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1.  Cardiovascular and neuropsychiatric safety of varenicline and bupropion compared with nicotine replacement therapy for smoking cessation: study protocol of a retrospective cohort study using the QResearch general practice database 
BMJ Open  2014;4(8):e005281.
Cigarette smoking continues to be the leading cause of preventable death and is the main risk factor of major diseases such as chronic obstructive pulmonary disease (COPD). The best treatment to help smokers quit is a combination of behavioural support with pharmacotherapy. Varenicline is the newest drug on the market and has been shown to be effective in the general smoking population and in smokers with COPD. The safety profile of varenicline was initially established using standard approaches to pharmacovigilance, but postmarketing reports have raised concerns about a possible association between the use of varenicline and cardiovascular and neuropsychiatric events. Although recent studies have not confirmed such an association, further research is needed given the large number of smokers who are being prescribed varenicline, including important subgroups such as smokers with COPD who may be particularly vulnerable to side effects of drugs. The aim of this study is to assess the cardiovascular and neuropsychiatric safety of varenicline using data from the QResearch general practice (GP) database.
Methods and analysis
We will conduct a retrospective cohort study in the QResearch GP database. Patients will be categorised into three exposure groups: prescription of (1) varenicline, (2) bupropion or (3) nicotine replacement therapy (NRT Rx; =reference group). We will separately consider major incident neuropsychiatric and cardiovascular outcomes that occur during 6 months of follow-up using Cox proportional hazards models, adjusted for confounders. Furthermore, propensity score analysis will be used as an analytical approach to account for potential confounding by indication.
Ethics and dissemination
This work involves analysis of anonymised, routinely collected data. The protocol has been independently peer-reviewed by the QResearch Scientific Board and meets the requirements of the Trent research ethics committee. We plan to disseminate the results from this study via articles in international peer-reviewed journals and presentations at relevant national and international health conferences.
PMCID: PMC4156814  PMID: 25168037
Epidemiology; Mental Health
2.  Profiling of Volatile Organic Compounds in Exhaled Breath As a Strategy to Find Early Predictive Signatures of Asthma in Children 
PLoS ONE  2014;9(4):e95668.
Wheezing is one of the most common respiratory symptoms in preschool children under six years old. Currently, no tests are available that predict at early stage who will develop asthma and who will be a transient wheezer. Diagnostic tests of asthma are reliable in adults but the same tests are difficult to use in children, because they are invasive and require active cooperation of the patient. A non-invasive alternative is needed for children. Volatile Organic Compounds (VOCs) excreted in breath could yield such non-invasive and patient-friendly diagnostic. The aim of this study was to identify VOCs in the breath of preschool children (inclusion at age 2–4 years) that indicate preclinical asthma. For that purpose we analyzed the total array of exhaled VOCs with Gas Chromatography time of flight Mass Spectrometry of 252 children between 2 and 6 years of age. Breath samples were collected at multiple time points of each child. Each breath-o-gram contained between 300 and 500 VOCs; in total 3256 different compounds were identified across all samples. Using two multivariate methods, Random Forests and dissimilarity Partial Least Squares Discriminant Analysis, we were able to select a set of 17 VOCs which discriminated preschool asthmatic children from transient wheezing children. The correct prediction rate was equal to 80% in an independent test set. These VOCs are related to oxidative stress caused by inflammation in the lungs and consequently lipid peroxidation. In conclusion, we showed that VOCs in the exhaled breath predict the subsequent development of asthma which might guide early treatment.
PMCID: PMC3994075  PMID: 24752575
3.  Environmental Smoking and Smoking Onset in Adolescence: The Role of Dopamine-Related Genes. Findings from Two Longitudinal Studies 
PLoS ONE  2014;9(1):e86497.
Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents' and friends' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system.
PMCID: PMC3897729  PMID: 24466121
4.  Sex Differences in the Relationship between Asthma and Overweight in Dutch Children: a Survey Study 
PLoS ONE  2013;8(10):e77574.
Obesity has been identified as a risk factor for asthma in children. However, in the Netherlands, the obesity prevalence is rising while the asthma prevalence in children is stabilising. The aim of this study is to clarify the association between asthma and Body Mass Index (BMI) in children and whether this association is influenced by sex.
Study Design
Parents of 39,316 children (6-16 years) in the south of the Netherlands were invited to complete an online questionnaire on respiratory symptoms, anthropometric variables and several potential confounding factors for asthma and obesity (including sex, birth weight and breastfeeding). Data was analysed by multivariable logistic regression models and an ordinal regression model.
The response rate was 24% (n boys= 4,743, n girls= 4,529). The prevalence of asthma, overweight and obesity was 8%, 15% and 2% respectively. Body mass index - standard deviation Score (BMI-SDS) was related to current asthma (adjusted OR: 1.29; 95%CI: 1.14-1.45, p≤0.001). When stratified for sex, asthma and BMI-SDS were only related in girls (Girls: adjusted OR: 1.31; 95%CI: 1.13-1.51, p≤0.001. Boys: adjusted OR: 1.01; 95%CI: 0.91-1.14, p=0.72).
