Structural and magnetic study of Yb3+ in the perovskites Sr2YbMO6 (M = Nb, Ta, Sb)

The compounds Sr2YbNbO6, Sr2YbTaO6 and Sr2YbSbO6 have been prepared using solid state methods by heating pelleted reagents in air at temperatures up to 1400°C. Rietveld refinement against room temperature neutron powder diffraction data show that all three compounds crystallise with a cationordered variant of the perovskite structure in the P21/n space group. Complete cation ordering occurs between M5+ and Yb3+ over two octahedrally-coordinated sites in the structure and all compounds are stoichiometric in oxygen. The Sb-O bond lengths are similar to related perovskite compounds but differ slightly from those indicated by bond valence sums. Magnetic susceptibility data resemble Curie-Weiss paramagnetic behaviour, but can be better understood as arising from the effect of the octahedral crystal field on the 2F5/2 ground state of Yb3+ leading to a temperature dependent magnetic moment on this ion below 100 K

Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer

The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells. In contrast, when the AKT inhibitor AZD7328 was applied to patient-derived prostate cultures that retained expression of PTEN, activation of a compensatory Ras/MEK/ERK pathway was observed. Moreover, whilst autophagy was induced following treatment with AZD7328, cell viability was less affected in the patient-derived cultures than in cell lines. Surprisingly, treatment with a combination of both AZD7328 and two separate MEK1/2 inhibitors further enhanced phosphorylation of ERK1/2 in primary prostate cultures. However, it also induced irreversible growth arrest and senescence.Ex vivo treatment of a patient-derived xenograft (PDX) of prostate cancer with a combination of AZD7328 and the mTOR inhibitor KU-0063794, significantly reduced tumour frequency upon re-engraftment of tumour cells.The results demonstrate that single agent targeting of the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway in near-patient samples. Therefore, blockade of one pathway is insufficient to treat prostate cancer in man

The 'Antiretrovirals, Sexual Transmission Risk and Attitudes' (ASTRA) study. Design, methods and participant characteristics.

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV

Are profiles of social, cultural, and economic capital related to living well with dementia? Longitudinal findings from the IDEAL programme

Rationale: Research exploring social, cultural, and economic capital among people with dementia is scarce. Objective: We describe levels of social, cultural, and economic capital in people with dementia at baseline and levels of social and cultural capital 12 and 24 months later. We identify groups of people with dementia having different combinations of capital and explore whether the identified groups differ in personal characteristics at baseline and in quality of life (QoL), satisfaction with life (SwL), and well-being over time. Method: Baseline, 12-months, and 24-months data from 1537 people with dementia (age, mean = 76.4 years; SD = 8.5; Alzheimer's Disease = 55.4%) enrolled in the IDEAL cohort were analyzed. Social (interactions with friends, civic participation, social participation, neighborhood trust, social network), cultural (education, cultural participation) and economic (annual income) capital, QoL, SwL, well-being, and personal characteristics were assessed. Results: Compared to people their age, people with dementia reported slightly lower frequency of interactions with friends, social networks and social support, civic and cultural participation, education, and annual income. However, social engagement, cultural participation, and annual income are low among British older adults. Latent profile analysis identified four groups that, based on their levels of social, cultural, and economic capital were named socially and economically privileged (18.0% of participants); financially secure (21.0% of participants); low capital (36.9% of participants); and very low capital (24.1% of participants). Latent growth curve models showed that over time QoL, SwL, and well-being remained largely stable for all groups. Compared to the low capital group, the socially and economically privileged and financially secure groups had higher QoL and well-being whereas the group with very low capital had poorer QoL, SwL, and well-being. Conclusions: New policies and efforts from the government, philanthropic foundations, the voluntary and primary care sectors are needed to address social, cultural, and economic disadvantage among people with dementia

Dyadic perspectives on loneliness and social isolation among people with dementia and spousal carers: findings from the IDEAL programme

