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Photoemission electron microscopy (PEEM) is a unique and powerful tool for studying the electronic properties of materials and surfaces. However, it requires intense and well-controlled light sources with photon energies ranging from the UV to soft X-rays for achieving high spatial resolution and image contrast. Traditionally, many PEEMs were installed at synchrotron light sources to access intense and tunable soft X-rays. More recently, the maturation of solid-state lasers has opened a new avenue for laboratory-based PEEMs using laser-based UV light at lower photon energies. Here, we report on the characteristics of a laser-based UV light source that was recently integrated with a PEEM instrument. The system consists of a high repetition rate, tunable wavelength laser coupled to a harmonics generation module, which generates deep-UV radiation from 192 nm to 210 nm. We comment on the spectral characteristics and overall laser system stability, as well as on the effects of space charge within the PEEM microscope at high UV laser fluxes. Further, we show an example of imaging on gallium nitride, where the higher UV photon energy and flux of the laser provides considerably improved image quality, compared to a conventional light source. These results demonstrate the capabilities of laser-based UV light sources for advancing laboratory-based PEEMs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Angina with no obstructive coronary artery disease (ANOCA) is a common entity. There is still under-recognition of this condition, but it is unclear if the referral patterns for chest pain diagnosis have changed. We aimed to determine if the prevalence of patients diagnosed with ANOCA by means of coronary angiography has changed over time., Methods: A population-based cohort of patients who had their first coronary angiogram for a chest pain syndrome in Alberta from 1995 to 2020 was extracted retrospectively from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. A temporal trend analysis was performed to compare patients with ANOCA vs obstructive coronary artery disease (CAD), and the predictors of ANOCA were investigated., Results: In our analysis, 121,066 patients were included (26% ANOCA, 31% female, overall mean age 62 years). The percentages of ANOCA vs obstructive CAD ranged from 24.2% to 26.7% in all patients (P < 0.001), from 19.4% to 21.4% in patients with acute coronary syndromes (P = 0.002), and from 30.6% to 37.5% in patients with stable angina (P < 0.001). Independent predictors of ANOCA were female sex (odds ratio [OR] 3.34, 95% confidence interval [CI] 3.05-3.66), younger age (OR 0.96, 95% CI 0.95-0.96), history of atrial fibrillation (OR 2.18, 95% CI 1.73-2.73), and stable angina (vs myocardial infarction: OR 0.25, 95% CI 0.23-0.28; vs unstable angina: OR 0.79, 95% CI 0.70-0.89). Traditional cardiovascular risk factors were associated with obstructive CAD., Conclusions: There remained a high prevalence of ANOCA detected during invasive coronary angiography, which remained stable over time. This study demonstrates an opportunity to exclude obstructive CAD with less invasive testing, particularly in women., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.5 mg once daily) should be considered in patients with recent myocardial infarctions-within 30 days and, ideally, within 3 days-or with stable CAD to improve cardiovascular outcomes. Colchicine should not be used in patients with severe renal or hepatic disease because of the risk of severe toxicity. No serious adverse effect was associated with the combined use of colchicine and high-intensity statin therapy in large trials. The impact of colchicine in high-risk populations of patients with peripheral arterial disease and in those with diabetes for the primary prevention of CAD remains to be established., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma, praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GHTN), are independent risk factors for future maternal cardiovascular disease. Epidemiologic evidence has demonstrated that women with HDP have abnormal cardiovascular risk factors in the early postpartum period, but this has not been fully characterized., Objective: This study aimed to assess the lipid profiles among women with PE, GHTN, and normal blood pressure in the first 4 years postpartum., Methods: Discharge Abstract Database was used to identify women hospitalized for a delivery in Calgary, Alberta, Canada, between January 2010 and December 2012 (N = 27,300). This was linked with Calgary Laboratory Services (for lipid levels) and the Pharmaceutical Information Network database (for lipid medication prescriptions) over the first 4 years postpartum (2010-2016). Logistic regression analysis was used to compare the frequency of lipid tests among HDP subtypes, adjusted for maternal age, gestational age at delivery, and parity., Results: Only about half of the women with HDP had a lipid test in the first 4 years postpartum: 50.8% (PE) and 48.8% (GHTN) vs 41.5% in normotensive women (P < .001). Low-density lipoprotein cholesterol levels were significantly higher in women with HDP: 106.3 ± 35.2 mg/dL (2.75 ± 0.91 mmol/L) in PE, 102.5 ± 30.5 mg/dL (2.65 ± 0.79 mmol/L) in GHTN, and 96.7 ± 29.0 mg/dL (2.50 ± 0.75 mmol/L) in normotensive women (P < .001)., Conclusion: Postpartum lipid screening helps identify women at risk of cardiovascular disease; however, only 50% of women with HDP were tested in the first years postpartum. As such, an early opportunity for primary CVD prevention strategies in young women may be lost., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac surgery waitlist recommendations, which were developed based on expert opinion, poorly predict preoperative mortality. Studies reporting risk factors for waitlist mortality have not evaluated the risks including nonadherence to waitlist benchmarks., Methods: In patients who underwent cardiac surgery or died on the waitlist between 2005 and 2015, we used a Fine and Gray competing risk model to identify independent predictors of waitlist mortality in 12,106 patients scheduled for urgent, semiurgent, or nonurgent surgery. The predictive variables were compared with Canadian Cardiovascular Society (CCS) waitlist recommendations using the Akaike information criterion., Results: A total of 101 (0.8%) patients died awaiting surgery. The median wait times and frequency waitlist deaths among emergent, urgent, semi-urgent, and nonurgent surgery were 0.6, 7.4, 69.0, 55.5 days (P < 0.001) and 6.3%, 0.8%, 0.3%, 0.6% (P < 0.001), respectively. Adherence to CCS waitlist recommendations was higher in patients who died on the waitlist (51.6% vs 70.8%, P = 0.001) and was not predictive of waitlist mortality (hazard ratio 1.48, 95% confidence interval 0.62-0.56). Independent predictors of waitlist mortality were age, aortic surgery, ejection fraction < 35%, urgent surgery, prior myocardial infarction, haemodynamic instability during cardiac catheterization, hypertension, and dyslipidemia. These variables were superior to current CCS guidelines (Akaike information criterion 1251 vs 1317, likelihood ratio test P < 0.001)., Conclusions: CCS waitlist recommendations were poorly predictive of waitlist mortality and the majority of waitlist deaths occur within recommended benchmarks. We identified variables associated with waitlist mortality with improved clinical performance. Our findings suggest a need to re-evaluate cardiac surgical triage criteria using evidence-based data., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) are markers of lipoprotein metabolism. Although their relationship to cardiovascular disease has been well documented, little is known regarding their correlation to measures of vascular structure and function. This study was conducted to investigate the relationship between apoA-1, apoB, and measures of vascular function, as well their relationship to adverse cardiovascular events. Moreover, we evaluated whether apoB or the apoB/apoA-1 ratio was more closely related to vascular markers than was