Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells

Objective: HMG-CoA reductase inhibitors (statins) possess anti-inflammatory and immunomodulatory properties that are independent of their lipid-lowering action. As the CD40-CD40L signaling pathway is implicated in the modulation of inflammatory responses between vascular cells, involving adhesion molecules, pro-inflammatory cytokines, chemokines, we sought to investigate the potential role of statins in regulating the expression of CD40. Methods and Results: Using Western blot, flow cytometry and immunohistochemistry analyses, we observed that four different statins reduced IFN-γ-induced CD40 expression in human vascular cells (endothelial cells, smooth muscle cells, macrophages and fibroblasts). This effect was dose-dependent (from 5 μM to 80 nM) and reversed by addition of l-mevalonate. Activation of vascular cells by human recombinant CD40L, as measured by ELISA for IL-6, IL-8 and MCP-1, was strongly reduced when cells were treated with statins. Immunostaining of human carotid atherosclerotic lesions of patients subjected to statin treatment revealed less CD40 expression on a ‘per vascular cell' basis compared to control patients. Although many pleiotropic effects of statins are mediated by nitric oxide synthase (NOS)- or peroxisome proliferator-activated receptor (PPAR)-dependent signaling pathways, we observed similar statin-induced reduction of CD40 expression using NOS inhibitors or different PPAR ligands. Conclusion: Statins decrease CD40 expression and CD40-related activation of vascular cells. These effects are partially reversed by the HMG-CoA reductase product l-mevalonate and are mediated by NOS- or PPAR-dependent pathways. Altogether, these findings provide mechanistic insight into the beneficial effects of statins on atherogenesis. They also provide a scientific rationale for the use of statins as immunomodulators after organ transplantatio

Are hemispherical caps of boron-nitride nanotubes possible?

We report all-electron, density-functional calculations with large Gaussian polarization basis set of the recently synthesized octahedral B24N24 cage that is perfectly round by symmetry, and boron-nitride (BN) clusters that its existence might suggest. We consider whether it is energetically possible that the two halves of this round cage could cap the BN nanotubes, modeled by B28N28 and B32N32. The energetics show that BN nanotubes with such round caps, are only slightly less favorable than the BN clusters containing six squares as the only defects in the otherwise perfect hexagonal lattice. A larger B96N96 octahedral cage formed from B24N24 by adding sufficient hexagons to isolate all squares is not very favorable energetically. The squares protrude noticeably from its otherwise round surface.Comment: Uses elsart.cls (Elsevier Science), (Better pictures can be obtained from authors); Manuscript to appear in Chemical Physics Letter

Low alanine aminotransferase and higher cardiovascular events in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes and associated with higher risk of cardiovascular disease. This study aimed to determine whether alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT), as markers of liver health and NAFLD, might predict cardiovascular events in this population. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (nonfatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years. Results ALT had a linear inverse relationship with the first cardiovascular event on study. After adjustment, for every standard deviation higher baseline ALT (13.2U/L), the risk of an event was 7%(95%CI 4–13, P=0.02) lower. Participants with ALT below and above the reference range 8–41 U/L for women and 9–59 U/L for men, had a hazard ratio of an event of 1.86(95%CI, 1.12–3.09) and 0.65(95%CI, 0.49–0.87), respectively (P=0.001). No relationship was found for GGT. Conclusions The data may indicate that in type 2 diabetes — associated with higher ALT due to prevalent NAFLD — lower ALT is a marker of hepatic or systemic frailty rather than health

Serum 25-hydroxy vitamin D: a predictor of macrovascular and microvascular complications in patients with type 2 diabetes