YesThis study aims to investigate the impact of self and partner experiences of loneliness and social isolation on life satisfaction in people with dementia and their spousal carers. We used data from 1042 dementia caregiving dyads in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) programme cohort. Loneliness was measured using the six-item De Jong Gierveld loneliness scale and social isolation using the six-item Lubben Social Network Scale. Data were analysed using the Actor-Partner Interdependence Model framework. Self-rated loneliness was associated with poorer life satisfaction for both people with dementia and carers. The initial partner effects observed between the loneliness of the carer and the life satisfaction of the person with dementia and between social isolation reported by the person with dementia and life satisfaction of the carer were reduced to nonsignificance once the quality of the relationship between them was considered. Experiencing greater loneliness and social isolation is linked with reduced life satisfaction for people with dementia and carers. However, having a positive view of the quality of the relationship between them reduced the impact of loneliness and social isolation on life satisfaction. Findings suggest the need to consider the experiences of both the person with dementia and the carer when investigating the impact of loneliness and social isolation. Individual interventions to mitigate loneliness or isolation may enhance life satisfaction for both partners and not simply the intervention recipient.‘Improving the experience of Dementia and Enhancing Active Life: living well with dementia. The IDEAL study’ was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health and Care Research (NIHR) through grant ES/L001853/2. ‘Improving the experience of Dementia and Enhancing Active Life: a longitudinal perspective on living well with dementia. The IDEAL-2 study’ is funded by Alzheimer’s Society, grant number 348, AS-PR2-16- 001

Regulation of the stem cell marker CD133 is independent of promoter hypermethylation in human epithelial differentiation and cancer

BackgroundEpigenetic control is essential for maintenance of tissue hierarchy and correct differentiation. In cancer, this hierarchical structure is altered and epigenetic control deregulated, but the relationship between these two phenomena is still unclear. CD133 is a marker for adult stem cells in various tissues and tumour types. Stem cell specificity is maintained by tight regulation of CD133 expression at both transcriptional and post-translational levels. In this study we investigated the role of epigenetic regulation of CD133 in epithelial differentiation and cancer.MethodsDNA methylation analysis of the CD133 promoter was done by pyrosequencing and methylation specific PCR; qRT-PCR was used to measure CD133 expression and chromatin structure was determined by ChIP. Cells were treated with DNA demethylating agents and HDAC inhibitors. All the experiments were carried out in both cell lines and primary samples.ResultsWe found that CD133 expression is repressed by DNA methylation in the majority of prostate epithelial cell lines examined, where the promoter is heavily CpG hypermethylated, whereas in primary prostate cancer and benign prostatic hyperplasia, low levels of DNA methylation, accompanied by low levels of mRNA, were found. Moreover, differential methylation of CD133 was absent from both benign or malignant CD133+/α2β1integrinhi prostate (stem) cells, when compared to CD133-/α2β1integrinhi (transit amplifying) cells or CD133-/α2β1integrinlow (basal committed) cells, selected from primary epithelial cultures. Condensed chromatin was associated with CD133 downregulation in all of the cell lines, and treatment with HDAC inhibitors resulted in CD133 re-expression in both cell lines and primary samples.ConclusionsCD133 is tightly regulated by DNA methylation only in cell lines, where promoter methylation and gene expression inversely correlate. This highlights the crucial choice of cell model systems when studying epigenetic control in cancer biology and stem cell biology. Significantly, in both benign and malignant prostate primary tissues, regulation of CD133 is independent of DNA methylation, but is under the dynamic control of chromatin condensation. This indicates that CD133 expression is not altered in prostate cancer and it is consistent with an important role for CD133 in the maintenance of the hierarchical cell differentiation patterns in cancer

Interpreting ambiguous ‘trace’ results in Schistosoma mansoni CCA Tests: Estimating sensitivity and specificity of ambiguous results with no gold standard

Background The development of new diagnostics is an important tool in the fight against disease. Latent Class Analysis (LCA) is used to estimate the sensitivity and specificity of tests in the absence of a gold standard. The main field diagnostic for Schistosoma mansoni infection, Kato-Katz (KK), is not very sensitive at low infection intensities. A point-of-care circulating cathodic antigen (CCA) test has been shown to be more sensitive than KK. However, CCA can return an ambiguous ‘trace’ result between ‘positive’ and ‘negative’, and much debate has focused on interpretation of traces results. Methodology/Principle findings We show how LCA can be extended to include ambiguous trace results and analyse S. mansoni studies from both Côte d’Ivoire (CdI) and Uganda. We compare the diagnostic performance of KK and CCA and the observed results by each test to the estimated infection prevalence in the population. Prevalence by KK was higher in CdI (13.4%) than in Uganda (6.1%), but prevalence by CCA was similar between countries, both when trace was assumed to be negative (CCAtn: 11.7% in CdI and 9.7% in Uganda) and positive (CCAtp: 20.1% in CdI and 22.5% in Uganda). The estimated sensitivity of CCA was more consistent between countries than the estimated sensitivity of KK, and estimated infection prevalence did not significantly differ between CdI (20.5%) and Uganda (19.1%). The prevalence by CCA with trace as positive did not differ significantly from estimates of infection prevalence in either country, whereas both KK and CCA with trace as negative significantly underestimated infection prevalence in both countries. Conclusions Incorporation of ambiguous results into an LCA enables the effect of different treatment thresholds to be directly assessed and is applicable in many fields. Our results showed that CCA with trace as positive most accurately estimated infection prevalence

