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A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference ( ICV-TBV ), ratio ( TBV / ICV ), and regression-residual method (TBV∼ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales ( r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline ( r = 0.36), frailty ( r = 0.24), age-moderated brain shrinkage ( r = 0.45), and longitudinally-measured atrophic changes ( r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV ( r g = 0.75). We performed the largest genetic study of LBA to date ( N = 43,110), which was highly heritable ( h 2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h 2 = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16 , a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

Objective: To develop international consensus-based recommendations for early referral of individuals with suspected polymyalgia rheumatica (PMR)., Methods: A task force including 29 rheumatologists/internists, 4 general practitioners, 4 patients and a healthcare professional emerged from the international giant cell arteritis and PMR study group. The task force supplied clinical questions, subsequently transformed into Population, Intervention, Comparator, Outcome format. A systematic literature review was conducted followed by online meetings to formulate and vote on final recommendations. Levels of evidence (LOE) (1-5 scale) and agreement (LOA) (0-10 scale) were evaluated., Results: Two overarching principles and five recommendations were developed. LOE was 4-5 and LOA ranged between 8.5 and 9.7. The recommendations suggest that (1) each individual with suspected or recently diagnosed PMR should be considered for specialist evaluation, (2) before referring an individual with suspected PMR to specialist care, a thorough history and clinical examination should be performed and preferably complemented with urgent basic laboratory investigations, (3) individuals with suspected PMR with severe symptoms should be referred for specialist evaluation using rapid access strategies, (4) in individuals with suspected PMR who are referred via rapid access, the commencement of glucocorticoid therapy should be deferred until after specialist evaluation and (5) individuals diagnosed with PMR in specialist care with a good initial response to glucocorticoids and a low risk of glucocorticoid related adverse events can be managed in primary care., Conclusions: These are the first international recommendations for referral of individuals with suspected PMR, which complement the European Alliance of Associations for Rheumatology/American College of Rheumatology management guidelines for established PMR., Competing Interests: Competing interests: KKK: Research grants from Independent Research Fund Denmark, Danish Rheumatic Association and Central Denmark Region unrelated to this project. SES: Research grants from Rheumatology Research Foundation, Bristol Myers Squibb Foundation. Clinical trial support from AstraZeneca, GlaxoSmithKline; Consulting fees from Sanofi (funds toward research support); Data Safety Monitoring Board on MINT trial, Advisory Board for Sanofi (funds toward research support). E-MH: Has received grants unrelated to this manuscript from Novo Nordic Foundation, Roche, Novartis; Personal fees from AbbVie, Sanofi, SOBI, Merck Sharp & Dohme and Union Chimique Belge. AD: Consulting fees from Sanofi; Participation on a Data Safety Monitoring Board or Advisory Board for Sanofi; Board member Vasculitis Foundation. LN: Has received Honorarium from Abbvie; Trustee of the charity PMR-GCA Scotland. SM: Consulting fees from Astrazeneca; Honoraria from Vifor. KJW: Grants from Eli Lilly, Kiniksa, BMS; Consulting fees from Amgen, Sanofi. Honoraria from Amgen. CP: Consulting fee from Pfizer. MP: Consulting fee from Novartis; Clinical trial participant for Abbvie, Amgen, AstraZeneca. HIK: Honoraria from Roche, eTherapeutic Guidelines Australia; Board member Australian Rheumatology Association; Clinical trials for Roche, Abbvie, Sun, Emerald, Novartis, Biogen, Sanofi, Syneos. CEO: Consultancy for Abbvie; Speaking honoraria from Abbvie, Janssen, Novartis and Roche; Advisory board for Abbvie. WAS: Has received honoraria from Abbvie, Chugai, GlaxoSmithKline, Medac, Novartis, Roche, Sanofi ; Support for attending meetings/travel from Abbvie, Chugai, GlaxoSmithKline, Medac, Novartis, Roche, Sanofi; Participated in advisory board from Abbvie, GlaxoSmithKline, Novartis, Sanofi; Principle investigator of phases 2 and 3 studies sponsored by Abbvie, GlaxoSmithKlinie, Novartis and Sanofi. EBrouwer: As an employee of the UMCG received a speaker fee for a talk on GCA at a post EULAR symposium in the Netherlands in 2023 which was paid to the UMCG; As an employee of the UMCG received grants from the Dutch Arthritis Society DAS and the EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking Immune-Image grant no 831514 which were paid to the UMCG. SM: Consultancy