Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Addressing Risk in Conditions of Uncertainty Ignorance and Partial Knowledge

Recommendations from the 2016 Theo Murphy High Flyers Think Tank: An Interdisciplinary approach to living in a complex worl

Hematopoietic Stem/Progenitor Cell Proliferation and Differentiation Is Differentially Regulated by High-Density and Low-Density Lipoproteins in Mice

<div><h3>Rationale</h3><p>Hematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.</p> <h3>Objectives</h3><p>We hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.</p> <h3>Methods and Results</h3><p>HSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr^−/−) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G₂M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr^−/− mice. When BM Lin-Sca-1+cKit+ (i.e. “LSK”) cells were cultured in the presence of LDL <em>in vitro</em> we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin−) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM <em>in vivo</em>. HDL also reversed the LDL-induced monocyte and granulocyte differentiation <em>in vitro</em>.</p> <h3>Conclusion</h3><p>Our data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.</p> </div

Welfare analysis of changing food prices: a nonparametric examination of rice policies in India

The paper examines the welfare impact of the Indian government’s rice price policies in the light of the global food crisis of 2007–08 using a nonparametric approach for regression and density estimation. In particular, the impact of a ban on export of rice and increased farm gate price support for farmers, implemented to keep domestic consumer prices lower and producer prices higher than they would otherwise have been, was analysed. The net impact of the export ban was positive, as it was able to cushion the Indian population (84 % of whom are net consumers of rice) from the adverse effects of the crisis. However, the extent of welfare varied among different household types, as the poor in India are heterogeneous in nature. Thus agriculture-price policies do not have a homogenous effect on the poor in India. The majority of rice-producing farmers are relatively poor but benefitted from the increase in farm gate prices. Poor households that did not cultivate rice were the worst affected in the food crisis, as their budget share of rice is higher than that of rich households

LDL increased myeloid cell production in vitro.

<p>Sorted LSK cells of C57BL/6 mice were seeded at 1000 cells per well in 96-well plate and cultured in SFEM supplemented with IL-3, IL-6 and SCF for 14 days. LDL or LDL plus HDL were added as indicated. GM-CSF was used as the positive control. Total cells and cells with morphological features of differentiated cells were enumerated under the microscopy. (A) Data were expressed as the percentage of undifferentiated cells in total cells. Cells were stained with antibodies against CD11b PE and Ly-6c PE-Cy7 (B), CD11b PE and F4/80 APC-Cy7 (C), and CD11b PE and Ly-6G APC (D) for FACS analysis.</p

Hypercholesterolemia promotes leukocytosis in peripheral blood of LDLr^−/− mice.

<p>Hypercholesterolemic LDLr^−/− mice were used to study the effect of LDL on HSPC. At the age of 8 weeks, mice were placed either on normal diet or on high fat diet for 2 months. Two months after normal or high fat diet, blood cells of LDLr^−/− mice were stained with antibodies against Ly-6c, F4/80, Ly-6G and CD11b. The percentage of Ly-6c^hi monocytes (A), F4/80+ monocytes (B) and Ly-6G^hi granulocytes (C) was quantified by FACS.</p