We are all one together : peer educators\u27 views about falls prevention education for community-dwelling older adults - a qualitative study

Background: Falls are common in older people. Despite strong evidence for effective falls prevention strategies, there appears to be limited translation of these strategies from research to clinical practice. Use of peers in delivering falls prevention education messages has been proposed to improve uptake of falls prevention strategies and facilitate translation to practice. Volunteer peer educators often deliver educational presentations on falls prevention to community-dwelling older adults. However, research evaluating the effectiveness of peer-led education approaches in falls prevention has been limited and no known study has evaluated such a program from the perspective of peer educators involved in delivering the message. The purpose of this study was to explore peer educators’ perspective about their role in delivering peer-led falls prevention education for community-dwelling older adults. Methods: A two-stage qualitative inductive constant comparative design was used.In stage one (core component) focus group interviews involving a total of eleven participants were conducted. During stage two (supplementary component) semi-structured interviews with two participants were conducted. Data were analysed thematically by two researchers independently. Key themes were identified and findings were displayed in a conceptual framework. Results: Peer educators were motivated to deliver educational presentations and importantly, to reach an optimal peer connection with their audience. Key themes identified included both personal and organisational factors that impact on educators’ capacity to facilitate their peers’ engagement with the message. Personal factors that facilitated message delivery and engagement included peer-to-peer connection and perceived credibility, while barriers included a reluctance to accept the message that they were at risk of falling by some members in the audience. Organisational factors, including ongoing training for peer educators and formative feedback following presentations, were perceived as essential because they affect successful message delivery. Conclusions: Peer educators have the potential to effectively deliver falls prevention education to older adults and influence acceptance of the message as they possess the peer-to-peer connection that facilitates optimal engagement. There is a need to consider incorporating learnings from this research into a formal large scale evaluation of the effectiveness of the peer education approach in reducing falls in older adults

High-resolution monitoring of catchment nutrient response to the end of the 2011-2012 drought in England, captured by the demonstration test catchments.

The Demonstration Test Catchments (DTC) project is a UK Government funded initiative to test the effectiveness of on-farm mitigation measures designed to reduce agricultural pollution without compromising farm productivity. Three distinct catchments in England have been chosen to test the efficacy of mitigation measures on working farms in small tributary sub-catchments equipped with continuous water quality monitoring stations. The Hampshire Avon in the south is a mixed livestock and arable farming catchment, the River Wensum in the east is a lowland catchment with predominantly arable farming and land use in the River Eden catchment in the north-west is predominantly livestock farming. One of the many strengths of the DTC as a national research platform is that it provides the ability to investigate catchment hydrology and biogeochemical response across different landscapes and geoclimatic characteristics, with a range of differing flow behaviours, geochemistries and nutrient chemistries. Although numerous authors present studies of individual catchment responses to storms, no studies exist of multiple catchment responses to the same rainfall event captured with in situ high-resolution nutrient monitoring at a national scale. This paper brings together findings from all three DTC research groups to compare the response of the catchments to a major storm event in April 2012. This was one of the first weather fronts to track across the country following a prolonged drought period affecting much of the UK through 2011–2012, marking an unusual meteorological transition when a rapid shift from drought to flood risk occurred. The effects of the weather front on discharge and water chemistry parameters, including nitrogen species (NO3-N and NH4-N) and phosphorus fractions (total P (TP) and total reactive P (TRP)), measured at a half-hourly time step are examined. When considered in the context of one hydrological year, flow and concentration duration curves reveal that the weather fronts resulted in extreme flow, nitrate and TP concentrations in all three catchments but with distinct differences in both hydrographs and chemographs. Hysteresis loops constructed from high resolution data are used to highlight an array of potential pollutant sources and delivery pathways. In the Hampshire Avon DTC, transport was dominated by sub-surface processes, where phosphorus, largely in the soluble form, was found to be transport-limited. In the Wensum DTC, transport was largely dominated by rapid sub-surface movement due to the presence of under-drainage, which mobilised large quantities of nitrate during the storm. In the Eden DTC, transport was found to be initially dominated by surface runoff, which switched to subsurface delivery on the falling limb of the hydrograph, with the surface delivery transporting large amounts of particulate phosphorus to the river, with a transport-limited response. The lack of exhaustion of nutrient delivery in response to such extreme flow generation indicates the size of the nutrient pools stored in these catchments, and highlights the scale of the challenges faced by environmental managers when designing mitigation measures to reduce the flux of nutrients to UK river systems from diffuse agricultural sources