Objective People with diabetes frequently develop vascular disease. We investigated the relationship between blood 25-hydroxy vitamin D (25OH-D) concentration and vascular disease risk in type 2 diabetes. Research design and methods The relationships between blood 25OH-D concentration at baseline and the incidence of macrovascular (including myocardial infarction, stroke) and microvascular (retinopathy, nephropathy, neuropathy, and amputation) disease were analysed with Cox proportional-hazards models and logistic regression in an observational study of patients in the 5-year Fenofibrate Intervention and Event Lowering in Diabetes trial. Results 50% of the patients had low vitamin D concentrations, as indicated by median blood 25OH-D concentration of 49nmol/L. These patients with a blood 25OH-D concentration < 50nmol/L had a higher cumulative incidence of macrovascular and microvascular events than those with levels ≥ 50nmol/L. Multivariate analysis, stratified by treatment and adjusted for relevant confounders, identified blood 25OH-D concentration as an independent predictor of macrovascular events. A 50nmol/L difference in blood 25OH-D concentration was associated with a 23% (P=0.007) change in risk of macrovascular complications during the study and further adjustments for seasonality, hs-CRP and physical activity level had little impact. The unadjusted risk of microvascular complications was 18% (P=0.006) higher during the study, though the excess risk declined to 11-14% and lost significance with adjustment for HbA1C, seasonality or physical activity. Conclusions Low blood 25OH-D concentrations are associated with an increased risk of macrovascular and microvascular disease events in type 2 diabetes. However, a causal link remains to be demonstrated

Rates and predictors of risk of stroke and its subtypes in diabetes: a prospective observational study

Background Small vessel disease is reported to be a more common cause of ischaemic stroke in people with diabetes than in others. However, population based studies have shown no difference between those with and those without diabetes in the subtypes of stroke. We determined the rates and predictors of risk of stroke and its subtypes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Methods 9795 patients aged 50–75 years with type 2 diabetes were followed up for a median of 5 years. Annual rates were derived by the Kaplan–Meier method and independent predictors of risk by Cox proportional hazards regression analyses. Results The annual rate of stroke was 6.7 per 1000 person years; 82% were ischaemic and caused by small artery disease (36%), large artery disease (17%) and embolism from the heart (13%); 10% were haemorrhagic. Among the strongest baseline predictors of ischaemic or unknown stroke were age (60–65 years, HR 1.98; >65 years, HR 2.35) and a history of stroke or transient ischaemic attack (TIA) (HR 2.06). Other independent baseline predictors were male sex, smoking, history of hypertension, ischaemic heart disease, nephropathy, systolic blood pressure and blood low density lipoprotein (LDL) cholesterol, HbA1c and fibrinogen. A history of peripheral vascular disease, low high density lipoprotein, age and history of hypertension were associated with large artery ischaemic stroke. A history of diabetic retinopathy, LDL cholesterol, male sex, systolic blood pressure, smoking, diabetes duration and a history of stroke or TIA were associated with small artery ischaemic stroke. Conclusions Older people with a history of stroke were at highest risk of stroke, but the prognosis and prognostic factors of subtypes were heterogeneous. The results will help clinicians quantify the absolute risk of stroke and its subtypes for typical diabetes patients.FIELD trial sponsored by Laboratoires Fournier SA, Dijon, France (part of Abbott

Study of a Nonlocal Density scheme for electronic--structure calculations

An exchange-correlation energy functional beyond the local density approximation, based on the exchange-correlation kernel of the homogeneous electron gas and originally introduced by Kohn and Sham, is considered for electronic structure calculations of semiconductors and atoms. Calculations are carried out for diamond, silicon, silicon carbide and gallium arsenide. The lattice constants and gaps show a small improvement with respect to the LDA results. However, the corresponding corrections to the total energy of the isolated atoms are not large enough to yield a substantial improvement for the cohesive energy of solids, which remains hence overestimated as in the LDA.Comment: 4 postscript figure

Prevalence and factors associated with burnout among frontline primary health care providers in low- and middle-income countries: A systematic review [version 3; referees: 2 approved]

