research fields. Synthesis is limited, while at the same time, the provision of community compensation in practice is moving from an ad hoc to a more institutionalized approach. Therefore, it is important to take stock of the literature. This paper provides a review of the community compensation literature in the form of four debates, drawing together environmental social science research on different low carbon technologies (e.g. CCS, renewable energy). In addition, current practices in community compensation for four European countries are discussed. The two parts of this paper are brought together in a set of lessons for the provision of community compensation for future CCS projects; in turn, suggestions for further research are made to address remaining knowledge gaps

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives

Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: Implications for Alzheimer's disease

© 2016 The Author(s). Background: Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including β-amyloid (Aβ). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME). Results: Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ (APP fragments produced by β-secretase cleavage) were significantly reduced but Aβ40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce β-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression. Conclusions: The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of β-CTF which is increasingly considered to be an important mediator in AD independent of Aβ. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD

A patient-centred intervention to improve the management of multimorbidity in general practice:the 3D RCT

Background: People with multimorbidity experience impaired quality of life, poor health and a burden from treatment. Their care is often disease-focused rather than patient-centred and tailored to their individual needs. Objective: To implement and evaluate a patient-centred intervention to improve the management of patients with multimorbidity in general practice. Design: Pragmatic, cluster randomised controlled trial with parallel process and economic evaluations. Practices were centrally randomised by a statistician blind to practice identifiers, using a computer-generated algorithm. Setting: Thirty-three general practices in three areas of England and Scotland. Participants: Practices had at least 4500 patients and two general practitioners (GPs) and used the EMIS (Egton Medical Information Systems) computer system. Patients were aged ≥ 18 years with three or more long-term conditions. Interventions: The 3D (Dimensions of health, Depression and Drugs) intervention was designed to offer patients continuity of care with a named GP, replacing separate reviews of each long-term condition with comprehensive reviews every 6 months. These focused on individualising care to address patients’ main problems, attention to quality of life, depression and polypharmacy and on disease control and agreeing treatment plans. Control practices provided usual care. Outcome measures: Primary outcome – health-related quality of life (assessed using the EuroQol-5 Dimensions, five-level version) after 15 months. Secondary outcomes – measures of illness burden, treatment burden and patient-centred care. We assessed cost-effectiveness from a NHS and a social care perspective. Results: Thirty-three practices (1546 patients) were randomised from May to December 2015 [16 practices (797 patients) to the 3D intervention, 17 practices (749 patients) to usual care]. All participants were included in the primary outcome analysis by imputing missing data. There was no evidence of difference between trial arms in health-related quality of life {adjusted difference in means 0.00 [95% confidence interval (CI) –0.02 to 0.02]; p = 0.93}, illness burden or treatment burden. However, patients reported significant benefits from the 3D intervention in all measures of patient-centred care. Qualitative data suggested that both patients and staff welcomed having more time, continuity of care and the patient-centred approach. The economic analysis found no meaningful differences between the intervention and usual care in either quality-adjusted life-years [(QALYs) adjusted mean QALY difference 0.007, 95% CI –0.009 to 0.023] or costs (adjusted mean difference £126, 95% CI –£739 to £991), with wide uncertainty around point estimates. The cost-effectiveness acceptability curve suggested that the intervention was unlikely to be either more or less cost-effective than usual care. Seventy-eight patients died (46 in the intervention arm and 32 in the usual-care arm), with no evidence of difference between trial arms; no deaths appeared to be associated with the intervention. Limitations: In this pragmatic trial, the implementation of the intervention was incomplete: 49% of patients received two 3D reviews over 15 months, whereas 75% received at least one review. Conclusions: The 3D approach reflected international consensus about how to improve care for multimorbidity. Although it achieved the aim of providing more patient-centred care, this was not associated with benefits in quality of life, illness burden or treatment burden. The intervention was no more or less cost-effective than usual care. Modifications to the 3D approach might improve its effectiveness. Evaluation is needed based on whole-system change over a longer period of time. Trial registration: Current Controlled Trials ISRCTN06180958. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 5. See the NIHR Journals Library website for further project information