on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, AstraZeneca, Pfizer; Investigator on clinical trials for Sanofi, GSK, Sparrow; speaking/lecturing on behalf of her institution for Roche/Chugai, Vifor, Pfizer, UCB, Novartis and AbbVie; chief investigator on STERLING-PMR trial, funded by NIHR; patron of the charity PMRGCAuk. No personal remuneration was received for any of the above activities. Support from Roche/Chugai to attend EULAR2019 in person and from Pfizer to attend ACR Convergence 2021 virtually. SM is supported in part by the NIHR Leeds Biomedical Research Centre. VD-P has received honorarium from Abbvie, Chugai, Novartis, BMS, Support for attending meetings/travel from Novartis; Participated in advisory borad from Abbvie, Novartis. All other authors have no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Environmental exposures including toxins and nutrition may hamper the developing brain in utero, limiting the brain's reserve capacity and increasing the risk for Alzheimer's disease (AD). The purpose of this systematic review is to summarize all currently available evidence for the association between prenatal exposures and AD-related volumetric brain biomarkers. We systematically searched MEDLINE and Embase for studies in humans reporting on associations between prenatal exposure(s) and AD-related volumetric brain biomarkers, including whole brain volume (WBV), hippocampal volume (HV) and/or temporal lobe volume (TLV) measured with structural magnetic resonance imaging (PROSPERO; CRD42020169317). Risk of bias was assessed using the Newcastle Ottawa Scale. We identified 79 eligible studies (search date: August 30th, 2020; Ntotal=24,784; median age 10.7 years) reporting on WBV (N = 38), HV (N = 63) and/or TLV (N = 5) in exposure categories alcohol (N = 30), smoking (N = 7), illicit drugs (N = 14), mental health problems (N = 7), diet (N = 8), disease, treatment and physiology (N = 10), infections (N = 6) and environmental exposures (N = 3). Overall risk of bias was low. Prenatal exposure to alcohol, opioids, cocaine, nutrient shortage, placental dysfunction and maternal anemia was associated with smaller brain volumes. We conclude that the prenatal environment is important in shaping the risk for late-life neurodegenerative disease., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: A positive patient experience is a key component of good quality of care. Post-pandemic healthcare systems face the challenge of addressing burnout among healthcare staff, who are directly involved in the delivery of healthcare, which has implications for the patient experience. There is an established association between staff and patient experience; exploring the experience of staff may give insights into factors that negatively impact the patient experience. Experience-based design (EBD) is a quality improvement approach that uses the experience of service users to derive improvements. The purpose of this study is to design, validate, and test an EBD tool that may be used to capture the staff experience. Methods: A focus group of clinical and nonclinical staff (identified through the NHS Elect networks) and the development team coproduced an EBD survey based on nine "touch-points" of a typical working day. Once the survey questionnaire was tested and agreed with it was distributed to 1300 members of NHS networks. Results: A total of 377 NHS staff responded to the questionnaire. Analysis revealed effective teamwork had a positive psychological impact on staff. However, increased workload, missed meal breaks, and an increased administrative/IT burden were associated with the greatest negative responses by clinical and nonclinical staff. Conclusion: Overall, factors impacting staff well-being are multifaceted and varied between trusts. However, leaders in healthcare can use EBD to identify targeted improvements for the day-to-day experiences of staff., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Introduction: The aim of the Specialised Clinical Frailty Network (SCFN) was to develop frailty-attuned pathways in specialised services in England., Methods: We developed a breakthrough series collaborative involving a range of specialised services, using quality improvement methods (including experience-based design) to implement improvements designed to enhance the experience and outcomes of older people living with frailty who have specialised healthcare needs., Results: Specialised teams responded positively to the SCFN, many implementing process changes aligned to the needs of older people living with frailty. Some were able to demonstrate improvements in service and/or patient outcomes, including greater identification of frailty, more holistic care and increased use of shared decision making., Discussion: The network has successfully demonstrated how frailty can be assessed both at individual, as well as population level, to support both local teams and systems to best manage the health of their patients., (© Royal College of Physicians 2022. All rights reserved.)

