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Background Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer’s disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions. Aims To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent. Methods We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia. We only included instruments which are preference-based, allowing index scores/utility values to be attached to each health state they describe based on preferences obtained from population surveys. Summary results were presented by respondent type (self or proxy), type of instrument, geographical location and, where possible, stage of disease. Health state utility values derived using the EuroQoL 5-Dimensions (EQ-5D) were meta-analysed by pooling reported results across all studies by disease severity (MCI, mild, mild to moderate, moderate, severe dementia, not specified) and by respondent (person with dementia, carer, general public, not specified), using a fixed-effects approach. Results We identified 61 studies which reported HR-QoL for people with MCI or dementia using preference-based instruments, of which 48 used the EQ-5D. Thirty-six studies reported HR-QoL for mild and/or moderate disease severities, and 12 studies reported utility values for MCI. We found systematic differences between self-rated and proxy-rated HR-QoL, with proxy-rated utility valued being significantly lower in more severe disease states. Conclusions A substantial literature now exists quantifying the impact of dementia on HR-QoL using preference-based measures, giving researchers and modellers a firmer basis on which to select appropriate utility values when estimating the effectiveness and cost-effectiveness of interventions in this area. Further research is required on HR-QoL of people with preclinical and prodromal AD and MCI, possible differences by type of dementia, the effects of comorbidities, study setting and the informal caregiver’s own HR-QoL, including any effect of that on their proxy-ratings.

Students following a preparatory vocational education track seem most in need of an intervention stimulating their competencies and preventing the development of problems in the intrapersonal and interpersonal domain. The aim of the present study was to examine, first, whether Rock & Water, a social emotional learning intervention that uses active forms of learning, is effective in improving students' competencies and preventing problems in the intra- and interpersonal domain, and second, whether intervention effects were influenced by the extent to which multiple systems are involved in the intervention. We conducted a randomized controlled trial with a sample of 7th grade students (N = 1299, Mage = 12.38, 54% boys). Students reported on outcomes of the intra- and interpersonal domains using digital questionnaires. The data were analyzed with Latent Growth Curve models. Results showed that the intervention was most effective when only a core team of teachers was involved in the intervention. The intervention improved several proximal outcomes (i.e., self-control and emotional self-regulation) and distal outcomes in students' intrapersonal and interpersonal domains. The intervention effects were strongest, albeit moderate, in the first year of the intervention. These results show that interventions with an active form of learning and implemented by a core team might be promising interventions for prevocational students, although effort should be put in increasing its effectiveness.

Background School-based mental health services have been advocated to increase access to psychological support for children and adolescents. However, concerns have been raised about the potential stigma associated with selection of students and the visibility of school-based service contact. Methods This review assessed findings from qualitative studies to identify potential stigmatising effects of participation in targeted school-based mental health interventions for students attending primary- or secondary-level education. Eight articles (reflecting seven studies) were identified through electronic database searches (PsycInfo, EMBASE, Medline, CINAHL, ERIC), supplemented by citation and reference searches and expert consultations. Data were synthesised according to established guidelines for thematic synthesis. Results Three overarching themes were identified: “anticipated and experienced stigma”, “consequences of stigma” and “mitigating strategies”. These findings illustrate how pervasively stigma can compromise efforts to increase access to mental health care through targeted school-based provision, but also outline strategies endorsed by students for alleviating the risk and/or impact of stigma. Limitations These findings need to be considered in view of the relative scarcity of surveyed evidence. Furthermore, as all evidence came from high-income and Western countries, the applicability to other contexts is unclear. Conclusions This synthesis reflects the first overview of qualitative evidence regarding stigmatising experiences and concerns associated with students’ engagement with targeted school-based mental health interventions. The findings can inform efforts to mitigate stigma-related barriers to students’ engagement in targeted mental health support, and serve to guide future research in this area.

IntroductionDementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life.Methods and analysisA systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity.Ethics and disseminationThis systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer’s disease spectrum for better care: multimodal data access platform (ROADMAP).Trial registration numberCRD42017071416.

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.