low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C)., Methods: One thousand five hundred twenty-two healthy middle-aged men of the Firefighters and Their Endothelium (FATE) cohort were assessed for risk factors and flow-mediated dilatation (FMD), hyperemic velocity (VTI), and carotid intima-media thickness (CIMT). Participants were then followed for 7.2 ± 1.7 years. ApoA-1 and apoB levels were measured at baseline., Results: ApoA-1 was not correlated with VTI, FMD, or CIMT, whereas apoB was significantly related to VTI and CIMT. Multiple regression analyses confirmed apoB as being related to both VTI (β = -0.083; P = 0.001) and CIMT (β = 0.055; P = 0.022) in models adjusted for age; blood pressure; high-density lipoprotein C (HDL-C), triglyceride and insulin levels; waist circumference; and C-reactive protein levels. In substituted models, LDL-C (β = -0.092; P < 0.001) and non-HDL-C (β = -0.089; P = 0.001) levels appeared to have the same degree of association as apoB for VTI but were not associated with CIMT. ApoB was found to be associated with cardiovascular events (hazard ratio, 1.349; 95% confidence interval, 1.073-1.695; P = 0.010)., Conclusions: ApoB had an independent but weak relationship with indices of microvascular health. Nevertheless, it was associated with occurrence rates of adverse cardiovascular events., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Bleeding complications accompanying coronary revascularization are associated with increased mortality; however, few data are available on subsequent bleeding risk. We used administrative data to assess the incidence of late bleeding events in patients with acute coronary syndrome (ACS) according to treatment allocation., Methods: The cohort and bleeding events were identified through the Canadian Institute for Health Information discharge abstract database. Crude and adjusted odds ratios (ORs) were calculated for index and postindex admission bleeding up to 1 year after discharge., Results: Of 31,941 patients hospitalized with ACS, 7681 (32.4%) patients were treated with medication alone, 3728 (15.2%) underwent angiography without intervention, and 13,075 (53.4%) underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The overall incidence of readmission with bleeding based on administrative codes was low (3.8% for medically treated patients, 2.8% for patients who underwent angiography alone, 2.6% for patients who underwent CABG, and 1.8% for patients who underwent PCI; P < 0.0001). Bleeding codes were mainly gastrointestinal bleeding (52%), but 7.8% were intracranial episodes of bleeding. Patients who received PCI had significantly lower odds of late bleeding compared with medically treated patients (OR, 0.76; 95% CI, 0.62-0.94). Late bleeding during the first year after ACS was associated with mortality (OR, 4.96; 95% CI, 2.47-9.93)., Conclusions: Patients who underwent revascularization procedures had a relatively low risk for late bleeding events after a hospitalization for ACS. Late bleeding events were associated with an increased risk of death., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The treatment of dyslipidemia with lifestyle interventions and statin-based therapy has been an important defense against atherosclerotic cardiovascular disease and its complications. It has been well documented for more than 2 decades that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce the risk of events. The evolution of drug development and randomized clinical trials in cardiovascular medicine has resulted in the conclusion that lower cholesterol concentrations result in greater benefit. However, how aggressive one should be in lowering cholesterol levels and to what level has not been definitively established. In this brief review I aim to defend the hypothesis that lower is better on the basis of the evidence to date. This will include indirect evidence from randomized clinical trials with statins and novel lipid-modifying drugs. In addition, there is a wealth of epidemiology and Mendelian randomization genetic data to support this. Also, on-treatment low-density lipoprotein cholesterol concentrations show a robust relationship with cardiovascular disease events. Finally, most national guidelines groups around the world continue to advocate for a treat to target philosophy. As such, the prevailing philosophy is that lowering low-density lipoprotein cholesterol to very low levels is our best preventative strategy particularly for those at the highest risk. We eagerly await the results of ongoing clinical trials that will more firmly establish if this concept will ultimately be proven correct., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease., Background: Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden., Methods: As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models., Results: Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment., Conclusions: Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Since the publication of the 2012 guidelines new literature has emerged to inform decision-making. The 2016 guidelines primary panel selected a number of clinically relevant questions and has produced updated recommendations, on the basis of important new findings. In subjects with clinical atherosclerosis, abdominal aortic aneurysm, most subjects with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy is recommended. For all others, there is an emphasis on risk assessment linked to lipid determination to optimize decision-making. We have recommended nonfasting lipid determination as a suitable alternative to fasting levels. Risk assessment and lipid determination should be considered in individuals older than 40 years of age or in those at increased risk regardless of age. Pharmacotherapy is generally not indicated for those at low Framingham Risk Score (FRS; <10%). A wider range of patients are now eligible for statin therapy in the FRS intermediate risk category (10%-19%) and in those with a high FRS (> 20%). Despite the controversy, we continue to advocate for low-density lipoprotein cholesterol targets for subjects who start therapy. Detailed recommendations are also presented for health behaviour modification that is indicated in all subjects. Finally, recommendation for the use of nonstatin medications is provided. Shared decision-making is vital because there are many areas in which clinical trials do not fully inform practice. The guidelines are meant to be a platform for meaningful conversation between patient and care provider so that individual decisions can be made for risk screening, assessment, and treatment., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: Since 2012, all community care recipients in New Zealand have undergone a standardised needs assessment using the Home Care International Residential Assessment Instrument (interRAI-HC). This study describes the national interRAI-HC population, assesses its data quality and evaluates its ability to be matched., Methods: The interRAI-HC instrument elicits information on 236 questions over 20 domains; conducted by 1,800+ trained health professionals. Assessments between 1 July 2012 and 30 June 2014 are reported here. Stratified by age, demographic characteristics were compared to 2013 Census estimates and selected health profiles described. Deterministic matching to the Ministry of Health's mortality database was undertaken., Results: Overall, 51,232 interRAI-HC assessments were conducted, with 47,714 (93.1%) research consent from 47,236 unique individuals; including 2,675 Māori and 1,609 Pacific people. Apart from height and weight, data validity and reliability were high. A 99.8% match to mortality data was achieved., Conclusions: The interRAI-HC research database is large and ethnically diverse, with high consent rates. Its generally good psychometric properties and ability to be matched enhances its research utility., Implications: This national database provides a remarkable opportunity for researchers to better understand older persons' health and health care, so as to better sustain older people in their own homes., (© 2016 Public Health Association of Australia.)

Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore, lifestyle interventions and pharmacological approaches to decrease cholesterol are widely used in cardiovascular disease prevention. The introduction and widespread use of 3-hydroxy-3 methylglutaryl coenzyme A inhibitors (statins) for individuals at risk of atherosclerotic disease has been an important advance in cardiovascular care. There can be no doubt that better control of dyslipidemia, even in subjects whose low-density lipoprotein cholesterol level is not particularly high, has reduced overall event rates. On a background of lifestyle interventions, statins are routinely used to decrease risk along with aspirin and interventions to control hypertension and diabetes. More than other risk factors, the approach to the identification and treatment of dyslipidemia has been heterogeneous and widely debated. The recent release of the 2013 American College of Cardiology/American Heart Association dyslipidemia guidelines has reignited the controversy over the best approach for risk stratification and treatment. In this article we review the importance of statin therapy for global cardiovascular risk reduction, compare the Canadian Cardiovascular Society dyslipidemia guidelines with other standards, and discuss the points of debate. Despite the seeming variety of recommendations, their common link is a systematic approach to risk stratification and treatment, which will continue to benefit our patients at risk., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The real promise of the metabolic syndrome concept was the opportunity to elucidate a singular common mechanism for its component abnormalities and consequently a singular therapy. That promise has not produced. This relates to the following considerations: (1) metabolic syndrome remains a syndrome not a disease, (2) its diagnosis offers little more than what can be determined by measuring waist circumference, (3) risk assessment is not improved by the diagnosis of metabolic syndrome, (4) the diagnosis of metabolic syndrome does not impact the treatment of each component of the syndrome, and (5) there is no effective therapy for metabolic syndrome in its entirety., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOFMS) is a well-established instrumental platform for complex samples. However, chemometric data analysis is often required to fully extract useful information from the data. We demonstrate that retention time shifting from one modulation to the next, Δ(2)tR, is not sufficient alone to quantitatively describe the trilinearity of a single GC×GC-TOFMS run for the purpose of predicting the performance of the chemometric method parallel factor analysis (PARAFAC). We hypothesize that analyte peak width on second dimension separations, (2)Wb, also impacts trilinearity, along with Δ(2)tR. The term trilinearity deviation ratio, TDR, which is Δ(2)tR normalized by (2)Wb, is introduced as a quantitative metric to assess accuracy for PARAFAC of a GC×GC-TOFMS data cube. We explore how modulation ratio, MR, modulation period, PM, temperature programming rate, Tramp, sampling phase (in-phase and out-of-phase), and signal-to-noise ratio, S/N, all play a role in PARAFAC performance in the context of TDR. Use of a PM in the 1-2 s range provides an optimized peak capacity for the first dimension separation (500-600) for a 30 min run, with an adequate peak capacity for the second dimension separation (12-15), concurrent with an optimized two-dimensional peak capacity (6000-7500), combined with sufficiently low TDR values (0-0.05) to facilitate low quantitative errors with PARAFAC (0-0.5%). In contrast, use of a PM in the 5s or greater range provides a higher peak capacity on the second dimension (30-35), concurrent with a lower peak capacity on the first dimension (100-150) for a 30 min run, and a slightly reduced two-dimensional peak capacity (3000-4500), and furthermore, the data are not sufficiently trilinear for the more retained second dimension peaks in order to directly use PARAFAC with confidence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There is a growing focus on interdisciplinary team approaches in science and public health research, including cardiology. This trend is apparent in a large body of team publications and the strong interest from the funding agencies to support interdisciplinary research. Despite this increased emphasis on the importance and roles of teams, schools fail to better prepare their students and trainees with skills that allow them to work in or lead teams. In this article, we discuss the strengths and weaknesses of different team models and highlight the training program implemented by the Alberta Heart Failure Etiology and Analysis Research Team (HEART), which involves 24 scientists/mentors across the research and health care spectrum focused on understanding heart failure with preserved ejection fraction., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: To determine the effect of extended release (ER) niacin on endothelial and vascular function assessed by brachial flow-mediated dilatation (FMD), peak hyperemic velocity (VTiRH) and pulse arterial tonometry (PAT) in patients with established coronary artery disease (CAD), already treated with high dose statins. Endothelial dysfunction is common in patients with established coronary artery disease (CAD) and has prognostic implications. Niacin has proven clinical benefit in patients with CAD, but its additive effect in patients on statin therapy is being evaluated. The effect of niacin on endothelial function, in the presence of optimal LDL cholesterol is unclear., Methods and Results: Sixty-six patients with CAD (mean age 57.9 ± 8.5 yrs) received ER niacin (1500 mg per day) and placebo in a randomized crossover fashion for 3 months of each therapy. All patients received atorvastatin 80 mg per day. FMD, VTiRH and PAT measurements were performed at baseline and after each treatment period. Treatment with niacin improved dyslipidemia parameters (LDL placebo 1.52 ± 0.51 vs. niacin 1.30 ± 0.43; p = 0.004; HDL placebo 0.95 ± 0.16 vs. niacin 1.11 ± 0.22; p < 0.001). However, there was no observed improvement in endothelial function as assessed by FMD (placebo 6.1 ± 4.9 vs. niacin 6.6 ± 4.8%; p = 0.48), VTiRH (placebo 75 ± 28 vs. niacin 78 ± 26 cm; p = 0.23) or PAT (placebo 1.8 ± 0.42 vs. niacin 1.79 ± 0.5; p = 0.43)., Conclusion: Niacin as add-on treatment to high dose statins in patients with established CAD significantly improves lipid profile. However, these changes were not associated with improved endothelial or microvascular function. Registered clinical trial with clinicaltrials.gov: NCT00150722., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border., Methods: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms., Findings: 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010., Interpretation: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years., Funding: The Wellcome Trust and National Institutes of Health., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Despite recent advancements in the treatment of coronary artery disease (CAD), it remains the number one cause of death in the world. While traditional risk factors partially account for the development of CAD, other novel risk factors have recently been implicated. Specifically, chronic inflammation has been postulated to play a role in the development and propagation of this disease. The purpose of this systematic review is to examine the available evidence to determine if patients with chronic inflammatory diseases have higher rates of cardiovascular disease. A MEDLINE search was conducted for articles published between 1980-2009. We focused on studies that assessed hard cardiovascular endpoints in subjects with chronic inflammatory conditions such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, polymyositis/dermatomyositis, and inflammatory bowel disease. Although largely based on small studies, our review indicates that patients with chronic inflammatory conditions are likely at elevated risk for the development of CAD. Further research consisting of prospective cohort studies is needed to better quantify this risk., (Copyright © 2011. Published by Elsevier Inc.)

