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Background Contested evidence suggests that obesity confers no risk to health in people who have a healthy lifestyle, particularly if there are no metabolic complications of obesity. The aim was to examine the association between adherence to lifestyle recommendations and the absence of metabolic complications on the incident or fatal cardiovascular disease and all-cause mortality across different categories of body mass index (BMI). Methods This contemporary prospective cohort study included 339,902 adults without cardiovascular disease at baseline, recruited between 2006 and 2010 from the UK Biobank and followed until 2018–2020. The main exposures were four healthy lifestyle behaviours: never smoker, alcohol intake ≤ 112g/ week, 150 min moderate physical activity or 75 min vigorous activity/week, ≥ 5 servings of fruit or vegetables/day, and we assessed these overall and across the BMI groups. Metabolic complications of excess adiposity were hypertension, diabetes and hyperlipidaemia, and we examined whether obesity was associated with increased risk in the absence of these complications. The outcomes were all-cause mortality, death from, and incident cardiovascular disease (CVD). Results Individuals who met four lifestyle recommendations but had excess weight had higher all-cause mortality; for BMI 30–34.9 kg/m 2 , the hazard ratio (HR) was 1.42 (95% confidence interval 1.20 to 1.68), and for BMI ≥ 35 kg/m 2 , HR was 2.17 (95% CI 1.71 to 2.76). The risk was lower, but still increased for people with no metabolic complications; for all-cause mortality, BMI 30–34.9 kg/m 2 had an HR of 1.09 (95% CI 0.99 to 1.21), and BMI ≥ 35 kg/m 2 had an HR of 1.44 (95% CI 1.19 to 1.74) for all-cause mortality. Similar patterns were found for incident and fatal CVD. Conclusions Meeting healthy lifestyle recommendations, or the absence of metabolic complications of obesity offsets some, but not all, of the risk of subsequent CVD, and premature mortality in people with overweight or obesity. Offering support to achieve and maintain a healthy weight and to adopt healthy behaviours are likely to be important components in effective preventative healthcare.

Background Action on smoking, obesity, excess alcohol, and physical inactivity in primary care is effective and cost-effective, but implementation is low. The aim was to examine the effectiveness of strategies to increase the implementation of preventive healthcare in primary care. Methods CINAHL, CENTRAL, The Cochrane Database of Systematic Reviews, Dissertations & Theses – Global, Embase, Europe PMC, MEDLINE and PsycINFO were searched from inception through 5 October 2023 with no date of publication or language limits. Randomised trials, non-randomised trials, controlled before-after studies and interrupted time series studies comparing implementation strategies (team changes; changes to the electronic patient registry; facilitated relay of information; continuous quality improvement; clinician education; clinical reminders; financial incentives or multicomponent interventions) to usual care were included. Two reviewers screened studies, extracted data, and assessed bias with an adapted Cochrane risk of bias tool for Effective Practice and Organisation of Care reviews. Meta-analysis was conducted with random-effects models. Narrative synthesis was conducted where meta-analysis was not possible. Outcome measures included process and behavioural outcomes at the closest point to 12 months for each implementation strategy. Results Eighty-five studies were included comprising of 4,210,946 participants from 3713 clusters in 71 cluster trials, 6748 participants in 5 randomised trials, 5,966,552 participants in 8 interrupted time series, and 176,061 participants in 1 controlled before after study. There was evidence that clinical reminders (OR 3.46; 95% CI 1.72–6.96; I 2  = 89.4%), clinician education (OR 1.89; 95% CI 1.46–2.46; I 2  = 80.6%), facilitated relay of information (OR 1.95, 95% CI 1.10–3.46, I 2  = 88.2%), and multicomponent interventions (OR 3.10; 95% CI 1.60–5.99, I 2  = 96.1%) increased processes of care. Multicomponent intervention results were robust to sensitivity analysis. There was no evidence that other implementation strategies affected processes of care or that any of the implementation strategies improved behavioural outcomes. No studies reported on interventions specifically designed for remote consultations. Limitations included high statistical heterogeneity and many studies did not account for clustering. Conclusions Multicomponent interventions may be the most effective implementation strategy. There was no evidence that implementation interventions improved behavioural outcomes. Trial registration PROSPERO CRD42022350912.

