Exploring multi-ethnic younger and middle-aged adults’ understandings of dementia and approaches to help-seeking

This research involved the participation of a hitherto under researched groups, namely younger and middle aged adults from lay public multi-ethnic communities. The overall aim of this research was to explore understandings of dementia and approaches to help-seeking. A qualitative study using grounded theory was conducted to develop insights about factors and issues that shaped understandings of dementia, including its framing to ageing and help-seeking. This research utilised focus groups with lay public participants to access a diverse range of perspectives and experiences. These were supplemented with interviews conducted with community workers to provide contextualised accounts of issues related to dementia help-seeking and care in diverse ethnic communities. A life stage approach was used to denote generational age and used to recruit lay public participants to the following three generational groups, namely 18-30 years, 30-40 years, and 40-55 years, from white British, Indian and Caribbean communities. Five community workers and volunteers were also recruited to participate in face-to-face semi-structured interviews. The findings from the focus groups suggest that ethnicity did not play a mediating role in the possession of knowledge and understandings of dementia. Other factors were identified, including: exposure to the media; caring for relatives; dementia in their social networks; exposure to dementia in higher education studies, and participants’ own information seeking behaviours. Ethnicity and generational age was suggested to adversely mediate access to mainstream health and media information for older generations from ethnic minority groups outside of this research sample. Two forms of conceptualisations of dementia were evident. These included the concept of dementia as a mental illness and as a normal consequence of ageing, although their expressions were nuanced. These concepts of dementia were inextricably linked to old age but there were indications of generational changes in the way old age was conceptualised. There was a move away from chronological age definitions to an emphasis on the ageing process, including how well individuals took responsibility for managing their own ageing process and mitigating their risk of developing dementia. A typology of help-seeking approaches and care strategies was developed. This consisted of four types; traditional, flexible, constrained and individualised, which were developed to convey differentiated approaches to help-seeking by ethnicity and generational age. These types encompassed adaptions and reinforcement of filial piety in response to structural changes and factors. These encompassed perceptions and experiences of racism in the mental health system and the availability of care home support. This research emphasises the importance of future research encompassing intersectional approaches to research design to capture the heterogeneity of perspectives within and across all ethnic communities. The key message to healthcare providers and commissioners is that they need to address structural barriers to diagnosis and care, some of which may be common across ethnic communities, whilst others maybe specific. This research makes a number of unique contributions to knowledge, one of which is the need for more nuanced approaches to conceptualisations of dementia. It also explicates and interrogates how ageing is framed in relation to dementia, including individualised responsibility for ageing in a multi-ethnic research sample. Finally, this research also differentiates help-seeking strategies within and across ethnic groups by taking into account generational differences, dynamic interactions between culture and structural factors

Final Report: Leicester Ageing Together (LAT): Evaluation Report

Executive Summary According to the Office for National Statics (2018) the UK population has been steadily getting older and this trend is projected to continue. In 2016, there were 11.8 million UK residents aged 65 years and over, representing 18% of the total population – 25 years before, there were 9.1 million, accounting for 15.8% of the population. Linked to these statistics over 9 million people in the UK – almost a fifth of the population – say they are always or often lonely, but almost two thirds feel uncomfortable admitting to it (British Red Cross and Co-Op, 2016) and over half (51%) of all people aged 75 and over live alone (ONS, 2010). The Leicester Ageing Together partnership, known as LAT, has been working since October 2015 to reduce isolation and loneliness in older people in Leicester. So far, they have reached almost 6,000 older people, nearly half of whom were aged 80 years plus. This large and extensive programme recruited over 1,300 volunteers, as well as funding local jobs worth £1.5 million. LAT is part of Ageing Better, a programme set up by The National Lottery Community Fund, the largest funder to date of community activity in the UK. Ageing Better aimed to develop creative ways for older people to be actively involved in their local communities, helping to combat social isolation and loneliness. It was one of five major programmes set up by The National Lottery Community Fund to test and learn from new approaches to designing services which aimed to make people’s lives healthier and happier. This report commissioned by the LAT board in December 2018 was conducted by De Montfort University and reports the findings of a qualitative evaluation conducted at the end of the funding stream for the programme. The evaluation aimed to gauge the views and experiences of beneficiaries, stakeholders and provider organisations who were involved in the delivery of the programme. This evaluation was conducted over a four month period in early 2019 and where possible aimed to gain insights from across a range of ethnic groups, contexts and viewpoints. In total 50 participants shared their experiences of the programme, for which the evaluation team at De Montfort and LAT are extremely grateful. This report should be read with the understanding that the views shared in this report are not necessarily the views of everyone involved in the programme. They are time specific based on hindsight offering a snap shot of views at the end of the programme rather than throughout. The findings relate to data collected over a months in 2019 involving 50 participants who were at the time of data collection actively engaged in an activity as a beneficiary or were delivering programmes as a provider. The majority of the views shared in this report are generated from the 35 older people classed as the LAT programme beneficiaries with a further 15 interviews undertaken with provider and stakeholder organisations. This evaluation did not seek the views of the LAT board members. Ageing Better, the Big Lottery funders or organisations that were no longer offering LAT funded activities. The findings and therefore the recommendations are solely based on the evidence gathered during this evaluation exercise and it would be useful for these to be considered in light of the other extensive evaluations that have been commissioned not just for the Leicester programme but others commissioned across the sector. For example at the time of submitting this final report we understand there is an ongoing national evaluation by the Big Lottery which is anticipated to have cross cutting themes to other local evaluations. It would be wise, therefore, to review these in the context of Leicester and other UK Cities and similar programmes aimed to support loneliness and social isolation amongst older people (those aged over 50) and the communities to which they live. The report findings aim to capture the essence of the LAT programme including highlights, strengths and opportunities for future learning for similar programmes of activity

