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Background: Including participants in patient and public involvement activities is increasingly acknowledged as a key pillar of successful research activity. Such activities can influence recruitment and retention, as well as researcher experience and contribute to decision making in research studies. However, there are few established methodologies of how to set up and manage participant involvement activities. Further, there is little discussion of how to do so when dealing with collaborative projects that run across countries and operate in multiple linguistic and regulatory contexts. Methods: In this paper we describe the set-up, running and experiences of the EPAD participant panel. The EPAD study was a pan-European cohort study with the aim to understand risks for developing Alzheimer's disease and build a readiness cohort for Phase 2 clinical trials. Due to the longitudinal nature of this study, combined with the enrolment of healthy volunteers and those with mild cognitive impairments, the EPAD team highlighted participant involvement as crucial to the success of this project. The EPAD project employed a nested model, with local panels meeting in England, France, Scotland, Spain and The Netherlands, and feeding into a central study panel. The local panels were governed by terms of reference which were adaptable to local needs. Results: The impact of the panels has been widespread, and varies from feedback on documentation, to supporting with design of media materials and representation of the project at national and international meetings. Conclusions: The EPAD panels have contributed to the success of the project and the model established is easily transferable to other disease areas investigating healthy or at-risk populations. [ABSTRACT FROM AUTHOR]

This article describes and reflects upon the work of a co-research team on the Healthy Ageing in Scotland (HAGIS) 'COVID-19 Impact and Recovery' study (January 2021 to November 2022). The co-research team (seven older adults and three academics) was constituted near the start of this project; the team contributed to the development of recruitment materials and research tools and undertook qualitative research and analysis with older adults living across Scotland. This article provides a collaborative autoethnography about the activities undertaken by the team, the impact of the co-research process on the individuals involved, and the research findings and reflects the realities of co-research during the COVID-19 pandemic. Team members describe benefits, including increased confidence, new skills, and social connections, and reflect on the increased validity of the findings through their close involvement in the co-creation of knowledge. The process of team building and the adoption of an 'ethics of care' in our practice underpinned the success of this project and the sustainability of the group during and after the challenging circumstances of the pandemic.

Background: Plasma growth differentiation factor 15 (GDF15) and N-terminal proB-type natriuretic peptide (NT-proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification., Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all P FDR  < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36-1.41, P FDR  < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R 2 range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population., Conclusions: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification., (© 2024. The Author(s).)

Purpose: Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental determinants of physical and mental health. It comprises extensive genetic, sociodemographic and clinical data from volunteers in Scotland., Participants: A total of 24 084 adult participants, including 5501 families, were recruited between 2006 and 2011. Within the cohort, 59% (approximately 14 209) are women, with an average age at recruitment of 49 years. Participants completed a health questionnaire and attended an in-person clinic visit, where detailed baseline data were collected on lifestyle information, cognitive function, personality traits and mental and physical health. Genotype array data are available for 20 026 (83%) participants, and blood-based DNA methylation (DNAm) data for 18 869 (78%) participants. Linkage to routine National Health Service datasets has been possible for 93% (n=22 402) of the cohort, creating a longitudinal resource that includes primary care, hospital attendance, prescription and mortality records. Multimodal brain imaging is available in 1069 individuals., Findings to Date: GS has been widely used by researchers across the world to study the genetic and environmental basis of common complex diseases. Over 350 peer-reviewed papers have been published using GS data, contributing to research areas such as ageing, cancer, cardiovascular disease and mental health. Recontact studies have built on the GS cohort to collect additional prospective data to study chronic pain, major depressive disorder and COVID-19., Future Plans: To create a larger, richer, longitudinal resource, 'Next Generation Scotland' launched in May 2022 to expand the existing cohort by a target of 20 000 additional volunteers, now including anyone aged 12+ years. New participants complete online consent and questionnaires and provide postal saliva samples, from which genotype and salivary DNAm array data will be generated. The latest cohort information and how to access data can be found on the GS website (www.generationscotland.org)., Competing Interests: Competing interests: REM is a scientific advisor to Optima Partners and the Epigenetic Clock Development Foundation. DM is a part-time employee of Optima Partners., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification., Competing Interests: DG, DM, SZ, AS, YC, CF, CN, AC, RF, SH, RW, LS, ET, CG, AP, MW, JG, AM, ID, DP, CH, PV, SC, KE, AM, KS No competing interests declared, RH has received consultant fees from Illumina, RM has received speaker fees from Illumina and is an advisor to the Epigenetic Clock Development Foundation, (© 2022, Gadd et al.)

