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Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma.

Rationale: Epidemiological studies have reported on the detrimental effects on lung function after natural, and thus limited, weight gain in unselected populations. Studies on bariatric surgery, on the contrary, have indicated large improvements in lung function after substantial weight loss. Objectives: To study the associations between profound weight loss or gain and pulmonary function within the same population. A second objective was to investigate the effect of weight cycling on pulmonary function. Methods: From our lung function database, we selected the records of subjects in follow-up for continuous positive airway pressure therapy for sleep apnea with a weight change of ⩾20 kg within 5 years. Lung function ( N  = 255) at baseline was normal except for a tendency toward mild restriction in morbid obesity. Within this sample, 73 subjects were identified with significant "weight cycling", defined as a ⩾10-kg opposite change in body weight before or after the ⩾20-kg weight change. Results: Weight change affected pulmonary function more in men than in women ( P  < 0.001). In men, forced vital capacity (FVC) increased an average of 1.4% predicted per unit of body mass index after weight loss and the reverse after weight gain, whereas women exhibited a smaller change of 0.9% predicted per unit of body mass index. Weight loss slightly increased the ratio of forced expiratory volume in 1 second to FVC and decreased the specific airway resistance, whereas the opposite occurred with weight gain. Greater effects of weight change on lung function were observed in leaner subjects ( P  = 0.02) and in older subjects ( P  < 0.002). Changes in total lung capacity followed the changes in FVC, with no change in residual volume, and the greatest change was observed in functional residual capacity. In subjects with weight cycling, the improvement in lung function due to weight loss was reversed by subsequent weight gain and vice versa. Conclusions: This study provides evidence that the detrimental effect of obesity on lung function is a passive and reversible process.

Background: Results of studies evaluating the relationship between asthma occurrence and early life antibiotic use have been conflicting. The aim of this study was to investigate the relationship between occurrence of asthma in children and systemic antibiotic use in the first year of life based on an incidence density study with careful consideration of the temporal aspects of the determinant-outcome relationship., Methods: We conducted an incidence density study nested in a data collection project with information on 1128 mother-child pairs. Systemic antibiotic use in the first year of life was defined as excessive (≥ 4 courses) vs. non-excessive (< 4 courses) use based on information from weekly diaries. Events (cases) were defined as the first parent-reported occurrence of asthma in a child between 1 and 10 years of age. Population time 'at risk' was probed by sampling population moments (controls). Missing data were imputed. Multiple logistic regression was used to assess the association between current first asthma occurrence (incidence density) and systemic antibiotic use in the first year of life, to evaluate effect modification and adjust for confounding., Results: Forty-seven first asthma events and 147 population moments were included. Excessive systemic antibiotic use in the first year of life showed more than twice the incidence density of asthma compared to non-excessive use (adjusted IDR [95% CI]: 2.18 [0.98, 4.87], p = 0.06). The association was more pronounced in children who have had lower respiratory tract infections (LRTIs) in the first year of life compared to children who had no LRTIs in the first year of life (adjusted IDR [95% CI]: 5.17 [1.19, 22.52] versus 1.49 [0.54, 4.14])., Conclusions: Excessive use of systemic antibiotics in the first year of life may play a role in the genesis of asthma in children. This effect is modified by the occurrence of LRTIs in the first year of life, with a stronger association observed in children experiencing LRTIs in the first year of life., (© 2023. The Author(s).)

Good research is driven by study design encompassing theoretical design, design of data collection and design of data processing. In epidemiological research, theoretical design is based on a functional relationship between the occurrence and determinants studied (occurrence function) and should also define that part of the theoretical population and the context to which the results pertain (domain). Both are essential for the design of data collection, the design of data processing and the interpretation of the study results and should be explicitly reported. In order to gain insight into the role of theoretical design in the entire research process before publication, it was decided to informally question the corresponding authors of a selection of 30 articles (20 most recent and 10 less recent) reporting on causal observational epidemiological studies on asthma and early life exposure to antibiotics. The objective was to appraise the perceived knowledgeability of theoretical design among the authors of the selected articles. Fifteen authors responded. Authors were asked to indicate their knowledgeability with the concepts of theoretical design, causal theory, confounding and effect modification on a 5-level Likert scale. Other questions were related to the theoretical design of their study. The vast majority of the authors perceived themselves to be moderately to extremely knowledgeable with confounding and effect modification. Perceived knowledgeability of theoretical design and causal theory was more diverse. When provided with options for an occurrence function, almost all authors indicated "current occurrence as a function of past exposure" for their study. Nevertheless, half of these authors conducted their study based on "future occurrence as a function of current exposure". Even though the authors perceive themselves to be knowledgeable with theoretical design, this is not reflected in their articles. Theoretical design should be well known, implemented and explicitly reported., Competing Interests: The authors declare that they have no competing interests in this work., (© 2023 Bentouhami and Weyler.)