Agora (https://agora.adknowledgeportal.org) is an openly available web application developed to enable a broad spectrum of Alzheimer's disease (AD) researchers access to the target-based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora accelerates AD research and maximizes therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence. Agora enables sharing information about potential AD therapeutic targets by surfacing data visualizations, aggregating summary evidence, and displaying results from targeted validation studies. Agora users can browse a list of over 950 potential therapeutic targets that have been nominated by the NIA's Accelerating Medicines Partnership in AD (AMP-AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome-wide analyses of high-dimensional human transcriptomic, proteomic, and metabolomic data; use interactive tools designed to enable non-bioinformaticians to evaluate and compare complex multi-omic data; leverage results that objectively rank and organize targets based on their role in AD; investigate the experimental reagents and bioinformatics packages that are available to support further investigation of select targets; and access the underlying data that drives the results and visualizations presented in the application. Agora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) new TREAT-AD target nominations and 2) enhanced connections to external resources, including the introduction of a new drug development resource section and UniprotKB integration. Advancing potential AD therapeutics through the drug development pipeline requires efforts from research groups and specialties spanning both academia and industry. Agora enables the AD research community to unite by enabling the development and sharing of target hypotheses to accelerate the investigation of promising new AD therapeutic targets, pathways and mechanisms.

To identify disease-modifying therapies and drug targets for Alzheimer's disease (AD), it is necessary to assess the impact of cellular and molecular dysfunction on disease aetiology. The AD Knowledge Portal (Portal) (https://adknowledgeportal.org), Exceptional Longevity Portal (ELITE) and Agora (https://agora.adknowledgeportal.org) are community-driven resources that support researchers as they: 1) identify new molecular hypotheses and mechanisms, 2) evaluate hypotheses via independent experimental assessments, and 3) prioritise new molecular mechanisms for therapeutic development. The Portals and Agora are free, open-access tools built to maximise therapeutic discovery by enabling researchers to re-use data from 41,000+ biospecimens collected from 12,000+ individuals across four species and browse or access analytical results related to putative drug targets. The Portals and Agora empower the research community with a trusted repository of data, computational and experimental tools and potential gene targets to test target hypotheses and therapeutics. The portals are also integrated with external Trusted Research Environments (TREs) like CAVATICA and integrate the portals with Terra and AD Workbench. The Portal supports research outputs from 55 grants (including the Accelerating Medicines Partnership-Alzheimer's Disease), each generating data and computational/experimental tools related to dementia and ageing. Utilizing samples from brain banks, longitudinal cohorts, and model systems, available data spans 55+ assays, including genomics, metabolomics, imaging, cognitive assessments, and more. Model systems in the Portal include iPSC-derived cell types and organoids and novel Late-Onset AD mouse models based on gene targets identified from human data. These mouse models are available with no limitation on use. The Portal also features a cloud-based analytical workspace providing access to preconfigured computational resources to process, integrate, and analyse data. A subset of the processed data is also presented in Agora, a visual results explorer that compiles evidence of genes' association with AD. Agora hosts a list of nominated targets and presents the results of omics analyses generated from Portal data. It also includes a catalogue of details and results from targeted validation studies. The AD Knowledge Portal, the ELITE Portal and Agora offer the research community an accessible, rich data source, tools, and results.

Since the 1980s, activist archaeologists have used quantitative studies of journal authorship to show that the demographics of archaeological knowledge production are homogeneous. This literature, however, focuses almost exclusively on the gender of archaeologists, without deeply engaging with other forms of identity or adequately addressing the methodological limitations of assigning binary gender identifications based on first names. This paper rectifies these limitations through an intersectional study of inequities in academic archaeological publications by presenting the results of a survey of authors who published in 21 archaeology journals over a 10-year period (2007–2016). This survey asked them to provide their self-identifications in terms of gender, race/ethnicity, and sexual orientation. The results demonstrate that although there has been an influx of women archaeologists in recent decades, we have not yet reached gender parity. They also show that because many women archaeologists are cisgender, white, and heterosexual, the discipline's knowledge producers remain relatively homogeneous. Furthermore, although there is demographic variation between journals, there is a strong correlation between journal prestige and the percentage of authors who are straight, white, cisgender men. This intersectional study of journal authorship demographics provides a comprehensive perspective on issues of diversity, equity, and inclusion in the discipline of archaeology.

The temporal molecular changes that lead to disease onset and progression in Alzheimer’s disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage–or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P  = 1.0 × 10 −5 ), Aβ (CERAD score, P  = 1.8 × 10 −5 ), and cognitive diagnosis ( P  = 3.5 × 10 −7 ) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data. The limited understanding of the temporal molecular changes in late-onset Alzheimer’s disease hinder the development of therapeutic treatment. The authors use manifold learning to develop a molecular model for disease progression from RNASeq data from human postmortem brain samples.