Introduction: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology., Methods: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V)., Results: Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage., Discussion: Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies., Competing Interests: S.R.C received payment from the Society of Biological Psychiatry (plenary at SOBP2021). R.E.M. is an advisor to the Epigenetic Clock Development Foundation and has received a speaker fee from Illumina. A.C. is member of Edinburgh MVM Research Ethics Committee. J.M.W is involved in European Stroke Organisation Guideline on Covert Small Vessel Disease 2021 and European Stroke Organisation Chair of Conference Planning Group 2021 and 2022. D.S. helped to set up CAPE study. A.M. received speaker fees from Janssen and Illumina. S.L. is an employee of Janssen Medical UK and Co‐founder of Akrivia Health Ltd. He is also named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past 5 years has advised for Optum labs, Merck, SomaLogic, and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. N.B. is a member of Mehta Family Centre for Engineering in Medicine, Kanpur, India as well as the editorial board of Stem Cells. A.N.H. is the main PI of a project funded by J&J, and another projects funded by GSK, all unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease. Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543., Summary: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: UC, MS, MJT, GB, AM, OH, CM, FND and JMW hold academic grants from government and charitable funding agencies, outlined below., (© European Stroke Organisation 2020.)

Background: Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment and patient-service needs., Aims: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. We aim to recruit a wide range of patients with stroke, presenting to geographically diverse UK hospitals, into a longitudinal study to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess potential mechanisms and improve prediction models., Methods: We will recruit at least 2000 patients within six weeks of stroke with or without capacity to consent and collect baseline demographic, clinical, socioeconomic, lifestyle, cognitive, neuropsychiatric and informant data using streamlined patient-centred methods appropriate to the stage after stroke. We will obtain more detailed assessments at four to eight weeks after the baseline assessment and follow-up by phone and post yearly to at least two years. We will assess diagnostic neuroimaging in all and high-sensitivity inflammatory markers, genetics, blood pressure and diffusion tensor imaging in mechanistic sub-studies. Planned outputs: R4VaD will provide reliable data on long-term cognitive function after stroke, stratified by prior cognition, stroke- and patient-related variables and improved risk prediction. It will create a platform enabling sharing of data, imaging and samples. Participants will be consented for re-contact, facilitating future clinical trials and providing a resource for the stroke and dementia research communities., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RMT, HE, AP-J, NS, YHM, TR, FD, HSM, None; PB was a co-Chief Investigator of PHADER and reports receiving honoraria from Phagenesis, DiaMedica, Moleac, Nestle, Sanofi; TQ has received investigator initiated funding from BMS and Pfizer for projects on cardiovascular disease and cognition; FD holds an NHS Research Scotland Research Fellowship; DW Honoraria (speaking) from Bayer 2016, 2017, 2018 (talks or debates on ICH, atrial fibrillation, dementia); Honoraria (chairing) from Portola and Bayer (2019); Consultancy fees from Bayer (2017; embolic stroke of undetermined source), Alnylam (2019; CAA), Portola (2019, 2020; andexanet alpha); RM has received BP monitoring equipment for research from Omron and is working with them to develop a telemonitoring system. All fees for this work are paid to his institution., (© European Stroke Organisation 2020.)

It is unknown whether relations between early-life factors and overall health in later life apply to burden of cerebral small vessel disease (cSVD), a major cause of stroke and dementia. We explored relations between early-life factors and cSVD in the Lothian Birth Cohort, a healthy aging cohort. Participants were recruited at age 70 (N = 1091); most had completed a test of cognitive ability at age 11 as part of the Scottish Mental Survey of 1947. Of those, 700 participants had brain MRI that could be rated for cSVD conducted at age 73. Presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all MRI cSVD features. We tested associations with early-life factors using multivariate logistic regression. Greater SVD score was significantly associated with lower age-11 IQ (OR higher SVD score per SD age-11 IQ = .78, 95%CI 0.65-.95, p=.01). The associations between SVD score and own job class (OR higher job class, .64 95%CI .43-.95, p=.03), age-11 deprivation index (OR per point deprivation score, 1.08, 95%CI 1.00-1.17, p=.04), and education (OR some qualifying education, .60 95%CI .37-.98, p=.04) trended towards significance (p<.05 for all) but did not meet thresholds for multiple testing. No early-life factor was significantly associated with any one individual score component. Early-life factors may contribute to age-73 burden of cSVD. These relations, and the potential for early social interventions to improve brain health, deserve further study., Competing Interests: The authors declare ni conflicts of interest.

Background: Methylation is an inactivation mechanism for tumor suppressor genes, that can have important clinical implications., Aim: To analyze the methylation status of 11 tumor suppressor genes in pathological samples of diffuse gastric cancer., Material and Methods: Eighty three patients with diffuse gastric cancer with information about survival and infection with Epstein Barr virus, were studied. DNA was extracted from pathological slides and the methylation status of genes p14, p15, p16, APC, p73, FHIT, E-cadherin, SEMA3B, BRCA-1, MINT-2 y MGMT, was studied using sodium bisulphite modification and polymerase chain reaction. Results were grouped according to the methylation index or Hierarchical clustering (TIGR MultiExperiment Viewer)., Results: Three genes had a high frequency of methylation (FHIT, BRCA1, APC), four had an intermediate frequency (p15, MGMT, p14, MINT2) and four had a low frequency (p16, p73, E-cadherin, SEMA3B). The methylation index had no association with clinical or pathological features of tumors or patients survival. Hierarchical clustering generated two clusters. One grouped clinical and pathological features with FHIT, BRCA1, and APC and the other grouped the other eight genes and Epstein Barr virus infection. Two significant associations were found, between APC and survival and p16/p14 and Epstein Barr virus infection., Conclusions: Hierarchical clustering is a tool that identifies associations between clinical and pathological features of tumors and methylation of tumor suppressor genes.