Leukotriene B(4) (LTB(4)) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA(4)-hydrolase. LTB(4) signals primarily through its G protein-coupled receptor BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominal aortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe(-/-) mice were treated with a 4-week infusion of Angiotensin II (AngII, 1000 ng/(kg min)) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Recent observational studies have reported differential quantitative relationships between the different anthropometric indices of obesity and risk for cardiovascular (CV) events. Specifically, waist circumference and waist-to-hip ratio (WHR) as crude measures of abdominal obesity were shown to be more predictive of CV events than body mass index (BMI). However, it remains undetermined whether indices of abdominal obesity are also more strongly associated with early subclinical atherosclerosis in asymptomatic individuals., Methods: The associations between carotid intimal-medial thickness (cIMT) as a validated marker of subclinical atherosclerosis and each of BMI, waist circumference and WHR were compared among 1578 middle-aged men free of clinical CV disease enrolled in the Fire Fighter and Their Endothelium (FATE) study., Results: In univariate analyses, the correlation with cIMT as well as the ability to predict substantially increased atherosclerotic burden (cIMT>75% percentile of the cohort) was strongest for WHR, intermediate for waist circumference, and weakest for BMI (Pearson's coefficient of 0.21, 0.18 and 0.12, respectively; area under the receiver operating characteristics curve [AUC] of 0.65, 0.62 and 0.58, respectively, P<0.01 for differences). Within each traditional BMI category, WHR uniformly outperformed waist circumference in further refining discrimination for increased atherosclerotic burden. In multivariable analyses, WHR consistently demonstrated the strongest graded independent relationship with cIMT, beyond most of the established risk factors of atherosclerosis, and superseded both waist circumference and BMI., Conclusion: Our findings support the use of WHR for estimating adiposity-related atherosclerotic burden in clinical practice and in obesity research. Moreover, our study suggests that the increased CV risk associated with abdominal obesity may be mediated in part by the increased anatomic extent of atherosclerotic vascular disease.