The increasing requirement to harmonize multiomic datasets and apply interpretable biological mappings onto large scale analysis prompted us to incorporate the 19 Alzheimer's Disease (AD) Biological Domains into the Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) bioinformatics pipeline. To further refine the specific biology implicated within each domain, we have broken the biological domains into a set of Alzheimer's associated subdomains for more meaningful mapping of large datasets onto disease enriched biology. There are two fundamental components to the TREAT-AD bioinformatics pipeline: 1) the genome-wide application of a gene-centric risk score drawn from multiomic assessments; 2) the application of the risk score to drive enrichment into the endophenotypic and sub-endophenotypic areas of disease associated biology. The latter part is performed in two steps, in which first the 19 biological domains are defined by an exhaustive set of Gene Ontology (GO) terms. Second, kappa-networks are constructed from (a) the leading-edge disease associated genes and (b) from the enriched GO terms. Within both network systems, the nodes represent the GO terms and the edges represent the conserved annotation of a set of genes between GO terms. This approach allows us to map \"families\" of biological processes that are linked to disease. Through filtration of the kappa-value, the networks are deconstructed into subnetworks that represent subdomains, or subendophenotypes, associated with disease risk. Employing the top-down (GO-term driven) and the bottom-up (leading-edge gene driven) methods of kappa-network construction and subsequent fragmentation, we find a core set of biological subdomains associated with AD. Collectively, 115 subdomains are identified that are more specifically aligned with disease-linked biology. For example, within mitochondrial metabolism (a leading downregulated domain) we observe electron transport chain (ETC) and tricarboxylic acid cycle (TCA cycle) as two of the 11 emergent subdomains. The AD Biological Domains and subdomain development will facilitate future alignment of multiomic datasets onto a common open-source, open-science platform for integrative analysis and hypothesis generation. Data-driven standards for hypothesis generation may speed up the development of new therapeutic directions and drug target selection, opening new objective methods for translational advancement in AD.

The AD Knowledge Portal (https://adknowledgeportal.org) is a National Institute on Aging (NIA) sponsored resource for Alzheimer's Disease data and other research tools. The AD Portal allows researchers to share human and non-human data with appropriate attribution for reuse, and in compliance with necessary data governance and ethical guardrails. This is accomplished through the use of the secure Synapse data sharing platform and a user-friendly data portal website. The AD Portal hosts resources from 14 NIH-funded research programs and 97 grants related to dementia and aging, including ∼800TB of data from over 11,000 individuals. This diverse collection includes next-generation sequencing, imaging, and behavioral data from brain banks, longitudinal cohorts, cell lines, and animal model systems. A decade after its inception, the Portal remains an important resource for contemporary AD research, as demonstrated by the ∼290TB of multimodal single-cell omics data currently available. Users can also explore experimental mouse and marmoset models, publications, and summarized evidence for putative AD drug targets via multiple integrated results explorers. Portal data can be combined with external research datasets via interoperability with cloud-based analysis platforms including CAVATICA and Terra (in development). These integrations provide users with an alternative to direct download and enable data reuse. In total, 12.57 PB of data from the Portal has been downloaded by more than 6,000 unique users since January 2022. Average downloads (TB/month) increased by 79% year-over-year between 2022 and 2023 and doubled between 2023 and 2024. Expansion of available resources and increases in both volume and number of data downloads correlates with a similar increase in data reuse. Portal data has been referenced in over one thousand publications since 2019, with more than half of those publications representing secondary data reuse. The AD Knowledge Portal continues to serve the research community by sharing rich, high-throughput data and other resources that enable novel discoveries in the field of Alzheimer's disease. Upcoming features include interoperability with AD Workbench, NACC, NIAGADS, and LONI and valuable new data types, including spatial transcriptomics and longitudinal molecular and behavioral data from mouse and marmoset models of AD.

The aim was to investigate the impact of a group-based weight management programme on symptoms of depression and anxiety compared with self-help in a randomised controlled trial (RCT). People with overweight (Body Mass Index [BMI]≥28kg/m2) were randomly allocated self-help (n = 211) or a group-based weight management programme for 12 weeks (n = 528) or 52 weeks (n = 528) between 18/10/2012 and 10/02/2014. Symptoms were assessed using the Hospital Anxiety and Depression Scale, at baseline, 3, 12 and 24 months. Linear regression modelling examined changes in Hospital Anxiety and Depression Scale between trial arms. At 3 months, there was a -0.6 point difference (95% confidence interval [CI], -1.1, -0.1) in depression score and -0.1 difference (95% CI, -0.7, 0.4) in anxiety score between group-based weight management programme and self-help. At subsequent time points there was no consistent evidence of a difference in depression or anxiety scores between trial arms. There was no evidence that depression or anxiety worsened at any time point. There was no evidence of harm to depression or anxiety symptoms as a result of attending a group-based weight loss programme. There was a transient reduction in symptoms of depression, but not anxiety, compared to self-help. This effect equates to less than 1 point out of 21 on the Hospital Anxiety and Depression Scale and is not clinically significant.

The current health system aims to cope with the epidemic of chronic pain. The narrative urgently needs to be reset to one that strives for excellence. This reflection illustrates what excellence may look like and also highlights where system biases are preventing positive change from occurring.