Age, anticoagulants, hypertension and cardiovascular genetic traits predict cranial ischaemic complications in patients with giant cell arteritis

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.Objectives: This project aimed to determine whether cranial ischaemic complications at the presentation of giant cell arteritis (GCA) were associated with pre-existing cardiovascular (CV) risk factors, CV disease or genetic risk of CV-related traits. Methods: 1946 GCA patients with clinicodemographic data at GCA presentation were included. Associations between pre-existing CV-related traits (including Polygenic Risk Scores (PRS) for CV traits) and cranial ischaemic complications were tested. A model for cranial ischaemic complications was optimised using an elastic net approach. Positional gene mapping of associated PRS was performed to improve biological understanding. Results: In a sample of 1946 GCA patients (median age=71, 68.7% female), 17% had cranial ischaemic complications at presentation. In univariable analyses, 10 variables were associated with complications (likelihood-ratio test p≤0.05). In multivariable analysis, the two variables with the strongest effects, with or without PRS in the model, were anticoagulant therapy (adjusted OR (95% CI)=0.21 (0.05 to 0.62), p=4.95 710-3) and age (adjusted OR (95% CI)=1.60 (0.73 to 3.66), p=2.52 710-3, for ≥80 years versus <60 years). In sensitivity analyses omitting anticoagulant therapy from multivariable analysis, age and hypertension were associated with cranial ischaemic complications at presentation (hypertension: adjusted OR (95% CI)=1.35 (1.03 to 1.75), p=0.03). Positional gene mapping of an associated transient ischaemic attack PRS identified TEK, CD96 and MROH9 loci. Conclusion: Age and hypertension were risk factors for cranial ischaemic complications at GCA presentation, but in this dataset, anticoagulation appeared protective. Positional gene mapping suggested a role for immune and coagulation-related pathways in the pathogenesis of complications. Further studies are needed before implementation in clinical practice

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Background: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. Methods: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. Findings: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13). Interpretation: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. Funding: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Researc

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Complementary perspectives as a means of understanding regional change: frontier settlement in the Ecuador Amazon

Illustrated in this paper is a research protocol wherein regional change in the Ecuador Amazon, measured in terms of changing settlement patterns, is explored from three distinct but complementary vantage points -- idiographic, context-dependent generalizations, and universally applicable frameworks. All analyses are anchored to the study area itself; the region's ground-level reality plays a prominent role throughout; and the Amazon as a place is the object of study. The more universal the explanation, the less information it provides about the Ecuador Amazon per se; but each conceptualization illuminates a distinct aspect of the Amazon experience. A comprehensive understanding is the end result. The research protocol is situated within current concerns over place, the new regional geography, and related research strategies.

Simulation of multi-fracturing rock media including fluid/structure coupling

The objective of the paper is to present the essential issues related to an effective computational implementation of a continuum/discontinuum formulation of rock masses under various loading conditions, including fluid interaction for two classes of problems; fluid flow through fracturing rock masses and rock blasting. The applicability of the methodology developed is illustrated through practical examples related to borehole breakout phenomena, hydraulic fracturing and the simulation of rock blasting operations

Resilience and green spaces: association with stress among contact centre agents in the Philippines

ABSTRACTThe work environment in Philippine contact centres had been shown to expose employees to factors that contribute to work-related stress; health promotion strategies that could mitigate the impacts are needed. With the framework that stress is experienced as a result of the interactions of an individual with the environment, this study examined the relationship of stress with individual resilience and the presence of urban green spaces (UGS) in the environment. The study involved employees (N = 186) from six contact centres in the capital region of the Philippines, where a large number of contact centre service providers are located. A two-stage survey was administered online using standardised instruments to measure stress (10-item Perceived Stress Scale) and resilience (Connor-Davidson Resilience Scale), customised questions to gather demographic information, and open-ended questions to probe on participants’ insights. Google Earth Pro was used to conduct satellite mapping of UGS, followed by on-site ocular inspection. This study revealed that participants’ average stress level was categorised as high. The percentages of UGS in the vicinity of the study sites were categorised as low. Linear regression revealed that amongst individual and environment factors, resilience, household income, and awareness of UGS in the vicinity were significant predictors of the participants’ stress levels. Health promotion in Philippine contact centres could consider strategies that include resilience building, enhancing income security, and promoting the awareness of UGS within the workplace vicinity.</jats:p

Actividad física mujer y deporte

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Resilience and Green Spaces: Association with Stress among Contact Centre Workers in the Philippines

Issue Addressed Philippine contact centres are rife with factors that contribute to work-related stress; health promotion strategies are needed to mitigate the impacts. With a transactional framework with the environment, this study examined the relationship of stress with resilience and the presence of urban green spaces (UGS) in the environment, while accounting for individual characteristics (ie, age, household income, exercise frequency). Methods: Participants include employees (Stage 1 N = 186; Stage 2 N = 89) from six contact centres in the capital region of the Philippines. A two-stage online survey included standardised instruments to measure stress (10-item Perceived Stress Scale) and resilience (Connor-Davidson Resilience Scale), customised questions to gather demographic information and probe on participants\u27 insights. Google Earth Pro was used for satellite mapping of UGS, followed by on-site ocular inspection. Results Participants\u27 average stress level was categorised as high; primary stressors included client demands and workload. The objectively measured percentages of UGS in the study sites\u27 vicinity were categorised as low. Participants found UGS visible after careful observation, and majority were aware of UGS in their workplace vicinity. Resilience, household income and awareness of UGS in the vicinity significantly predicted stress levels. Conclusion Contact centre workers experienced high stress levels and their workplaces had little accessible UGS. Resilience, household income and awareness of UGS are significant contributors to stress levels. So What? Health promotion in Philippine contact centres could consider strategies that include building resilience, enhancing income security and promoting the awareness of UGS within the workplace vicinity