Do current methods of measuring the impact of chronic pain on work reflect the experience of working-age adults? : An integrated mixed methods systematic narrative review

The authors would like to acknowledge contributions to the QUICK study by members of the study advisory group: Patrice Forget, Siladitya Bhattacharya, Peter Goadsby, Cathy Price, David Coggon, Maureen McAllister, Stephen Bevan. The work presented in this manuscript was funded by the Medical Research Council (grant MR/V020676/1).Peer reviewe

Contribution of type 2 diabetes to all-cause mortality, cardiovascular disease incidence and cancer incidence in white Europeans and South Asians: findings from the UK Biobank population-based cohort study

Objective: To investigate whether the health implications of having type 2 diabetes (T2D) were different in South Asian compared with white European participants. Research design and methods: Prospective data from UK Biobank were used, and 457 935 participants of white European and 7102 of South Asian background were included. Cox proportional regression was performed to investigate the association between T2D and health outcome by ethnicity. Results: Over a mean of 7.0 years (IQR 6.3–7.6) of follow-up, 12 974 participants had died, and 30 347 and 27 159 developed cardiovascular disease (CVD) and cancer, respectively. South Asians had a higher risk for CVD mortality (HR: 1.42, 95% CI 1.07 to 1.89) and incidence (HR: 1.78, 95% CI 1.63 to 1.94), but a decreased risk for cancer mortality (HR: 0.59, 95% CI 0.41 to 0.85) and incidence (HR: 0.80, 95% CI 0.70 to 0.92) compared with white Europeans. Compared with individuals without T2D, both white Europeans and South Asians with T2D had a higher risk for all-cause mortality (1.59 (1.48 to 1.71) vs 2.83 (1.76 to 4.53)), CVD mortality (2.04 (1.82 to 2.28) vs 4.40 (2.37 to 8.16)) and CVD incidence (1.37 (1.31 to 1.44) vs 1.60 (1.31 to 1.95)), respectively. However, the magnitude of the risk was higher for South Asians than white Europeans. Conclusions: Although T2D was associated with a higher risk for all-cause mortality and CVD incidence and mortality, in both white Europeans and South Asians, the risk experienced by South Asians with T2D was higher than their white European counterparts

The Active Brains Digital Intervention to Reduce Cognitive Decline in Older Adults: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Increasing physical activity, improving diet, and performing brain training exercises are associated with reduced cognitive decline in older adults. OBJECTIVE: In this paper, we describe a feasibility trial of the Active Brains intervention, a web-based digital intervention developed to support older adults to make these 3 healthy behavior changes associated with improved cognitive health. The Active Brains trial is a randomized feasibility trial that will test how accessible, acceptable, and feasible the Active Brains intervention is and the effectiveness of the study procedures that we intend to use in the larger, main trial. METHODS: In the randomized controlled trial (RCT), we use a parallel design. We will be conducting the intervention with 2 populations recruited through GP practices (family practices) in England from 2018 to 2019: older adults with signs of cognitive decline and older adults without any cognitive decline. Trial participants were randomly allocated to 1 of 3 study groups: usual care, the Active Brains intervention, or the Active Brains website plus brief support from a trained coach (over the phone or by email). The main outcomes are performance on cognitive tasks, quality of life (using EuroQol-5D 5 level), Instrumental Activities of Daily Living, and diagnoses of dementia. Secondary outcomes (including depression, enablement, and health care costs) and process measures (including qualitative interviews with participants and supporters) will also be collected. The trial has been approved by the National Health Service Research Ethics Committee (reference 17/SC/0463). RESULTS: Results will be published in peer-reviewed journals, presented at conferences, and shared at public engagement events. Data collection was completed in May 2020, and the results will be reported in 2021. CONCLUSIONS: The findings of this study will help us to identify and make important changes to the website, the support received, or the study procedures before we progress to our main randomized phase III trial. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number 23758980; http://www.isrctn.com/ISRCTN23758980. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18929

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency:A Prospective Study of Dual-release Hydrocortisone Therapy

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo.Study Design and Methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls.Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue.Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC

Review of Alternatives to Incarceration Efforts Worldwide

Despite global interest in treating substance use disorders as a health issue, many countries choose a criminal justice response instead. The goal of this project was to research the readiness of countries to establish or expand alternatives to incarceration (ATIs) for persons with substance use disorders (SUDs) in countries around the globe. This report gathers, compiles and analyzes information on alternatives to incarceration for persons involved in the criminal justice with substance use disorders, worldwide (193 UN Member States plus Greenland, Kosovo, Palestine and Taiwan). As such, this report presents the first attempt to compile this information globally and completely. A video of the webinar meeting with the presentation of results is available at: https://www.youtube.com/watch?v=p3_h6hMOvTc

The Limits of Responsible Innovation: Exploring Care, Vulnerability and Precision Medicine

Drawing on insights from feminist and Science and Technology Studies writing on care and vulnerability, this paper will critically explore conceptualisations of responsibility, care and vulnerability in relation to contemporary approaches to Responsible Innovation (RI). Drawing on examples of some of the social and ethical challenges of precision medicine, we highlight the on-going, distributed and complex nature of innovation and responsibilities in relation to markets, patient and carer experience and data practices associated with these new technologies to highlight some of the limits of RI. We end by reflecting on the implications of our analysis for the social and ethical challenges of precision medicine and RI more generally

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy