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Stroke risk management in carotid atherosclerotic disease: a clinical consensus statement of the ESC Council on Stroke and the ESC Working Group on Aorta and Peripheral Vascular Diseases.
Carotid atherosclerotic disease continues to be an important cause of stroke, often disabling or fatal. Such strokes could be largely prevented through optimal medical therapy and carotid revascularization. Advancements in discovery research and imaging along with evidence from recent pharmacology and interventional clinical trials and registries and the progress in acute stroke management have markedly expanded the knowledge base for clinical decisions in carotid stenosis. Nevertheless, there is variability in carotid-related stroke prevention and management strategies across medical specialities. Optimal patient care can be achieved by (i) establishing a unified knowledge foundation and (ii) fostering multi-specialty collaborative guidelines. The emergent Neuro-Vascular Team concept, mirroring the multi-disciplinary Heart Team, embraces diverse specializations, tailors personalized, stratified medicine approaches to individual patient needs, and integrates innovative imaging and risk-assessment biomarkers. Proposed approach integrates collaboration of multiple specialists central to carotid artery stenosis management such as neurology, stroke medicine, cardiology, angiology, ophthalmology, vascular surgery, endovascular interventions, neuroradiology, and neurosurgery. Moreover, patient education regarding current treatment options, their risks and advantages, is pivotal, promoting patient's active role in clinical care decisions. This enables optimization of interventions ranging from lifestyle modification, carotid revascularization by stenting or endarterectomy, as well as pharmacological management including statins, novel lipid-lowering and antithrombotic strategies, and targeting inflammation and vascular dysfunction. This consensus document provides a harmonized multi-specialty approach to multi-morbidity prevention in carotid stenosis patients, based on comprehensive knowledge review, pinpointing research gaps in an evidence-based medicine approach. It aims to be a foundational tool for inter-disciplinary collaboration and prioritized patient-centric decision-making.
Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort.
PURPOSE: Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS: The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS: Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS: Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
Editor's Choice - Effect of Carotid Endarterectomy on 20 Year Incidence of Recorded Dementia: A Randomised Trial.
OBJECTIVE: Stroke and carotid atherosclerosis are associated with dementia. Carotid endarterectomy (CEA) reduces stroke risk, although its effect on later dementia is uncertain. Participants in the Asymptomatic Carotid Surgery Trial (ACST-1), randomly allocated to immediate vs. deferral of CEA (i.e., no intervention unless or until triggered by ipsilateral transient ischaemic attack or stroke), were followed, to study effects on dementia. METHODS: From 1993 to 2003, ACST-1 included 3 120 participants with asymptomatic tight carotid stenosis. All UK and Swedish patients (n = 1 601; 796 immediate vs. 805 deferral) were followed with trial records, national electronic health record linkage, and (UK only) by post and telephone. Cumulative incidence and competing risk analyses were used to measure the effects of risk factors and CEA on dementia risk. Intention to treat analyses yielded hazard ratios (HRs; immediate vs. deferral) of dementia. RESULTS: The median follow up was 19.4 years (interquartile range 16.9 - 21.7). Dementia was recorded in 107 immediate CEA patients and 115 allocated delayed surgery; 1 290 patients died (1 091 [538 vs. 536] before any dementia diagnosis). Dementia incidence rose with age and with female sex (men: 8.3% aged < 70 years at trial entry vs. 15.1% aged ≥ 70; women: 15.1% aged < 70 years at trial entry vs. 22.4% aged ≥ 70 years) and was higher in those with pre-existing cerebral infarction (silent or with prior symptoms; 20.2% vs. 13.6%). Dementia risk was similar in both randomised groups: 6.7% vs. 6.6% at 10 years and 14.3% vs. 15.5% at 20 years, respectively. The dementia HR was 0.98 (95% confidence interval [CI] 0.75 - 1.28; p = .89), with no heterogeneity in the neutral effect of immediate CEA on dementia related to age, carotid stenosis, blood pressure, diabetes, country of residence, or medical treatments at trial entry (heterogeneity values p > .05). CONCLUSION: CEA was not associated with significant reductions in the long term hazards of dementia, but the CI did not exclude a proportional benefit or hazard of about 25%.
MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy
The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.
Translational genomics of osteoarthritis in 1,962,069 individuals.
Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.
Association of Breakfast Consumption Frequency with Depression and Anxiety Symptoms Among School Students: A Cross-Sectional Study in Eastern China.
Objective: This study aimed to explore the relationship between breakfast consumption frequency and both depression and anxiety symptoms among middle and high school students in Eastern China. Methods: In this school-based cross-sectional study, 27,001 middle and high school students were investigated in 2022. Multivariable logistic regression models were used to examine the relationship between breakfast consumption frequency and both depression and anxiety symptoms. Results: The percentages of students who consumed breakfast daily, 6 days/week, 4-5 days/week, and ≤3 days/week were 71.0% (95%CI: 69.9-72.2), 8.3% (95%CI: 7.8-8.6), 11.9% (95%CI: 11.2-12.6), and 8.8% (95%CI: 8.2-9.5), respectively. After adjusting for socio-demographic and lifestyle factors, academic performance, self-reported health, and bullying victimization, compared to those consuming breakfast daily, the odds ratios (95%CI) for depression symptoms were 1.32 (1.15-1.52) for those consuming breakfast 6 days/week, 1.66 (1.49-1.84) for those consuming breakfast 4-5 days/week, and 1.74 (1.54-1.97) for those consuming breakfast ≤3 days/week, respectively (p < 0.001). The corresponding figures for anxiety symptoms were 1.31 (1.14-1.51), 1.35 (1.20-1.52), and 1.43 (1.23-1.66), respectively (p < 0.001). Conclusions: Breakfast skipping is common among middle and high school students in Eastern China. The frequency of breakfast consumption is inversely associated with both depression symptoms and anxiety symptoms among adolescents.