We genotyped 160 P. falciparum infections from Malawi for pfmdr-1 copy number changes and SNPs associated with in vivo tolerance and poor in vitro sensitivity to the component drugs of Coartem. We also measured in vitro susceptibility of 49 of these isolates to a variety of drugs in clinical use or with a potential for use in Africa. All 160 infections carried a single copy of pfmdr-1 but 34% exhibited sequence variation at 4 of the 5 polymorphic sites in pfmdr-1. Isolates carrying 86-Asn and 184-Tyr pfmdr-1 alleles were significantly less sensitive (p<0.001) to mefloquine, lumefantrine, artemether and dihydroartemisinin compared with those bearing 86-Tyr and 184-Phe polymorphisms. This study provides baseline measures prior to policy change: continued surveillance for changes in baseline drug susceptibility, pfmdr-1 copy number and SNPs, and other putative Coartem resistance loci will be necessary to provide an early warning of emerging Coartem resistance in this setting.

Background: Plasma levels of the inflammatory biomarker C-reactive protein (CRP) predict cardiovascular risk and may represent a target for treating and/or monitoring risk-reduction strategies. The effect of angiotensin-converting enzyme inhibitors on CRP levels has not been adequately studied., Methods: A total of 264 men and women, with CRP levels of 2 mg/L or greater and no history of cardiovascular disease, were enrolled in a 12-week randomized, double-blind, placebo-controlled study. Participants were randomly assigned to receive 10 mg/day of ramipril (n=132) or placebo (n=132) for 12 weeks. The main outcome measure was the change in CRP levels from baseline to 12 weeks in the ramipril- versus placebo treated patients., Results: The mean (+/- SD) age was 53+/-9 years (60% men). Baseline demographics were similar between the volunteers allocated to receive either placebo or ramipril. The geometric mean CRP at baseline was 3.84 mg/L (95% CI 3.62 mg/L to 4.06 mg/L). The percentage change in geometric mean CRP values over 12 weeks was --13.2% (95% CI --22.3% to --3.2% ) in the placebo group compared with --21.1% (95% CI --29.9% to --11.2%) in the ramipril group (P nonsignificant), indicating no significant reduction in the primary end point of the trial., Conclusions: A 12-week ramipril treatment protocol for healthy middle-aged volunteers did not lower CRP levels compared with placebo. However, because of the inherent variability of CRP levels, a much larger study is required to exclude a small treatment effect.

The role of new and emerging biomarkers in risk prediction has become a topic of significant interest and controversy in recent times. Currently, available models for risk prediction are reasonably good yet still misclassify a not insignificant portion of the population. The sheer number of new potential risk markers is daunting, and it is difficult to assess the importance of each one over and above the traditional risk factors. Endothelial function is one potential biomarker of risk that has been extensively studied. However, while it has demonstrated some utility in risk prediction, its use in daily clinical practice is yet to be clearly defined. The present review assesses the prognostic significance of measures of endothelial function.

Background: Obesity is an independent risk factor for cardiovascular disease. Endothelial dysfunction assessed in the peripheral circulation is associated with obesity, however, little is known if this association also exists in the coronary circulation., Methods: Stable patients with coronary artery disease were evaluated. Baseline characteristics were evaluated, including assessment of body mass index [(BMI), kg/m(2)]. Coronary diameter (quantitative coronary angiography) and blood flow (0.014 in. Doppler Flo-wire) were measured at baseline and in response to intracoronary acetylcholine (10(-7) and 10(-6) M) to evaluate endothelial dependent effects with endothelial independent effects evaluated in response to intracoronary nitroglycerin and adenosine. The cohort was divided into tertiles around BMI values, i.e. normal weight (BMI < 25), overweight (BMI 25-29.9) and obese (BMI ≥ 30) groups., Results: 83 patients were evaluated, with 20 patients in the normal weight (BMI 22.6 ± 0.3 kg/m(2)), 40 subjects in the overweight (BMI 27.3 ± 0.2 kg/m(2)) and 23 in the obese (BMI 34.3 ± 0.3 kg/m(2)) groups. A significant difference was seen in the primary endpoint of Ach mediated % change in coronary blood flow between the normal (101 ± 28%) and the obese (37 ± 15%) groups (p = 0.04). No significant difference was observed in epicardial constrictor response to acetylcholine across these three groups of patients., Conclusions: In a cohort of subjects with coronary artery disease, patients with a high BMI had associated impaired microvascular coronary endothelial dependent function., (© 2009 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

Background: C-reactive protein (CRP), a marker of inflammation, plays a role in the pathophysiology of atherosclerotic events. The relationship between CRP levels and myocardial necrosis assessed by troponin T (TnT) in patients undergoing percutaneous coronary intervention (PCI) has not been established. In addition, the long-term significance of TnT rise following PCI is not clear., Objectives: To examine the relationship between CRP and the rise in TnT levels, and evaluate the long-term prognostic implications of TnT rise following PCI., Methods: A total of 1208 patients underwent successful nonemergent PCI. Baseline demographic characteristics, CRP and TnT levels were prospectively collected before and 12 h to 18 h following PCI. Long-term follow-up data over two years were available., Results: Among the patients studied (mean age 62 years), 64% presented with acute coronary syndrome. A PCI procedure was associated with a significant increase in TnT levels (higher than 0.1 microg/L) in 238 patients (20%). Multivariate logistic regression identified presentation with acute coronary syndrome or myocardial infarction, no statin use at the time of the procedure, increased CRP and increasing length of stent as independent predictors of TnT rise following PCI. Periprocedural TnT rise was not associated with adverse events in follow-up examinations (OR 1.09, 95% CI 0.73 to 1.65)., Conclusions: Myocardial necrosis commonly occurred in otherwise successful PCI and was particularly prevalent in the proinflammatory milieu of a recent myocardial infarction. This response was blunted with statin therapy. However, there was no long-term adverse sequelae of these troponin rises following otherwise uncomplicated PCI.

Objective: The purpose of this study was to use a candidate gene approach to identify common polymorphisms that are associated with resting sinus heart rate in a population without overt cardiovascular disease., Background: Increased resting heart rate is significantly associated with susceptibility to development of myocardial infarction, sudden cardiac death, and overall cardiac mortality., Methods: A longitudinal cohort of 1468 individuals (active and retired middle-aged Canadian firefighters) who were enrolled in the Firefighters and Their Endothelium (FATE) study was evaluated. Resting heart rate was recorded from the electrocardiogram (ECG) obtained at enrollment. Candidate genes were selected for their known roles in sinus node automaticity and/or its regulation, and single nucleotide polymorphisms (SNPs) with a minor allele frequency of > or =0.20 were targeted. A total of 53 SNPs in 46 genes were selected and analyzed in a screening sample, and 33 SNPs in 29 genes were evaluated in the full population., Results: Univariate analysis detected five putative associations between HR and SNPs. As expected, environmental covariates were identified. Three polymorphisms, ADRB1 G389R, SCN5a H558R, and CASQ1 intron 2, remained statistically significant and independent of covariates. Some alleles were associated with higher and some with lower heart rates. A stepwise increase in heart rate was observed that was dependent on the number of tachycardia-associated alleles with progressive increases in mean heart rate from 51 to 66 bpm., Conclusions: Common polymorphisms are associated with heart rate in a stepwise allele-dependent manner.

Background: The antioxidant AGI-1067 was shown to reduce experimental atherosclerosis. The present study originally intended to study restenosis as a primary endpoint but was subsequently modified to primarily investigate the effects of AGI-1067 on coronary atherosclerosis., Methods and Results: This placebo-controlled randomized trial assessed the effects of AGI-1067 280 mg qd started before percutaneous coronary intervention (PCI) and administered for 12 months after PCI on atherosclerosis progression as assessed by coronary intravascular ultrasound (IVUS). Among patients with IVUS examinations considered technically adequate both at baseline and follow-up upon central laboratory assessments (n=232), plaque volume was not significantly modified with placebo (least squares mean change: -0.4mm(3), P=0.85 versus baseline), but was significantly reduced by -4.0mm(3) at end of treatment in the AGI-1067 group (P=0.001 versus baseline, P=0.12 versus placebo). LDL-cholesterol varied by -9% and +4% in the placebo and AGI-1067 groups, respectively (P<0.05 between groups), and HDL-cholesterol was reduced by 1% with placebo and 14% with AGI-1067 (P<0.05 between groups). Plasma myeloperoxidase was reduced by 6% with AGI-1067 (P<0.05) but hs-CRP was not significantly different between groups., Conclusions: Atherosclerosis regression (-4.0mm(3)) was observed in patients treated with AGI-1067, although this was not significantly different from placebo. The anti-inflammatory effect of AGI-1067 is supported by reduced levels of myeloperoxidase.