In previous studies, the strength of the association between childhood asthma and environmental tobacco smoke (ETS) differed depending on the way ETS was assessed and the type of study conducted. We investigated the relationship between asthma occurrence in children and recent exposure to ETS based on an incidence-density study driven by the explicit formulation of a theoretical design. Additionally, we assessed whether the relationship is modified by perinatal ETS exposure and parental inhalation atopy. The event was conceptualized as 'first doctor's diagnosis of asthma'. Population time was probed by sampling population moments. Exposure to ETS was conceptualized as recent exposure (1 year prior to diagnosis or at sampling) and perinatal exposure (in utero and/or during the first year of life). Thirty-nine events and 117 population moments were included. There was no indication for effect modification by perinatal exposure to ETS or parental inhalation atopy. After adjustment for confounding, an association was observed between occurrence of a first asthma diagnosis and recent ETS exposure: incidence-density ratio 4.94 (95% confidence interval 1.21, 20.13). Asthma occurrence in children is associated with recent exposure to ETS, and this association seems not to be modified by perinatal ETS exposure or parental inhalation atopy.

"Theoretical design" comprises the development of an occurrence relation and the specification of the study domain. In explanatory research, the occurrence relation causally relates one determinant to the occurrence (of an event or a state) taking into account other relevant characteristics (confounders and modifiers). Conflicting results in explanatory research might be (partially) explained by differences in the "theoretical design" or by a mismatch between the "theoretical design" and the "design of data collection". In this critical review, the reporting of "theoretical design" is assessed in articles on the association between early life antibiotic use and the occurrence of asthma. Articles investigating a relationship between early life antibiotic use and the occurrence of asthma were searched in PubMed and systematically selected for critical review. The full text was read and important elements of study design were extracted (the research question/hypothesis, seven key elements of "theoretical design" (measure of occurrence, case (event or state) definition, conceptualization (and operationalization) of the exposure, temporal relation between outcome and exposure, confounders and effect modifiers taken into account and the domain of the study), the method of data collection and the method of data processing). A comparison was made between articles published before and after the publication of the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) statement (2007). Sixty-three articles were included for review. Thirteen articles reported the seven key elements of "theoretical design" that were questioned. No marked differences in reporting were observed pre- and post-STROBE. All articles reported some key elements of "theoretical design"; however, the reporting is not structured and not linked to the concept of "theoretical design". Conceptualizing, delineating and explicit reporting of "theoretical design" is quintessential for the quality and transparency of explanatory research., Competing Interests: The authors declare that they have no conflicts of interest for this work., (© 2021 Bentouhami et al.)