The positive association between BMI-SDS and asthma is only present in girls, not boys. Future studies into obesity and asthma should correct for sex in their analyses.
PMCID: PMC3804131  PMID: 24204876
5.  Smoking-Specific Parenting and Smoking Onset in Adolescence: The Role of Genes from the Dopaminergic System (DRD2, DRD4, DAT1 Genotypes) 
PLoS ONE  2013;8(4):e61673.
Although only few studies have shown direct links between dopaminergic system genes and smoking onset, this does not rule out the effect of a gene-environment interaction on smoking onset. Therefore, the aim of this study was to examine the associations between smoking-specific parenting (i.e., frequency and quality of communication and house rules) and smoking onset while considering the potential moderating role of dopaminergic system genes (i.e., DRD2, DRD4, and DAT1 genotypes). Data from five annual waves of the ‘Family and Health’ project were used. At time 1, the sample comprised 365 non-smoking adolescents (200 younger adolescents, mean age = 13.31, SD = .48; 165 older adolescents, mean age = 15.19, SD = .57). Advanced longitudinal analyses were used (i.e., logistic regression analyses, (dual) latent growth curves, and cross-lagged path models). The results showed a direct effect of quality of communication on smoking onset. No direct effects were found for frequency of communication and house rules. Furthermore, no direct and moderating effects of the DRD2, DRD4, or DAT1 genotypes were found. In conclusion, the findings indicated that the effects of smoking-specific parenting on smoking are similar for adolescent carriers and non-carriers of the dopaminergic system genes.
PMCID: PMC3630129  PMID: 23637880
6.  Early assisted discharge with generic community nursing for chronic obstructive pulmonary disease exacerbations: results of a randomised controlled trial 
BMJ Open  2012;2(5):e001684.
To determine the effectiveness of early assisted discharge for chronic obstructive pulmonary disease (COPD) exacerbations, with home care provided by generic community nurses, compared with usual hospital care.
Prospective, randomised controlled and multicentre trial with 3-month follow-up.
Five hospitals and three home care organisations in the Netherlands.
Patients admitted to the hospital with an exacerbation of COPD. Patients with no or limited improvement of respiratory symptoms and patients with severe unstable comorbidities, social problems or those unable to visit the toilet independently were excluded.
Early discharge from hospital after 3 days inpatient treatment. Home visits by generic community nurses. Primary outcome measure was change in health status measured by the Clinical COPD Questionnaire (CCQ). Treatment failures, readmissions, mortality and change in generic health-related quality of life (HRQL) were secondary outcome measures.
139 patients were randomised. No difference between groups was found in change in CCQ score at day 7 (difference in mean change 0.29 (95% CI −0.03 to 0.61)) or at 3 months (difference in mean change 0.04 (95% CI –0.40 to 0.49)). No difference was found in secondary outcomes. At day 7 there was a significant difference in change in generic HRQL, favouring usual hospital care.
While patients’ disease-specific health status after 7-day treatment tended to be somewhat better in the usual hospital care group, the difference was small and not clinically relevant or statistically significant. After 3 months, the difference had disappeared. A significant difference in generic HRQL at the end of the treatment had disappeared after 3 months and there was no difference in treatment failures, readmissions or mortality. Early assisted discharge with community nursing is feasible and an alternative to usual hospital care for selected patients with an acute COPD exacerbation.
Trial registration: NetherlandsTrialRegister NTR 1129.
PMCID: PMC3488726  PMID: 23075570
Primary Care
7.  Care delivery pathways for Chronic Obstructive Pulmonary Disease in England and the Netherlands: a comparative study 
A remarkable difference in care delivery pathways for Chronic Obstructive Pulmonary Disease (COPD) is the presence of hospital-at-home for COPD exacerbations in England and its absence in the Netherlands. The objective of this paper is to explain this difference.
Descriptive COPD statistics and care delivery pathways on all care levels within the institutional context, followed by a comparison of care delivery pathways and an explanation of the difference with regard to hospital-at-home.
The Netherlands and England show broad similarities in their care delivery pathways for COPD patients. A major difference is the presence of hospital-at-home for COPD exacerbations in England and its absence in the Netherlands. Three possible explanations for this difference are presented: differences in the urgency for alternatives (higher urgency for alternative treatment models in England), the differences in funding (funding in England facilitated the development of hospital-at-home) and the differences in the substitution of tasks to nurses (substitution to nurses has taken place to a larger extent in England).
Discussion and Conclusion
The difference between the Netherlands and England regarding hospital-at-home for COPD exacerbations can be explained in three ways. Hospital-at-home has proved to be a safe alternative for hospital care for selected patients, and should be considered as a treatment option for COPD exacerbations in the Netherlands.
PMCID: PMC3440249  PMID: 22977431
comparative analysis; COPD; exacerbations; care delivery pathways; hospital-at-home, integrated care
8.  A Disease Model for Wheezing Disorders in Preschool Children Based on Clinicians' Perceptions 
PLoS ONE  2009;4(12):e8533.
Wheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult.
Methodology/Principal Findings
The aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children.
While there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.
PMCID: PMC2795203  PMID: 20046874

Results 1-9 (9)