Introduction: Children's social, emotional, and behavioural difficulties are associated with reduced academic performance, stressed teacher-child relationships, and other negative academic and life outcomes. The Incredible Years Teacher Classroom Management (IY TCM) programme is one intervention developed to address problematic behaviours via training teachers to use positive and proactive management strategies. The overall aim of this DPhil is to use the Incredible Years Teacher Classroom Management programme as a case study for applying mixed methods at the systematic review level to ascertain what is known about both the programme's effectiveness and how people experience the course, and subsequently to use the systematic review's findings as a springboard (rather than as an end goal) for more exploratory research into 'for whom' the programme might work. Method: Study One is a mixed methods systematic review of IY TCM. It applied multilevel meta-analysis to RCT outcome data and grounded theory meta-synthesis to interview and focus group data on stakeholders' experiences of IY TCM. Quantitative and qualitative findings were cross-synthesised and mapped using an integrative grid. Study Two moves the field forward by filling a gap in the evidence base, as identified in Study One. Semi-structured telephone interviews were conducted with special educational needs coordinators (SENCos) across Devon, exploring the acceptability and appropriateness of expanding IY TCM to the subgroup of children with special educational needs (SEN) in mainstream schools. Data were analysed thematically and mapped onto IY TCM content. Results: In Study One, nine studies reported across 14 papers met inclusion criteria for either quantitative or qualitative strands of this systematic review. Multilevel meta-analysis of RCTs (n=4) indicated that the programme produced teacher- and child-level results in the desired directions. Clear trends across all measured outcomes favoured the intervention group over the treatment-as-usual comparison. Qualitative meta-synthesis (n=5) illuminated a cyclical learning process and broader conceptualisation of teacher and child outcomes than was evident in the quantitative evidence. Notably, RCT data on teacher outcomes were limited to self-reported or observed behaviours, while teachers described other benefits from IY TCM including increased knowledge and emotional well-being. Cross-synthesis of findings from the two review strands highlighted harmony across the RCT and qualitative evidence but also a number of areas in which constructs that were prioritised by one type of research were not integrated into the other. Study Two generated classroom management strategies from SENCos, which aligned closely with strategies taught in IY TCM, indicating that IY TCM would be both acceptable and applicable (if not sufficient) for use when working with children identified with SEN and behavioural difficulties in schools. Discussion: Based on the positive effects of implementing IY TCM despite very few studies to power analyses, the programme appears to offer tangible benefits to both teachers and children. It is possible that results are underestimated due to limited types of outcomes measured and absence of experiential data from additional stakeholders (e.g., parents). Depending on current provision of special educational needs services, schools operating inclusion models are likely to find these strategies beneficial for children identified with SEN, and this subgroup should be explicitly examined in future IY TCM studies.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

Adenomatous polyposis coli (APC) mutations are found in most colorectal tumours. These mutations are almost always protein-truncating, deleting both central domains that regulate Wnt signalling and C-terminal domains that interact with the cytoskeleton. The importance of Wnt dysregulation for colorectal tumourigenesis is well characterized. It is, however, unclear whether loss of C-terminal functions contributes to tumourigenesis, although this protein region has been implicated in cellular processes-including polarity, migration, mitosis, and chromosomal instability (CIN)-that have been postulated as critical for the development and progression of intestinal tumours. Since almost all APC mutations in human patients disrupt both central and C-terminal regions, we created a mouse model to test the role of the C-terminus of APC in intestinal tumourigenesis. This mouse (Apc ΔSAMP) carries an internal deletion within Apc that dysregulates Wnt by removing the beta-catenin-binding and SAMP repeats, but leaves the C-terminus intact. We compared Apc ΔSAMP mice with Apc 1322T animals. The latter allele represented the most commonly found human APC mutation and was identical to Apc ΔSAMP except for absence of the entire C-terminus. Apc ΔSAMP mice developed numerous intestinal adenomas indistinguishable in number, location, and dysplasia from those seen in Apc 1322T mice. No carcinomas were found in Apc ΔSAMP or Apc 1322T animals. While similar disruption of the Wnt signalling pathway was observed in tumours from both mice, no evidence of differential C-terminus functions (such as cell migration, CIN, or localization of APC and EB1) was seen. We conclude that the C-terminus of APC does not influence intestinal adenoma development or progression. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley and Sons, Ltd.

Patients with Peutz-Jeghers syndrome (PJS) are affected by hamartomatous intestinal polyposis and increased risk of cancers in multiple organs caused by germline mutations in the tumour suppressor gene LKB1. Murine models that recapitulate aspects of PJS have been created. Here we examine the therapeutic effect of rapamycin, a macrolide with anti-tumourigenic and anti-angiogenic properties, in reducing tumour incidence in a large cohort of Lkb1(+/-) mice. To study the influence of early intervention, the animals were dosed with rapamycin from the age of 8 weeks, well before the onset of polyposis. These mice continued to receive the drug, which was well tolerated, throughout their lives. At sacrifice, we observed a reduction in gastric tumour burden in the rapamycin-treated mice (p = 0.0001) compared with age- and sex-matched controls. Treated animals also have a lower number of polyps per mouse than controls. In the polyps from the treated mice, phosphorylation of ribosomal p70 S6 kinase was maintained, while the phosphorylation of AKT at serine-473 was elevated, suggesting that mTORC1 function is maintained at this dosage. Despite this, a significant reduction in microvessel density was seen in polyps from the rapamycin-treated mice compared to those from the control mice (p = 5 x 10(-5)), suggesting that the anti-angiogenic effect of rapamycin played a role in polyp reduction. Overall, we demonstrated that prolonged oral administration of rapamycin from an early age is effective in lowering tumour burden in the Lkb1(+/-) mice without evident side effects.

Background Internet sex-seeking has been associated at the person level with sexual risk. However, the most robust method of encounter-level inference to determine associations between internet sex-seeking and sexual risk is to compare encounters against each other. We systematically reviewed within-subjects comparisons of sexual encounters that tested associations between internet sex-seeking and sexual risk in men who have sex with men. Methods: We systematically searched databases on 9 July 2013, then screened records and full-text articles in duplicate and independently. Studies were synthesised narratively. Results: Four studies were included. Although studies were generally of high quality, the findings were inconsistent and did not show clear evidence of a relationship between internet sex-seeking and sexual risk. Conclusions: Further research in internet sex-seeking among men who have sex with men is required, particularly as internet-enabled sexual sociality continues to evolve. Internet-based health promotion may wish to target person-level features instead of encounter-specific characteristics.

Objective The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. Research design and methods FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. Results About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). Conclusion The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.