Background: Fractional exhaled nitric oxide (FeNO) is a marker of type-2 inflammation used both to support diagnosis of asthma and follow up asthma patients. The associations of FeNO with lung function decline and bronchodilator (BD) response have been studied only scarcely in large populations., Objectives: To study the association between FeNO and a) retrospective lung function decline over 20 years, and b) lung function response to BD among asthmatic subjects compared with non-asthmatic subjects and with regards to current smoking and sex., Methods: Longitudinal analyses of previous lung function decline and FeNO level at follow-up and cross-sectional analyses of BD response and FeNO levels in 4257 participants (651 asthmatics) from the European Community Respiratory Health Survey., Results: Among asthmatic subjects, higher percentage declines of FEV 1 and FEV 1 /FVC were associated with higher FeNO levels (p = 0.001 for both) at follow-up. These correlations were found mainly among non-smoking individuals (p = 0.001) and females (p = 0.001) in stratified analyses.Percentage increase in FEV 1 after BD was positively associated with FeNO levels in non-asthmatic subjects. Further, after stratified for sex and smoking separately, a positive association was seen between FEV 1 and FeNO levels in non-smokers and women, regardless of asthma status., Conclusions: We found a relationship between elevated FeNO and larger FEV 1 decline over 20 years among subjects with asthma who were non-smokers or women. The association between elevated FeNO levels and larger BD response was found in both non-asthmatic and asthmatic subjects, mainly in women and non-smoking subjects., Competing Interests: DF reports grants from Asthma Foundation of Victoria, grants from Allen and Hanbury’s, grants from National Health & Medical Research Council, during the conduct of the study. VS reports grants from The Wood Dust Foundation (Project No. 444508795), during the conduct of the study. RJ reports grants from Estonian Research Council Personal Research Grant no 562, during the conduct of the study; personal fees from Consultancy, grants from Grants/grants pending, personal fees from Payment for lectures, personal fees from Travel/accommodations/meeting expenses, outside the submitted work. PD reports grants from ALK, Stallergenes Greer, grants from AstraZeneca, ThermoFisherScientific, Ménarini, grants from Bausch & Lomb, personal fees from Sanofi, Regeneron, outside the submitted work. RN reports grants and personal fees from AstraZeneca, grants from Novartis, grants from Boehringer Ingelheim, grants and personal fees from GlaxoSmithKline, outside the submitted work. IP reports other from NOVARTIS, other from ASTRA ZENECA, personal fees from AGIRadom, outside the submitted work. All other authors declare no conflicts of interests. The following grants contributed to funding ECRHS I. Australia: Asthma Foundation of Victoria, Allen and Hanbury’s. Belgium: Belgian Science Policy Office, National Fund for Scientific Research. Denmark: The Danish Lung Association. Estonia: Estonian Science Foundation, grant no 1088. France: Ministère de la Santé, Glaxo France, Institut Pneumologique d'Aquitaine, Contrat de Plan Etat-Région Languedoc-Rousillon, CNMATS, CNMRT (90MR/10, 91AF/6), Ministre delegué de la santé, RNSP, France; GSF. Germany: Bundesminister für Forschung und Technologie. Greece: The Greek Secretary General of Research and Technology, Fisons, Astra and Boehringer-Ingelheim. India: Bombay Hospital Trust. Italy: Ministero dell'Università e della Ricerca Scientifica e Tecnologica, CNR, Regione Veneto grant RSF n. 381/05.93. New Zealand: Asthma Foundation of New Zealand, Lotteries Grant Board, Health Research Council of New Zealand. Norway: Norwegian Research Council project no. 101422/310. Portugal: Glaxo Farmacêutica Lda, Sandoz Portugesa. Spain: Fondo de Investigación Sanitaria (#91/0016-060-05/E, 92/0319 and #93/0393), Hospital General de Albacete, Hospital General Juan Ramón Jiménez, Dirección Regional de Salud Pública (Consejería de Sanidad del Principado de Asturias), CIRIT (1997 SGR 00079), and Servicio Andaluz de Salud. Sweden: The Swedish Medical Research Council, the Swedish Heart Lung Foundation, and the Swedish Association against Asthma and Allergy. Switzerland: Swiss National Science Foundation grant 4026-28099. UK: National Asthma Campaign, British Lung Foundation, Department of Health, South Thames Regional Health Authority. USA: United States Department of Health, Education and Welfare Public Health Service (grant #2 S07 RR05521-28). The coordination of this work was supported by the European Commission. The following grants contributed to funding ECRHS III. Australia: National Health & Medical Research Council. Belgium: Antwerp South, Antwerp City – Research Foundation Flanders (FWO), grant code G.0.410.08.N.10 (both sites). Estonia: Tartu – SF0180060s09 from the Estonian Ministry of Education. France: (All) Ministère de la Santé, Programme Hospitalier de Recherche Clinique (PHRC) national 2010. Bordeaux: INSERM U897 Université Bordeaux Segalen. Grenoble: Comite Scientifique AGIRadom 2011. Paris: Agence Nationale de la Santé, Région Ile de France, domaine d’intérêt majeur (DIM). Germany: Erfurt: German Research Foundation HE 3294/10-1. Hamburg: German Research Foundation MA 711/6-1, NO 262/7-1. Iceland: Reykjavik, The Landspítali University Hospital Research Fund, University of Iceland Research Fund, ResMed Foundation, California, USA, Orkuveita Reykjavíkur (Geothermal plant), Vegagerðin (The Icelandic Road Administration (ICERA). Italy: All Italian centres were funded by the Italian Ministry of Health, Chiesi Farmaceutici SpA. Verona received additional funding from the Cariverona foundation, Education Ministry (MIUR). Norway: Norwegian Research Council grant no 214123, Western Norway Regional Health Authorities grant no 911631, Bergen Medical Research Foundation. Spain: Fondo de Investigación Sanitaria (PS09/02457, PS09/00716 09/01511) PS09/02185 PS09/03190), Servicio Andaluz de Salud, Sociedad Española de Neumología y Cirurgía Torácica (SEPAR 1001/2010), Fondo de Investigación Sanitaria (PS09/02457). Barcelona: Fondo de Investigación Sanitaria (FIS PS09/00716). Galdakao:Fondo de Investigación Sanitaria (FIS 09/01511). Huelva: Fondo de Investigación Sanitaria (FIS PS09/02185) and Servicio Andaluz de Salud. Oviedo: Fondo de Investigación Sanitaria(FIS PS09/03190). Sweden: All centres were funded by the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association, the Swedish Association against Lung and Heart Disease, and the Swedish Research Council for Health, Working Life and Welfare (FORTE). Göteborg also received further funding from the Swedish Council for Working Life and Social Research. Umeå also received funding from a Västerbotten County Council ALF grant. Switzerland: The Swiss National Science Foundation (grants no 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), The Federal office for Forest, Environment and Landscape, The Federal Office of Public Health, The Federal Office of Roads and Transport, the canton’s government of Aargan, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton’s Lung League of Basel Stadt/ Basel, Landschaft, Geneva, Ticino, Valais, and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA, UK: Medical Research Council (Grant Number 92091). Support was also provided by the National Institute for Health Research through the Primary Care Research Network., (© 2021 The Author(s).)