Objective: To evaluate the effect of the calcium channel blocker amlodipine on endothelial function in normotensive patients with coronary disease taking concomitant atorvastatin therapy., Methods and Results: Atorvastatin was titrated (10-80 mg/day) to maintain LDL-C<2.5 mmol/L and patients were randomized to receive amlodipine (5-10mg/day, n=64) or placebo (n=70) for 12 months. Brachial artery flow-mediated vasodilation (FMD) was assessed using vascular ultrasound. Inflammatory markers were also measured. At 12 months there was a significant decrease in mean low-density lipoprotein cholesterol (LDL-C) (4.4-2.1 mmol/L, P<0.0001), high-sensitivity C-reactive protein (hsCRP) (3.8-2.3mg/L, P<0.0001) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (710-665 ng/mL, P<0.0001) for all patients, compared with baseline. Amlodipine was associated with a mean blood pressure reduction of 8/3 mm Hg (P<0.0001) whereas patients on placebo had no significant change. In the atorvastatin-placebo group, mean FMD increased (7.3-9.5%, P<0.05) with no change in nitroglycerin-mediated dilation. No further benefit on FMD or inflammatory markers was observed with the addition of amlodipine., Conclusions: Intensive reduction of LDL-C with atorvastatin improves endothelium-dependent vasodilation and reduces markers of inflammation in patients with coronary disease. Amlodipine was not associated with a significant additional benefit on these variables.

Objectives: To determine whether myocardial contrast echocardiography (MCE) can quickly and accurately assess myocardial perfusion and infarct-related artery (IRA) patency before emergency angiography during acute myocardial infarction (AMI)., Background: Despite encouraging experimental and clinical studies, the reliability and practicality of MCE in predicting IRA patency during AMI before angiography has not been proven., Methods: Two-dimensional echocardiography and MCE were performed in 51 patients with AMI just before emergency angiography. With knowledge of the electrocardiogram findings and regional wall motion, myocardial perfusion was assessed to predict IRA patency., Results: Myocardial perfusion studies were adequate for interpretation in 40 patients. An occluded IRA was predicted in 28 patients; the artery was occluded in 22 patients, and six patients had Thrombolysis In Myocardial Infarction (TIMI) grade 2 flow or less. A patent IRA was predicted in 12 patients; eight patients had TIMI grade 3 flow, one patient had TIMI grade 2 flow and the IRA was occluded in three patients. In one of the three patients, the appropriate view was not obtained. In another patient, collateral flow was adequate for near-normal regional wall motion, and in the last, the findings suggested reperfusion of the proximal artery with distal embolic occlusion. Taken together, MCE accurately predicted either TIMI grade 2 flow or less, or TIMI grade 3 flow in 36 of 40 patients. Sensitivity was 87.5%, specificity and positive predictive value were 100% and negative predictive power was 66.7% (P<0.001)., Conclusions: MCE, together with the electrocardiogram and regional wall motion, can be used to quickly and reliably predict IRA patency early during AMI and may be useful to facilitate a management strategy.

Objective: Brain disorders can lead to a decreased ability to perform the physical and cognitive functions necessary for safe driving. This study aimed to determine how accurately a battery of computerized sensory-motor and cognitive tests (SMCTests) could predict driving abilities in persons with brain disorders., Methods: SMCTests and an independent on-road driving assessment were applied to 50 experienced drivers with brain disorders referred to a hospital-based driving assessment service. The patients comprised 36 males and 14 females, a mean age of 71.3 years (range 43-85 years) and diagnoses of 35 stroke, 4 traumatic brain injury, 4 Alzheimer's disease, and 7 other. Binary logistic regression (BLR) and nonlinear causal resource analysis (NCRA) were used to build model equations for prediction of on-road driving ability based on SMCTests performance., Results: BLR and NCRA correctly classified 94% and 90% of referrals respectively as on-road pass or fail. Leave-one-out cross-validation estimated that BLR and NCRA would correctly predict the classification of 86% and 76% respectively of an independent referral group as on-road pass or fail., Conclusions: Compared with other studies, SMCTests have shown the highest predictive accuracy against true on-road driving ability as estimated in an independent data set and in persons with brain disorders. SMCTests also have the advantage of being able to comprehensively and objectively assess both sensory-motor and higher cognitive functions related to driving.