Background: Primary health care (PHC) systems require motivated and well-trained frontline providers, but are increasingly challenged by the growing global shortage of health care workers. Burnout, defined as emotional exhaustion, depersonalization, and low personal achievement, negatively impacts motivation and may further decrease productivity of already limited workforces. The objective of this review was to analyze the prevalence of and factors associated with provider burnout in low and middle-income countries (LMICs). Methods: We performed a systematic review of articles on outpatient provider burnout in LMICs published up to 2016 in three electronic databases (EMBASE, MEDLINE, and CAB). Articles were reviewed to identify prevalence of factors associated with provider burnout. Results: A total of 6,182 articles were identified, with 20 meeting eligibility criteria. We found heterogeneity in definition and prevalence of burnout. Most studies assessed burnout using the Maslach Burnout Inventory. All three dimensions of burnout were seen across multiple cadres (physicians, nurses, community health workers, midwives, and pharmacists). Frontline nurses in South Africa had the highest prevalence of high emotional exhaustion and depersonalization, while PHC providers in Lebanon had the highest reported prevalence of low personal achievement. Higher provider burnout (for example, among nurses, pharmacists, and rural health workers) was associated with high job stress, high time pressure and workload, and lack of organizational support. Conclusions: Our comprehensive review of published literature showed that provider burnout is prevalent across various health care providers in LMICs. Further studies are required to better measure the causes and consequences of burnout and guide the development of effective interventions to reduce or prevent burnout

Improved global sea surface height and current maps from remote sensing and in situ observations

We present a new gridded sea surface height and current dataset produced by combining observations from nadir altimeters and drifting buoys. This product is based on a multiscale and multivariate mapping approach that offers the possibility to improve the physical content of gridded products by combining the data from various platforms and resolving a broader spectrum of ocean surface dynamic than in the current operational mapping system. The dataset covers the entire global ocean and spans from 1 July 2016 to 30 June 2020. The multiscale approach decomposes the observed signal into different physical contributions. In the present study, we simultaneously estimate the mesoscale ocean circulations as well as part of the equatorial wave dynamics (e.g. tropical instability and Poincaré waves). The multivariate approach is able to exploit the geostrophic signature resulting from the synergy of altimetry and drifter observations. Sea-level observations in Arctic leads are also used in the merging to improve the surface circulation in this poorly mapped region. A quality assessment of this new product is proposed with regard to an operational product distributed in the Copernicus Marine Service. We show that the multiscale and multivariate mapping approach offers promising perspectives for reconstructing the ocean surface circulation: observations of leads contribute to improvement of the coverage in delivering gap-free maps in the Arctic and observations of drifters help to refine the mapping in regions of intense dynamics where the temporal sampling must be accurate enough to properly map the rapid mesoscale dynamics. Overall, the geostrophic circulation is better mapped in the new product, with mapping errors significantly reduced in regions of high variability and in the equatorial band. The resolved scales of this new product are therefore between 5 % and 10 % finer than the Copernicus product (https://doi.org/10.48670/moi-00148, Pujol et al., 2022b).</p

Comparing health system performance assessment and management approaches in the Netherlands and Ontario, Canada

BACKGROUND: Given the proliferation and the growing complexity of performance measurement initiatives in many health systems, the Netherlands and Ontario, Canada expressed interests in cross-national comparisons in an effort to promote knowledge transfer and best practise. To support this cross-national learning, a study was undertaken to compare health system performance approaches in The Netherlands with Ontario, Canada. METHODS: We explored the performance assessment framework and system of each constituency, the embeddedness of performance data in management and policy processes, and the interrelationships between the frameworks. Methods used included analysing governmental strategic planning and policy documents, literature and internet searches, comparative descriptive tables, and schematics. Data collection and analysis took place in Ontario and The Netherlands. A workshop to validate and discuss the findings was conducted in Toronto, adding important insights to the study. RESULTS: Both Ontario and The Netherlands conceive health system performance within supportive frameworks. However they differ in their assessment approaches. Ontario's Scorecard links performance measurement with strategy, aimed at health system integration. The Dutch Health Care Performance Report (Zorgbalans) does not explicitly link performance with strategy, and focuses on the technical quality of healthcare by measuring dimensions of quality, access, and cost against healthcare needs. A backbone 'five diamond' framework maps both frameworks and articulates the interrelations and overlap between their goals, themes, dimensions and indicators. The workshop yielded more contextual insights and further validated the comparative values of each constituency's performance assessment system. CONCLUSION: To compare the health system performance approaches between The Netherlands and Ontario, Canada, several important conceptual and contextual issues must be addressed, before even attempting any future content comparisons and benchmarking. Such issues would lend relevant interpretational credibility to international comparative assessments of the two health systems

