Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Global Health Priority Box─Proactive Pandemic Preparedness.

The coronavirus pandemic outbreak of 2019 highlighted the critical importance of preparedness for current and future public health threats (https://www.mmv.org/mmv-open/global-health-priority-box/about-global-health-priority-box).

Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway.

Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S.

Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study.

Objectives: Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs.

Achievement of LDL-C goals depends on baseline LDL-C and choice and dose of statin: an analysis from the VOYAGER database.

Background: Reducing low-density lipoprotein cholesterol (LDL-C) levels decreases cardiovascular risk in direct proportion to the decrease in LDL-C.

Design: The aim of this study was to assess the importance of baseline LDL-C and choice and dose of statin in achievement of LDL-C goals of 100 and 70 mg/dl, using a novel statistical model. The analysis included 30,102 patient exposures to rosuvastatin 10-40 mg or atorvastatin 10-80 mg from 31 direct comparative trials in the VOYAGER database.

Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either <70 mg/dl or ≥ 50% reduction in high-risk patients: results from VOYAGER.

Objective: Guidelines published in 2011 by the European Atherosclerosis Society and the European Society of Cardiology recommend a goal of either low-density lipoprotein cholesterol (LDL-C) <70 mg/dl (~1.8 mmol/l) or ≥ 50% reduction in LDL-C for patients at very high cardiovascular risk. The aim of this study was to determine the percentage of high-risk patients from the VOYAGER individual patient data meta-analysis treated with rosuvastatin 10-40 mg, atorvastatin 10-80 mg or simvastatin 10-80 mg who achieved this goal.

Effect of rosuvastatin on the echolucency of the common carotid intima-media in low-risk individuals: the METEOR trial.

Background: The echolucency of the carotid intima-media is related to increased cardiovascular risk factor levels, morbidity, and mortality. The aim of this study was to assess the effect of statins on the echolucency of the common carotid intima-media in a low-risk population.

Methods: Data from the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin study were used.

Biologically implausible carotid intima-media thickness measurement values: effects on rate of change over time.

Objective: Carotid intima-media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT.

Multiple imputation of missing repeated outcome measurements did not add to linear mixed-effects models.

Objective: To assess the added value of multiple imputation (MI) of missing repeated outcomes measures in longitudinal data sets analyzed with linear mixed-effects (LME) models.

Study Design And Setting: Data were used from a trial on the effects of Rosuvastatin on rate of change in carotid intima-media thickness (CIMT). The reference treatment effect was derived from a complete data set.

Sample size requirements in trials using repeated measurements and the impact of trial design.

Objective: Sample size calculations for clinical trials generally use expected changes between groups, and variances obtained from the literature. However, this approach neglects the impact of differences in trial design. We studied the effects of variations in trial design on the required sample size.

Extensive or restricted ultrasound protocols to measure carotid intima-media thickness: analysis of completeness rates and impact on observed rates of change over time.

Background: Ultrasound protocols to measure carotid intima-media thickness (CIMT) vary considerably with regard to carotid sites and angles that are assessed. Measurements from the carotid bifurcation and internal carotid artery are thought to be affected by large numbers of missing data. Actual published quantification of completeness rates and the relation with cardiovascular risk factors, however, is scarce.

Algorithms to measure carotid intima-media thickness in trials: a comparison of reproducibility, rate of progression and treatment effect.

Background: Current ultrasound protocols to measure carotid intima-media thickness (CIMT) in trials differ considerably. The best CIMT protocol would be one that combines high reproducibility, a large and precise estimate of the rate of CIMT progression and a large and precise estimate of the treatment effect. We performed a post-hoc analysis to determine the best algorithm for determining CIMT using data from the METEOR study, a randomized double-blind, placebo-controlled study of the effect of rosuvastatin on CIMT progression in 984 low coronary heart disease risk individuals with increased CIMT.

The use of plaque score measurements to assess changes in atherosclerotic plaque burden induced by lipid-lowering therapy over time: the METEOR study.

Aim: To evaluate whether plaque scoring measurements are able to track changes in atherosclerotic plaque burden over time and to study whether this is affected by lipid-lowering therapy.

Methods: Data used were from METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin), a randomized controlled trial of rosuvastatin 40 mg among 984 low-risk patients with modest carotid intima-media thickening (CIMT). In this analysis, duplicate ultrasound images from 12 carotid sites were collected at the baseline and end of the study from 495 European patients and were evaluated for plaque presence and severity.

Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender.

Background: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk.

Methods And Results: We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT.

Effect of number of ultrasound examinations on the assessment of carotid intima-media thickness changes over time: the example of the METEOR study.

Objective: To evaluate the effect of the number and positioning during follow-up of ultrasound examinations on the rate of change in carotid intima-media thickness (CIMT) using METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin) as an example.

Methods: METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced progression of 2-year change in CIMT among low-risk patients with subclinical atherosclerosis. In the full METEOR protocol, ultrasound examinations were performed twice before randomization, once each at 6, 12, and 18 months after randomization, and then twice at the end of study at 24 months.

Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER).

Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin.

Does baseline carotid intima-media thickness modify the effect of rosuvastatin when compared with placebo on carotid intima-media thickness progression? The METEOR study.

Background: Many studies have used carotid intima-media thickness (CIMT) measurement to study atherosclerosis and the efficacy of interventions. The placebo-controlled Measuring Effects on intima-media Thickness: an Evaluation Of Rosuvastatin (METEOR) study showed significant reduction in the progression rate of maximum CIMT with 2 years of lipid treatment in asymptomatic individuals with subclinical atherosclerosis.

Design: The present post-hoc subgroup analysis of METEOR was carried out to determine whether the effect of rosuvastatin treatment varied according to baseline CIMT level.

Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database.

The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin.

Toxic epidermal necrolysis and neutropaenia: complications of omeprazole.

Worldwide, proton pump inhibitors (PPI) are one of the most frequently prescribed drugs; however, up to 70% of patients taking these drugs have no appropriate indication. Although PPI are relatively well tolerated, they are not free from side-effects and several life-threatening complications are associated with them. In the present report, a 43-year-old woman presented to her general practitioner with an erythematous rash over her face and chest, having been started on omeprazole for chronic abdominal bloating.

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.

Context: Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis.

Objective: To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years.

Design, Setting, And Participants: Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.

Carotid intima-media thickness in low-risk individuals with asymptomatic atherosclerosis: baseline data from the METEOR study.

Objective: Carotid intima-media thickness (CIMT) is an index for changes in atherosclerosis burden and changes in CIMT may relate to clinical events. We present baseline data from the METEOR study, a randomized, placebo-controlled trial evaluating the efficacy of rosuvastatin 40 mg on changes in CIMT. We set out to compare differences in CIMT between several subgroups of individuals.

Cerebellar neurotransmission in attention-deficit/hyperactivity disorder: does dopamine neurotransmission occur in the cerebellar vermis?

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry.

Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin in subclinical atherosclerosis--the rationale and methodology of the METEOR study.

Background: Increased carotid intima media thickness (IMT) is associated with established coronary heart disease (CHD) and is a marker of atherosclerosis. Statins are an effective treatment for dyslipidaemia, and have been shown to retard progression or promote carotid IMT regression in patients at high risk of CHD. Rosuvastatin is a highly efficacious statin, and the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) study is designed to assess the impact of rosuvastatin on carotid IMT progression in low risk subjects with signs of subclinical atherosclerosis.