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Background Older people are often explicitly or implicitly excluded from research, in particular clinical trials. This means that study findings may not be applicable to them, or that older people may not be offered treatments due to an absence of evidence. Aims The aim of this work was to develop recommendations to guide all research relevant to older people. Methods A diverse stakeholder group identified barriers and solutions to including older people in research. In parallel, a rapid literature review of published papers was undertaken to identify existing papers on the inclusion of older people in research. The findings were synthesised and mapped onto a socio-ecological model. From the synthesis we identified themes that were developed into initial recommendations that were iteratively refined with the stakeholder group. Results A range of individual, interpersonal, organisational, community and policy factors impact on the inclusion of older people in research. A total of 14 recommendations were developed such as removing upper age limits and comorbidity exclusions, involving older people, advocates and health and social care professionals with expertise in ageing in designing the research, and considering flexible or alternative approaches to data collection to maximise opportunities for participation. We also developed four questions that may guide those developing, reviewing and funding research that is inclusive of older people. Conclusion Our recommendations provide up to date, practical advice on ways to improve the inclusion of older people in health and care research. [ABSTRACT FROM AUTHOR]

Background: When patients with advanced dementia lose capacity to make medical decisions for themselves, a 'best interests' determination is usually made on their behalf by the responsible clinician. Where possible, this should be made in consultation with members of the multiprofessional team and the family, consistent with ethical and legal norms. This paper is about multidisciplinary approaches to education and practice in dementia care, using a framework. Approach: At a UK multiprofessional workshop in 2020, delegates discussed ethical and legal issues that arise when making decisions for patients with advanced dementia. After an initial presentation, providing context and background, delegates broke into small groups. They were tasked with responding to questions arising from anonymised cases based on real‐life scenarios. During plenary discussion afterwards, feedback was shared, and points of best practice were discussed. The authors took notes, and following positive evaluations after the event, they did further work on the framework with the intention of making it available for other health care professionals and clinical educators. Evaluation: Based on contemporaneous notes summarising the feedback, plus further reflections, the framework was developed into a 12‐point plan to assist health care teams and educators address difficulties in making 'best interests' determinations. Implications: Promoting understanding of ethics and law pertaining to 'best interests' should benefit patients and families, with the potential to reduce the need for cases to be decided in court. To help promote good clinical practice, educators may want to consider running case‐based workshops at their institution, using the framework as a scaffold for learners. [ABSTRACT FROM AUTHOR]

Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n = 431,167) and the Global Lipids Genetics Consortium (n = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n = 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications. [ABSTRACT FROM AUTHOR]

Summary Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR. [ABSTRACT FROM AUTHOR]

Prior research has not verified the theoretical or practical value of slice-of-life and slice-of-death advertising appeals in relation to advertising and branding constructs like advertising polysemy and consumer-based brand equity. The authors make conceptual, measurement, and managerial contributions to this research issue dealing with slice of life versus death advertising appeals. Across three studies, the authors measure, evaluate, compare, and contrast slice-of-life and slice-of-death (SOL/D) advertising appeals across British and American cultures. The authors demonstrate the interrelationships of SOL/D appeals with advertising polysemy, consumer-based brand equity, cultural differences in advertising attitudes, and purchase intentions. From a measurement perspective, the authors develop and validate parsimonious measures of slice-of-life and slice-of-death (SOL/D) advertising appeals. Furthermore, they test the assumptions that underlie these appeals for United States and British customers, and investigate how the cultural characteristic of uncertainty avoidance moderates the impact of SOL/D advertising attitudes on purchase intentions. Managerially, the research demonstrates that SOL/D appeals offer value in predicting (a) consumer-based brand equity through advertising polysemy, (b) consumers’ advertising attitudes across different cultures, (c) consumers’ intentions to purchase, and (d) advertising differences and varying consumer responses in the United States and Britain. [ABSTRACT FROM PUBLISHER]

Purpose: To determine if ultrasonography is necessary to detect progression of choroidal melanocytic tumors undergoing sequential multi-modal imaging with color photography, autofluorescence (AF) and optical coherence tomography (OCT). Methods: All patients with choroidal melanoma undergoing treatment at Moorfields Eye Hospital between January 2016 and March 2020 were reviewed to identify those with treatment deferred by ≥2 months. Tumors that showed progression prior to treatment, defined as an increase in (a) basal dimensions (b) thickness (c) orange pigment and/or (d) sub-retinal fluid, were included. Mushroom shape, Orange pigment, Large size, Enlargement and Sub-retinal fluid (MOLES) scores were assigned to all tumors at earliest date and date of treatment. Results: A total of 99 patients with a mean age of 66 years (range: 26–90) were included. The initial MOLES score was 1 in 2 cases, 2 in 23 cases, and ≥3 in 74 cases. Progression was detected with sequential color photography alone in 100% of MOLES 1/2 and 97% of lesions with a MOLES score of ≥3. When findings on AF and OCT were included, sensitivity for detecting subtle change without ultrasonography improved to 100% for MOLES 3 and 97% for MOLES 4/5. Only one patient included in this study had an isolated increase in thickness that may have been missed had sequential ultrasonography not been performed. Overall, the sensitivity for detecting progression with color photographs alone was 97% (95% CI 93–100%) and increased to 99% (95% CI 97–100%) by including autofluorescence and OCT. Conclusions: Monitoring of choroidal nevi, particularly those classified as MOLES 1 or 2 (i.e., low-risk or high-risk naevi), can be accomplished safely without the need for ultrasonography. The findings of this study may remove barriers to the implementation of tele-oncology clinics for the monitoring of choroidal melanocytic tumors. [ABSTRACT FROM AUTHOR]

Introduction: A lack of physical activity (PA) is one of the most pressing health issues today. Our individual propensity for PA is influenced by genetic factors. Stated liking of different PA types may help capture additional and informative dimensions of PA behavior genetics. Methods: In over 157,000 individuals from the UK Biobank, we performed genome-wide association studies of five items assessing the liking of different PA types, plus an additional derived trait of overall PA-liking. We attempted to replicate significant associations in the Netherlands Twin Register (NTR) and TwinsUK. Additionally, polygenic scores (PGS) were trained in the UK Biobank for each PA-liking item and for self-reported PA behavior, and tested for association with PA in the NTR. Results: We identified a total of 19 unique significant loci across all five PA-liking items and the overall PA-liking trait, and these showed strong directional consistency in the replication cohorts. Four of these loci were previously identified for PA behavior, including CADM2 , which was associated with three PA-liking items. The PA-liking items were genetically correlated with self-reported (r g = 0.38–0.80) and accelerometer (r g = 0.26–0.49) PA measures, and with a wide range of health-related traits. Each PA-liking PGS significantly predicted the same PA-liking item in NTR. The PGS of liking for going to the gym predicted PA behavior in the NTR (r 2 = 0.40%) nearly as well as a PGS based on self-reported PA behavior (r 2 = 0.42%). Combining the two PGS into a single model increased the r 2 to 0.59%, suggesting that PA-liking captures distinct and relevant dimensions of PA behavior. Conclusions: We have identified the first loci associated with PA-liking and extended our understanding of the genetic basis of PA behavior. [ABSTRACT FROM AUTHOR]