The modernized classification of cardiac anti-arrhythmic drugs: its application to clinical practice.
Cardiac arrhythmias pose a major public health problem and pharmacological intervention remains key to their therapy. The landmark Vaughan Williams (VW, 1970) classification utilizing known actions of then available anti-arrhythmic drugs (AADs) became and remains central to management, but requires revision in response to extensive subsequent advances. Our modernized antiarrhythmic drug (AAD) classification reflected and sought to facilitate such fundamental physiological and clinical development. We here respond to requests for an adaptation of our scheme specifically focussed at clinical practice. This adaptation: (1) improves accessibility of our original scheme to clinical practice, focussing on key AADs in clinical use rather than investigational new drugs (INDs) whilst still conserving and encompassing the classic VW scheme. We nevertheless (2) preserve a rational conceptual framework based on current understanding of the relevant electrophysiological events, their underlying cellular or molecular cardiomyocyte targets and the functional mechanisms they mediate. Additionally, (3) the adopted subclasses within each AAD class parallel clinical practice in including only subclasses containing established AADs, or approved potential off-label drugs, as opposed to those only including INDs. Finally, (4) the simplified scheme remains flexible, permitting drugs to be placed in multiple classes where required, and the future addition of classes and subclasses in the light of future investigations and clinical approvals. We thus derive from our comprehensive modernized AAD classification a more focussed and simpler scheme, for clinical use. This both modernizes but preserves the classic Vaughan Williams classification, and remains flexible accommodating for future developments.
Molecular basis for the phosphorylation of bacterial tyrosine kinase Wzc.
The regulation of polymerisation and translocation of biomolecules is fundamental. Wzc, an integral cytoplasmic membrane tyrosine autokinase protein serves as the master regulator of the biosynthesis and export of many bacterial capsular polysaccharides and exopolysaccharides. Such polysaccharides play essential roles in infection, defence, and some are important industrial products. Wzc comprises a large periplasmic domain, two transmembrane helices and a C-terminal cytoplasmic kinase domain with a tyrosine-rich tail. Wzc regulates polymerisation functions through cycling the formation and dissociation of an octameric complex, driven by changes in the phosphorylation status of the tyrosine-rich tail. E. coli Wzc serves a model for a wider family of polysaccharide co-polymerases. Here, we determine structures of intermediate states with different extents of phosphorylation. Structural and computational data reveal the pre-ordering of the tyrosine-rich tail, the molecular basis underlying the unidirectionality of phosphorylation events, and the underlying structural dynamics on how phosphorylation status is transmitted.
Amount and intensity of daily total physical activity, step count and risk of incident cancer in the UK Biobank.
OBJECTIVES: To investigate associations between daily physical activity, activity intensity and step counts with incident cancer risk. METHODS: Prospective analysis of UK Biobank participants who wore wrist-based accelerometers for 7 days, followed for cancer incidence (mean follow-up 5.8 years, SD 1.3). Time-series machine-learning models derived total physical activity, sedentary behaviour (SB), light-intensity physical activity (LIPA), moderate-vigorous-intensity physical activity (MVPA) and step counts. The outcome was a composite of 13 cancers previously associated with low physical activity in questionnaire-based studies. Cox proportional hazard models estimated HRs and 95% CIs, adjusted for demographic, health and lifestyle factors. We also explored associations of LIPA, MVPA and SB with cancer risk. RESULTS: Among 85 394 participants (median age 63 (IQR 56-68)), 2633 were diagnosed with cancer during follow-up. Compared with individuals in the lowest quintile of total physical activity (<21.6 milligravity units), those in the highest (34.3+) had a 26% lower cancer risk (HR=0.74 (95% CI 0.65 to 0.84)). After mutual adjustment, LIPA (HR=0.94 (95% CI 0.90 to 0.98)) and MVPA (HR=0.87 (95% CI 0.79 to 0.94)) were associated with lower risk, but SB was not. Similar associations were observed for substituting 1 hour/day of SB with LIPA or MVPA. Daily step counts were inversely associated with cancer, with the dose-response beginning to plateau at around 9 000 steps/day (HR=0.89 (95% CI 0.83 to 0.96) 7000 vs 5000 steps; HR=0.84 (95% CI 0.76 to 0.93) 9000 vs 5000 steps). There was no significant association between stepping intensity (peak 30-minute cadence) and cancer after adjusting for step count. CONCLUSION: Total physical activity, LIPA, MVPA and step counts were inversely associated with incident cancer.