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL

The pioneer factor PBX1 is a novel driver of metastatic progression in ERalpha-positive breast cancer

Over 30% of ERalpha breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERalpha binding. Here we demonstrate that PBX1 plays a central role in regulating the ERalpha transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERalpha genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERalpha-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERalpha positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERalpha positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERalpha-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERalpha positive breast cancer

Implementation of a diabetes prevention programme in a multi-ethnic community in primary care in England: An evaluation using constructs from the RE-AIM Framework

To implement a diabetes prevention programme in primary care METHODS: The programme was implemented for 12 months in two neighbouring towns, served by eight general practices. Practices requested a referral pathway involving an external administrator running electronic searches and sending postal invitations. If interested, people called and booked a place on the programme. Practices were also provided with resources to refer people directly. Six Educators were trained to deliver the programme. The RE-AIM constructs "Adoption", "Reach" and "Uptake" were assessed. All practices engaged in the searches and postal invitations. Overall, 3.9 % of those aged ≥ 25 years had an HbA1c level indicative of non-diabetic hyperglycaemia (NDH) and were invited. Overall uptake (attended as percentage of invited) was 16 % (practice range 10.5-26.6 %) and was highest in two practices where the invitation was followed by a telephone call. Four people were referred directly by their practice. Groups at risk of being excluded were the Bengali population and those unable to attend because of issues such as health, mobility and frailty. Comprehensive electronic searches meant everyone previously diagnosed with NDH was invited to attend. Follow-up telephone call improved uptake and providing practices with resources to make these calls themselves would likely increase uptake further

Expression of CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer

Purpose: CDK-activation kinase (CAK) is required for the regulation of the cell-cycle and is a trimeric complex consisting of Cyclin Dependent Kinase 7 (CDK7), Cyclin H and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics. Experimental Design: mRNA and protein expression of CDK7 and its essential co-factors cyclinH and MAT1, were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathological features and patient outcome. Results: We show that expression of CDK7, cyclinH and MAT1 are all closely linked at the mRNA and protein level and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumour grade and size and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity. Conclusions: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ER. Like ERα , CDK7 expression is inversely proportional to poor prognostic factors and survival

Development of a lifestyle intervention using the MRC framework for diabetes prevention in people with impaired glucose regulation

