Antibiotic usage, dosage and course length in children between 0 and 4 years

Antibiotic drugs are most frequently used by 0- to 4-year-old children. We performed a cross-sectional study in the Netherlands using a pharmacy prescription database to investigate the use, dose and course length of antibiotic drugs in 0- to 4-year-olds. We used a database with pharmacy drug-dispensing data. We investigated all prescriptions of systemic antibiotics prescribed in the years 2002-2006 for children of 0-4 years of age. Prescriptions for children under the age of 3 months were excluded. Children of 9-12 months of age received more antibiotics than children in other age groups. In the 3- to 6-month-olds, amoxicillin was prescribed in 75.2% of the cases. This percentage was 50.4% in the 4-year-olds. The contribution of other broad-spectrum antibiotics increased with age (clarithromycin and amoxicillin/clavulanic acid). Small-spectrum penicillins were prescribed less often than the broad-spectrum antibiotics. From the prescriptions of the five most used drugs, 97.6% were within the recommended dose range. Most course lengths corresponded with the guidelines. Of the prescriptions, 3.9% were unlicensed or off-label. Within the group of 0- to 4-year-old children, most antibiotics were used by 9- to 12-month-olds. The doses and course lengths were mostly correct, but the choice of antibiotics was not according to the guidelines. Young children received unlicensed and off-label prescribed antibiotics

Use of double-blind placebo-controlled N-of-1 trials among stimulant-treated youths in The Netherlands: a descriptive study.

Objectives An N-of-1 trial is a double-blind placebo-controlled randomized trial to objectively and systematically evaluate the individual's response. This approach seems extraordinarily suitable for assessing the efficacy of stimulants in the treatment of attention deficit hyperactivity disorder (ADHD). The aim is to examine the use of N-of-1 trials among youths in the Netherlands, the protocols used, and the continuation of stimulant treatment thereafter. Methods Physicians requesting N-of-1 trials with stimulants were interviewed about their rationale and protocol. Prevalence and continuation were investigated by extracting N-of-1 trials among youths <20 years of age from a large pharmacy dispensing database for 2000-2004. Results The main purpose of N-of-1 trials mentioned by physicians was the assessing of individuals' response and dose-finding. Trial length, dosing schedule and efficacy assessment differed per physician. Trials consisted of a maximum of two treatment periods per dose. The annual percentage of youths starting stimulant treatment with an N-of-1 trial fluctuated between 0.6% (3/462) and 3.3% (10/301). No statistical significant difference could be detected between the continuation of stimulant treatment with or without an N-of-1 trial (p=0.71). Conclusions N-of-1 trials with stimulants are infrequently and not optimally used in the Netherlands. The results of N-of-1 protocols described by physicians are of questionable value, due to the small number of treatment periods per dose. More uniformity in the protocols would make it easier to encompass the N-of-1 methodology in physicians' daily practice

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease

HRT use in 2001 and 2004 in The Netherlands - A world of difference

Objective: Did the publication of the Women Health Initiative (WHI) trial in 2002 and the Million Women Study (MWS) in 2003 lead to changes in prescription rates of hormone replacement therapy (HRT). Therefore, we compare the prescribing of HRT in 2004 (after) with that of 2001 (before the publications) in The Netherlands. Method: Community pharmacy dispensing data from a population of approximately 500,000 patients in The Netherlands. Women aged 40-74 years to whom at least one HRT prescription was dispensed in 2001 or 2004 were included. Annual prevalences of HRT in 2001 and 2004 and the percentage change (2004 versus 2001) were calculated for overall HRT (excluding vaginal products) and per HRT category (combined estrogens and progestagens, estrogens only, tibolon and vaginal preparations) and age category. Results: In 2001. 5.64% of the women aged 40-74 used HRT and this percentage declined to 2.39 in 2004. The use of vaginal products among these women did not change, 1.76% in 2001 and 1.65% in 2004. The percentage change was highest in the opposed HRT group (66% decrease) and in women aged 50-54 (64.4% decrease). In 2004, compared with 2001, the proportion of long-term users (> 3 year) increased with 12.7%. Conclusions: In The Netherlands, after publication of the WHI Study and the MWS the prescribing of HRT fell dramatically whereas the prescribing of vaginal products did not change. Future patterns of HRT use should be monitored to know whether this decrease will be sustained. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Small proportions:what to report for confidence intervals?

Purpose It is generally agreed that a confidence interval (CI) is usually more informative than a point estimate or p-value, but we rarely encounter small proportions with CI in the pharmacoepidemiological literature. When a CI is given it is sporadically reported, how it was calculated. This incorrectly suggests one single method to calculate CIs. To identify the method best suited for small proportions, seven approximate methods and the Clopper-Pearson Exact method to calculate CIs were compared. Methods In a simulation study for 90-, 95- and 99%CIs, with sample size 1000 and proportions ranging from 0.001 to 0.01, were evaluated systematically. Main quality criteria were coverage and interval width. The methods are illustrated using data from pharmacoepidemiology studies. Results Simulations showed that standard Wald methods have insufficient coverage probability regardless of how the desired coverage is perceived. Overall, the Exact method and the Score method with continuity correction (CC) performed best. Real life examples showed the methods to yield different results too. Conclusions For CIs for small proportions (p