Background: Very late-onset (aged ≥ 60 years) schizophrenia-like psychosis (VLOSLP) occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy or risks of antipsychotic treatment. Most patients are not prescribed treatment., Objectives: The study investigated whether or not low-dose amisulpride is superior to placebo in reducing psychosis symptoms over 12 weeks and if any benefit is maintained by continuing treatment thereafter. Treatment safety and cost-effectiveness were also investigated., Design: Three-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial. Participants who received at least one dose of study treatment were included in the intention-to-treat analyses., Setting: Secondary care specialist old age psychiatry services in 25 NHS mental health trusts in England and Scotland., Participants: Patients meeting diagnostic criteria for VLOSLP and scoring > 30 points on the Brief Psychiatric Rating Scale (BPRS)., Intervention: Participants were randomly assigned to three arms in a two-stage trial: (1) 100 mg of amisulpride in both stages, (2) amisulpride then placebo and (3) placebo then amisulpride. Treatment duration was 12 weeks in stage 1 and 24 weeks (later reduced to 12) in stage 2. Participants, investigators and outcome assessors were blind to treatment allocation., Main Outcome Measures: Primary outcomes were psychosis symptoms assessed by the BPRS and trial treatment discontinuation for non-efficacy. Secondary outcomes were extrapyramidal symptoms measured with the Simpson-Angus Scale, quality of life measured with the World Health Organization's quality-of-life scale, and cost-effectiveness measured with NHS, social care and carer work loss costs and EuroQol-5 Dimensions., Results: A total of 101 participants were randomised. Ninety-two (91%) participants took the trial medication, 59 (64%) completed stage 1 and 33 (56%) completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7.7 points (95% CI 3.8 to 11.5 points) greater with amisulpride than with placebo (11.9 vs. 4.2 points; p  = 0.0002). In stage 2, BPRS scores improved by 1.1 point in those who continued with amisulpride but deteriorated by 5.2 points in those who switched from amisulpride to placebo, a difference of 6.3 points (95% CI 0.9 to 11.7 points; p  = 0.024). Fewer participants allocated to the amisulpride group stopped treatment because of non-efficacy in stages 1 ( p  = 0.01) and 2 ( p  = 0.031). The number of patients stopping because of extrapyramidal symptoms and other side effects did not differ significantly between groups. Amisulpride treatment in the base-case analyses was associated with non-significant reductions in combined NHS, social care and unpaid carer costs and non-significant reductions in quality-adjusted life-years (QALYs) in both stages. Including patients who were intensive users of inpatient services in sensitivity analyses did not change the QALY result but resulted in placebo dominance in stage 1 and significant reductions in NHS/social care (95% CI -£8923 to -£122) and societal costs (95% CI -£8985 to -£153) for those continuing with amisulpride., Limitations: The original recruitment target of 300 participants was not achieved and compliance with trial medication was highly variable., Conclusions: Low-dose amisulpride is effective and well tolerated as a treatment for VLOSLP, with benefits maintained by prolonging treatment. Potential adverse events include clinically significant extrapyramidal symptoms and falls., Future Work: Trials should examine the longer-term effectiveness and safety of antipsychotic treatment in this patient group, and assess interventions to improve their appreciation of potential benefits of antipsychotic treatment and compliance with prescribed medication., Trial Registration: Current Controlled Trials ISRCTN45593573 and EudraCT2010-022184-35., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 67. See the NIHR Journals Library website for further project information., Competing Interests: Robert Howard reports membership of the Heath Technology Assessment (HTA) Commissioning Board. Peter Bentham reports grants from the HTA programme during the course of this study. Craig Ritchie reports grants and personal fees from Merck Sharp & Dohme Ltd (Kenilworth, NJ, USA), personal fees from Pfizer Inc. (New York City, NY, USA), Eisai Co. Ltd (Tokyo, Japan), Actinogen (Sydney, NSW, Australia), Kyowa Hakko Kirin (Tokyo, Japan), Eli Lilly and Company (Indianapolis, IN, USA), and F. Hoffmann-La Roche AG (Basel, Switzerland), grants from Biogen Inc. (Cambridge, MA, USA) and grants and non-financial support from Janssen EMEA (Beerse, Belgium) and Takeda Pharmaceutical Company Ltd (Osaka, Japan) during the conduct of the study. Craig Ritchie was also the co-coordinator and academic lead for the European Prevention of Alzheimer’s Dementia (EPAD) project, which has numerous commercial partners in keeping with the mechanisms of the European Union’s Innovative Medicine’s Initiative [i.e. Janssen, Eisai Co. Ltd, Pfizer, Eli Lilly and Company, Roche Diagnostics (Risch-Rotkreuz, Switzerland), Boehringher Ingelheim GmbH (Ingelheim am Rhein, Germany), Novartis International AG (Basel, Switzerland), AC Immune SA (Lausanne, Switzerland), IXICO (London, UK), Aridhia (Glasgow, UK), Amgen Inc. (Thousand Oaks, CA, USA), Berry Consultants (Abingdon, UK), H. Lundbeck A/S (Copenhagen, Denmark), Sanofi SA (Paris, France), IQVIA (formerly Quintiles IMS Holdings, Inc.) (Durham, NC, USA) and Takeda Pharmaceutical Company]. Andrew Sommerlad reports grants from the Wellcome Trust outside the submitted work. Ramin Nilforooshan reports personal fees from Eli Lilly and Company and non-financial support from Janssen outside the submitted work. Martin Knapp reports grants from Merck Sharp & Dohme outside the submitted work.

Objectives: We investigated the role that childhood and old age cognitive ability play in the association between functional health literacy and mortality., Design: Prospective cohort study., Setting: This study used data from the Lothian Birth Cohort 1936 (LBC1936) study, which recruited participants living in the Lothian region of Scotland when aged 70 years, most of whom had completed an intelligence test at age 11 years., Participants: 795 members of the LBC1936 with scores on tests of functional health literacy and cognitive ability in childhood and older adulthood., Primary and Secondary Outcome Measures: Participants were followed up for 8 years to determine mortality. Time to death in days was used as the primary outcome measure., Results: Using Cox regression, higher functional health literacy was associated with lower risk of mortality adjusting for age and sex, using the Shortened Test of Functional Health Literacy in Adults (HR 0.95, 95% CI 0.92 to 0.98), the Newest Vital Sign (HR 0.88, 95% CI 0.80 to 0.97) and a functional health literacy composite measure (HR 0.77, 95% CI 0.65 to 0.92), but not the Rapid Estimate of Adult Literacy in Medicine (HR 0.95, 95% CI 0.90 to 1.01). Adjusting for childhood intelligence did not change these associations. When additionally adjusting for fluid-type cognitive ability in older age, associations between functional health literacy and mortality were attenuated and non-significant., Conclusions: Current fluid ability, but not childhood intelligence, attenuated the association between functional health literacy and mortality. Functional health literacy measures may, in part, assess fluid-type cognitive abilities, and this may account for the association between functional health literacy and mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)