A B S T R AC T Background We report development of a group-based lifestyle intervention, Let's Prevent, using the UK Medical Research Council (MRC) framework, and delivered by structured education to prevent type 2 diabetes mellitus (T2DM) in people with impaired glucose regulation (IGR) in a UK multi-ethnic population. Methods Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) is the first national T2DM programme that meets National Institute for Health and Care Excellence criteria and formed the basis for Let's Prevent. An iterative cycle of initial development, piloting, collecting and collating qualitative and quantitative data, and reflection and modification, was used to inform and refine lifestyle intervention until it was fit for evaluation in a definitive randomized controlled trial (RCT). The programme encouraged IGR self-management using simple, non-technical language and visual aids. Results Qualitative and quantitative data suggested that intervention resulted in beneficial short-term behaviour change such as healthier eating patterns, improved health beliefs and greater participant motivation and empowerment. We also demonstrated that recruitment strategy and data collection methods were feasible for RCT implementation. Conclusions Let's Prevent was developed following successful application of MRC framework criteria and the subsequent RCT will determine whether it is feasible, reliable and transferable from research into a real-world NHS primary healthcare setting. Trial Registration ISRCTN80605705. Keywords complex intervention, diabetes prevention, impaired glucose regulation, structured education Introduction Screening studies carried out in primary care in the UK 1 have shown that screening for type 2 diabetes mellitus (T2DM) will identify around 15% of middle aged adults with impaired glucose tolerance or impaired fasting glucose, collectively termed impaired glucose regulation (IGR) and also known as pre-diabetes mellitus. 2 IGR is considered to be a high-risk state for T2DM, cardiovascular disease (CVD) and increased mortality 3,4 and is now referred to as 'at high risk of developing diabetes' under new guidelines on terminology. There is evidence that, in people with IGR, lifestyle modifications can substantially reduce the risk of developing T2DM. 6 Screening and lifestyle interventions are also likely to be costeffective. 7 The Diabetes Prevention Programme 8 and the Finnish Prevention study 9 showed that lifestyle programmes addressing weight loss, healthy diet and physical activity reduce the risk of developing T2DM in those with IGR by 58%. Successful lifestyle programmes have also been carried out in many other countries, including India, 10 China 11 and Japan. 12 There is limited evidence, however, regarding the feasibility of translating this research into practice. Many research-based prevention programmes have involved multiple one-to-one counselling sessions. The Diabetes Prevention Programme had a median of 20 individual counselling sessions over a 4-year period. 9 The intensity of such an intervention, even if cost-effective in the long term, is likely to place acute strain on healthcare resources in the short term. Even resource-rich countries, such as Germany and Finland, where diabetes prevention is a public health priority, have been unable to replicate the intensive nature of diabetes prevention programmes when implemented into clinical practice. 17 New guidelines from the National Institute for Health and Care Excellence (NICE) state that those identified with a moderate or high risk of developing T2DM should be offered culturally appropriate information or support, in a range of formats and languages, including structured education, to help them change their lifestyle. 5 Structured education refers to group-based patient-centred educational programmes that have a clear philosophy and a written curriculum with supporting resources, are underpinned by appropriate learning and psychological theory, and are evidence-based and delivered by trained, quality assessed educators. 19 Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) is the first national programme for T2DM that meets NICE criteria 20,21 and a randomized controlled trial (RCT) has demonstrated its effectiveness in improving weight, smoking behaviours and illness beliefs. 21 The DESMOND model is based on an empowerment philosophy that sees the participant as capable and responsible for their own health decisions and behaviours. The UK Medical Research Council (MRC) Framework for Complex Interventions to Improve Health has internationally recognized criteria to guide the development and evaluation of health behaviour change programmes. The most recent MRC guidance suggests including the following phases: development, feasibility and piloting, evaluation and implementation 23 There is an urgent need to design and test prevention programmes that meet the needs of ethnically diverse communities and are feasible, cost-effective and replicable in a real-world UK healthcare setting. The lifestyle intervention described was developed to meet this need and is currently being formally evaluated in an RCT. Methods Study design and recruitment The Let's Prevent intervention was developed by a core multidisciplinary team in collaboration with the DESMOND collaborative and the National Physical Activity Centre in Loughborough. It was designed as a group educational programme with a written curriculum suitable for the broadest range of participants, to be deliverable in a community setting for ease of access for patients, and to have the potential for integration into future routine clinical care. The session content was founded on a sound evidence base and guided by a review of the literature surrounding nutrition, exercise and educational principles with pragmatic decisions on best practice where the evidence was ambiguous, lacking or conflicting. Using the DESMOND model, the programme was 6 h long, deliverable in either one full day or as two half-day equivalents. It was designed to be facilitated by two trained healthcare professionals (educators) to a group of between 5 and 12 participants with IGR, who had the option of bringing an accompanying person. It was delivered as two versions. The first was broadly suitable for most White European groups, referred to as the Let's Prevent programme, and the second was adapted to suit SA patient groups and referred to as the SA Let's Prevent programme. Both versions of the educational intervention and the educator training programme were modelled and refined using an iterative process, including piloting, feedback, analysis, reflection and modification, based on a methodology previously developed for modifying an educational programme. 30 Key to the process was the collection and analysis of qualitative and quantitative data. A degree of objectivity and a high level of rigour were attained by involving academic researchers in this process. The Qualitative data were gathered to ascertain the experiences of both participants and educators of engaging in the programme. Data were collected via observation, telephone and face-to-face interviews and focus groups. Flexible topic guides were developed by trainers and qualitative researchers to inform and facilitate the qualitative data collection process. The SA Let's Prevent programme was developed concurrently to address the needs of the SA population living in the UK, many of whom do not speak English. Core educational messages were identical to Let's Prevent but changes were made to ensure that food and activity messages were culturally relevant. Teaching resources (images and models) were developed to ensure that the programme was not reliant on the written word. A previous action research project The nutritional goals from the Diabetes Prevention Programme 8 and the Finnish Prevention Study 9 and the physical activity goals from the PREPARE stud

Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.

BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS) of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12 µg (range 11.1-13.3 µg) of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis. RESULTS: Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome. CONCLUSION: This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples

Factors affecting DNA uptake by cells

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