PHC Progression Model: A novel mixed-methods tool for measuring primary health care system capacity

High-performing primary health care (PHC) is essential for achieving universal health coverage. However, in many countries, PHC is weak and unable to deliver on its potential. Improvement is often limited by a lack of actionable data to inform policies and set priorities. To address this gap, the Primary Health Care Performance Initiative (PHCPI) was formed to strengthen measurement of PHC in low-income and middle-income countries in order to accelerate improvement. PHCPI´s Vital Signs Profile was designed to provide a comprehensive snapshot of the performance of a country´s PHC system, yet quantitative information about PHC systems´ capacity to deliver high-quality, effective care was limited by the scarcity of existing data sources and metrics. To systematically measure the capacity of PHC systems, PHCPI developed the PHC Progression Model, a rubric-based mixed-methods assessment tool. The PHC Progression Model is completed through a participatory process by in-country teams and subsequently reviewed by PHCPI to validate results and ensure consistency across countries. In 2018, PHCPI partnered with five countries to pilot the tool and found that it was feasible to implement with fidelity, produced valid results, and was highly acceptable and useful to stakeholders. Pilot results showed that both the participatory assessment process and resulting findings yielded novel and actionable insights into PHC strengths and weaknesses. Based on these positive early results, PHCPI will support expansion of the PHC Progression Model to additional countries to systematically and comprehensively measure PHC system capacity in order to identify and prioritise targeted improvement efforts.Fil: Ratcliffe, Hannah L.. Brigham And Women's Hospital; Estados Unidos. Harvard T.H. Chan School of Public Health; Estados UnidosFil: Schwarz, Dan. Harvard T.H. Chan School of Public Health; Estados Unidos. Brigham And Women's Hospital; Estados UnidosFil: Hirschhorn, Lisa R.. Northwestern University; Estados UnidosFil: Cejas, Cintia. Ministerio de Desarrollo Social; Argentina. Ministerio de Salud de la Nación; ArgentinaFil: DIallo, Abdoulaye. Ministry Of Health And Social Action; SenegalFil: Garcia Elorrio, Ezequiel. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fifield, Jocelyn. Brigham And Women's Hospital; Estados Unidos. Harvard T.H. Chan School of Public Health; Estados UnidosFil: Gashumba, DIane. Ministry of Health; RuandaFil: Hartshorn, Lucy. Harvard T.H. Chan School of Public Health; Estados Unidos. Brigham And Women's Hospital; Estados UnidosFil: Leydon, Nicholas. Bill And Melinda Gates Foundation; Estados UnidosFil: Mohamed, Mohamed. Ministry Of Health And Social Welfare Dar Es Salaam; TanzaniaFil: Nakamura, Yoriko. Results For Development; Estados UnidosFil: Ndiaye, Youssoupha. Ministry Of Health And Social Action; SenegalFil: Novignon, Jacob. Kwame Nkrumah University Of Science And Technology; GhanaFil: Ofosu, Anthony. Ghana Health Service; GhanaFil: Roder Dewan, Sanam. Organización de las Naciones Unidas. Unicef. Fondo de las Naciones Unidas para la Infancia; ArgentinaFil: Rwiyereka, Angelique. Global Health Issues and Solutions; Estados UnidosFil: Secci, Federica. The World Bank Group; Estados UnidosFil: Veillard, Jeremy H.. The World Bank Group; Estados UnidosFil: Bitton, Asaf. Harvard T.H. Chan School of Public Health; Estados Unidos. Brigham And Women's Hospital; Estados Unido