Actual asthma control in a paediatric outpatient clinic population: Do patients perceive their actual level of control?

Several epidemiological studies described poor asthma control in children. However, the diagnosis of childhood asthma in these studies is uncertain, and asthma control in children of an outpatient clinic population during treatment by a paediatrician is unknown. (1) to investigate the hypothesis that asthma control in a paediatric outpatient clinic population is better than epidemiological surveys suggest; (2) to find possible explanations for suboptimal asthma control. Asthmatic children aged 6–16 years, known for at least 6 months by a paediatrician at the outpatient clinic, were selected. During a normal visit, both the responsible physicians and parent/children completed a standardised questionnaire about asthma symptoms, limitation of daily activities, treatment, asthma attacks and emergency visits. Overall, excellent asthma control of 8.0% in this study was not significantly better than of 5.8% in the European AIR study (Chi‐square, p = 0.24). Separate GINA goals like minimal chronic symptoms and no limitation of activities were better met in our study. Good to excellent controlled asthma was perceived by most children/parents (83%), but was less frequently indicated by the paediatrician (73%), or by objective criteria of control (45%) (chi‐square, p = 0.0001). The agreement between patient‐perceived and doctor assessed control was low, but improved in poorly controlled children. Patients were not able to perceive the difference between ‘excellent asthma control’ and ‘good control’ (p = 0.881).Too little children with uncontrolled disease got step‐up of their asthma treatment. Although separate GINA goals like ‘minimal chronic symptoms’ and ‘no limitation of activities’ were significantly better in our study, overall, asthma control in this outpatient clinic population, treated by a paediatrician, was not significantly better than in the European AIR study. Poorly controlled disease was related to several aspects of asthma management, which are potentially accessible for improvements.     

High intraindividual variation of B-type natriuretic peptide (BNP) and amino-terminal proBNP in patients with stable chronic heart failure

BACKGROUND: Plasma B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are promising markers for heart failure diagnosis, prognosis, and treatment. Insufficient data on the intraindividual biological variation (CV(i)) of BNP and NT-proBNP hamper interpretation of changes in concentration on disease progression or treatment optimization. We therefore investigated CV(i) values in stable heart failure patients. METHODS: We recruited 43 patients with stable chronic heart failure living in Curacao (22 males, 21 females; median age, 63 years; range, 20-86 years; New York Heart Association classes I-III). Samples were collected for within-day CV(i) (n = 6; every 2 h starting at 0800), day-to-day CV(i) (n = 5; samples collected between 0800 and 1000 on 5 consecutive days), and week-to-week CV(i) (n = 6; samples collected between 0800 and 1000 on the same day of the week for 6 consecutive weeks). NT-proBNP (Roche) and BNP (Abbott) were measured by immunoassay. RESULTS: Median (range) concentrations were 134 (0-1630) ng/L (BNP) and 570 (17-5048) ng/L (NT-proBNP). Analytical variation, week-to-week CV(i), and reference change values were 8.4%, 40%, and 113% (BNP), and 3.0%, 35%, and 98% (NT-proBNP). Week-to week CV(i)s were inversely related to median BNP concentrations. Week-to week CV(i)s for BNP were 44% (BNP < or =350 ng/L) and 30% (BNP >350 ng/L). Both BNP and NT-proBNP increased between 0800 and 1000. Median NT-proBNP/BNP ratios were inversely related to median BNP concentrations. CONCLUSIONS: The high CV(i)s hamper interpretation of changes in BNP and NT-proBNP concentrations and may partly explain their poor diagnostic values in chronic heart failure. Easily modifiable determinants to lower CV(i) have not been identified. The value of BNP and NT-proBNP for chronic heart failure diagnosis, and especially for follow-up and treatment optimization of individuals, remains largely to be established.     

Level of evidence for promising subgroup findings: The case of trends and multiple subgroups

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings.     

Matrix metalloproteinase‐9‐mediated type III collagen degradation as a novel serological biochemical marker for liver fibrogenesis

Background: During fibrogenesis in the liver, in which excessive remodelling of the extracellular matrix (ECM) occurs, both the quantity of type III collagen (CO3) and levels of matrix metalloproteinases (MMPs), including MMP‐9, increase significantly. MMPs play major roles in ECM remodelling, via their activity in the proteolytic degradation of extracellular macromolecules such as collagens, resulting in the generation of specific cleavage fragments. These neo‐epitopes may be used as markers of fibrosis. Aims: The current study investigated whether a novel enzyme‐linked immunosorbent assay (ELISA) assay specifically measuring an MMP‐9‐cleaved sequence of type III collagen located at position 610 (CO3‐610C) may be used as a marker of liver fibrosis. Material and methods: Bile duct ligation (BDL) was performed in 20 rats, with sham operations performed on another 20 rats. Serum levels of the neo‐epitope CO3‐610C (MMP‐mediated type III collagen degradation) were determined with an ELISA at 14 and 28 days post‐surgery. Liver fibrosis was evaluated by quantitative digital image analysis of Sirius red‐stained formalin‐fixed and paraffin‐embedded sections. Western blot and densitometry were performed to confirm the CO3‐610C ELISA data. Results: CO3‐610C levels in serum increased significantly in BDL rats compared with those undergoing sham operations (% increase: 14 days=153%, P<0.0001; 28 days=134%, P=0.0014). This increase was confirmed by Western blot and densitometry of the identified bands. The CO3‐610C levels correlated to liver fibrosis (R²=0.23 and P=0.01), as evaluated by quantitative digital histology. Discussion and conclusion: The data suggest that MMP‐9‐mediated CO3 turnover is a central event in the pathogenesis of fibrosis, and that the neo‐epitope generated may be a novel biochemical marker.     

Preoperative Evaluation of Patients with Possible Coronary Artery Disease

During noncardiac surgery, patients may be at risk for developing cardiac events, related to underlying coronary artery disease. Therefore, perioperative cardiac complications remain an area of clinical interest and concern in patients undergoing noncardiac surgery. Over the years, perioperative risk assessment has evolved significantly to detect surgical patients with myocardium at risk due the coronary artery disease. In addition, many efforts have been made to reduce the cardiac risk of patients undergoing noncardiac surgery. The present review article will focus on the definition of high cardiac risk surgery and will discuss patient-related cardiac risk factors. In addition, the preoperative cardiac tests available to detect patients with coronary artery disease and strategies to reduce perioperative cardiac risk, as recommended in most recent perioperative guidelines, will be outlined.     

The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans

In the mucosa, the immune pathways discriminating between colonizing and invasive Candida, thus inducing tolerance or inflammation, are poorly understood. Th17 responses induced by Candida albicans hyphae are central for the activation of mucosal antifungal immunity. An essential step for the discrimination between yeasts and hyphae and induction of Th17 responses is the activation of the inflammasome by C. albicans hyphae and the subsequent release of active IL-1β in macrophages. Inflammasome activation in macrophages results from differences in cell-wall architecture between yeasts and hyphae and is partly mediated by the dectin-1/Syk pathway. These results define the dectin-1/inflammasome pathway as the mechanism that enables the host immune system to mount a protective Th17 response and distinguish between colonization and tissue invasion by C. albicans.