Based on previous findings of impaired eye and arm motor control after mild closed head injury (CHI), this study examined whether early eye and arm motor function, and the level of post-injury cerebral dysfunction manifested in motor control, relates systematically to recovery at 3 and 6 months after mild CHI. At 1 week post-injury, we assessed oculomotor function, upper-limb visuomotor performance, and cognitive status in 37 mild CHI patients. Re-examination at 3 and 6 months determined outcome in terms of postconcussional symptoms and performance of everyday tasks, as assessed by the Rivermead Postconcussion Symptoms Questionnaire, the Rivermead Head Injury Follow-up Questionnaire and the SF-36 Health Survey. We then examined the association of early motor function, cognitive status and self-reported health condition with outcome using linear regression. Motor-based regression models explained a high proportion of the variance in outcome (70-89%), with motor function at 1 week being more closely related to outcome at 3 and 6 months than early psychometric assessment (13-32%) or self-reported health status (54-79%). These motor-based models incorporated subcortical/subconscious motor functions alongside motor functions that are subject to volitional control and are primarily mediated by frontal, parietal and temporal cortical brain regions. Early assessment of eye and arm motor function may help in improving accuracy of outcome prediction after mild CHI. Such assessment may assist in the better targeting of early health care intervention and help decrease head-trauma-related morbidity and rehabilitation costs.

Recent reports of late stent thrombosis events following deployment of drug-eluting stents (DES) have raised concerns about their safety and role in the management of coronary artery disease. The Canadian Association of Interventional Cardiology and the Canadian Cardiovascular Society have carefully examined the available evidence, including the data presented at the recent Food and Drug Administration Circulatory System Devices Advisory Panel meeting. The purpose of the present statement is to summarize the available evidence relating to DES thrombosis and to provide practical recommendations regarding DES use and antiplatelet therapy.

The understanding of the pathophysiology of atherosclerosis has advanced greatly in the past decade. Cardiovascular risk factors increase the likelihood of an adverse event by having a detrimental effect on the blood vessel wall. Abnormal interactions among cholesterol, inflammatory mediators, platelets and the vascular wall lead to atherogenesis and cardiac events. In an effort to better understand this process, develop surrogate end points for clinical trials and, ultimately, better risk stratify individuals, a variety of measures of arterial function have been studied. These include measures of endothelial health and arterial compliance. The current paper reviews the various techniques available for the study of vascular health. While not yet routinely used for clinical care, these measurements provide important insights into the pathophysiology and treatment of atherosclerosis.

Elevated soluble CD40 ligand (sCD40L) levels are associated with an increased risk of cardiovascular events in patients with acute coronary syndromes and in middle-aged healthy women. However, the relationship between sCD40L and global risk assessment remains unclear. The present study was designed to examine the relationship between sCD40L and Framingham Coronary Heart Disease Risk Scores (FCRS) in healthy middle-aged men. The study population consisted of 400 active and retired male firefighters, with no previous history of cardiovascular disease, as part of the Firefighters and Their Endothelium (FATE) study. FCRS correlated poorly with sCD40L levels (p=0.14). Soluble CD40L concentrations correlated only with total (r=0.105; p=0.035) and LDL cholesterol (r=0.104; p=0.039), and CRP levels (r=0.11; p=0.03). Compared with participants with sCD40L levels <4.36 ng/mL (75th percentile), participants with sCD40L levels >4.36 ng/mL had higher total (p=0.016) and LDL cholesterol (p=0.018), CRP levels (p=0.034) and FCRS (p=0.012). Multivariate analysis revealed that CRP level was the only parameter that independently correlated with the sCD40L levels (p=0.032). This is the first study to evaluate the relationship between sCD40L levels and Framingham global risk assessment in a large cohort of otherwise healthy individuals. We demonstrate that sCD40L levels poorly correlate with both the individual components and the calculated FCRS. Long-term follow-up of the FATE study will shed light on whether the predictive value of sCD40L is independent of Framingham based global risk assessment.

Understanding the frequency with which new resistance alleles arise and their subsequent patterns of spread is critical to our attempts to manage drug resistance in parasite populations. We review recent molecular evolutionary studies utilizing marker loci situated close to resistance loci on the Plasmodium falciparum genome that have given surprising insights into the origins and spread of drug resistance loci. We discuss possible reasons for the patterns observed, and highlight the implications of these results for resistance management. In particular, we show that many resistance mutations have rather few independent origins. De novo mutation appears to be less important than migration for introducing resistance alleles into parasite populations. Attempts to manage drug resistance will be of limited effectiveness unless this is taken into account.

The vascular endothelium has emerged as a critical determinant of cardiovascular health and disease, and improving endothelial function is an important target for therapy. Accumulating evidence suggests that insulin resistance in patients with diabetes and the metabolic syndrome may impair endothelial function, uncovering a proinflammatory, proatherosclerotic vascular phenotype. The rationale and design of the Glitazones and the Endothelium (GATE) study is presented. The GATE study is a randomized, double-blind study for the evaluation of the effects of rosiglitazone versus placebo on endothelial function when used as an add-on therapy in patients with diabetes currently treated with oral therapy. It is hypothesized that the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone will improve endothelium-dependent vasodilation, and that this effect will be related to improvements in insulin sensitivity, with concomitant reductions in whole-body insulin resistance. Furthermore, the beneficial effects of rosiglitazone will be additive to those of existing oral therapies that may modulate endothelial function. Because endothelial dysfunction plays a pivotal role in the development and progression of atherosclerosis, the GATE study may provide the rationale and impetus for the aggressive treatment of insulin-resistant patients with glitazone therapy.