Rationale: Few longitudinal studies have assessed the relationship between occupational exposures and lung-function decline in the general population with a sufficiently long follow-up. Objectives: To examine the potential association in two large cohorts: the ECRHS (European Community Respiratory Health Survey) and the SAPALDIA (Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults). Methods: General-population samples of individuals aged 18 to 62 were randomly selected in 1991-1993 and followed up approximately 10 and 20 years later. Spirometry (without bronchodilation) was performed at each visit. Coded complete job histories during follow-up visits were linked to a job-exposure matrix, generating cumulative exposure estimates for 12 occupational exposures. Forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) were jointly modeled in linear mixed-effects models, fitted in a Bayesian framework, taking into account age and smoking. Results: A total of 40,024 lung-function measurements from 17,833 study participants were analyzed. We found accelerated declines in FEV 1 and the FEV 1 /FVC ratio for exposure to biological dust, mineral dust, and metals (FEV 1  = -15.1 ml, -14.4 ml, and -18.7 ml, respectively; and FEV 1 /FVC ratio = -0.52%, -0.43%, and -0.36%, respectively; per 25 intensity-years of exposure). These declines were comparable in magnitude with those associated with long-term smoking. No effect modification by sex or smoking status was identified. Findings were similar between the ECRHS and the SAPALDIA cohorts. Conclusions: Our results greatly strengthen the evidence base implicating occupation, independent of smoking, as a risk factor for lung-function decline. This highlights the need to prevent or control these exposures in the workplace.

We estimated the association between regular physical activity and the incidence of restrictive spirometry pattern. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and physical activity were assessed in 2 population-based European cohorts (European Community Respiratory Health Survey: n = 2,757, aged 39-67 years; and Swiss Study on Air Pollution and Lung and Heart Diseases in Adults: n = 2,610, aged 36-82 years) first in 2000-2002 and again approximately 10 years later (2010-2013). Subjects with restrictive or obstructive spirometry pattern at baseline were excluded. We assessed the association of being active at baseline (defined as being physically active at least 2-3 times/week for ≥1 hour) with restrictive spirometry pattern at follow-up (defined as a postbronchodilation FEV1/FVC ratio of at least the lower limit of normal and FVC of <80% predicted) using modified Poisson regression, adjusting for relevant confounders. After 10 years of follow-up, 3.3% of participants had developed restrictive spirometry pattern. Being physically active was associated with a lower risk of developing this phenotype (relative risk = 0.76, 95% confidence interval: 0.59, 0.98). This association was stronger among those who were overweight and obese than among those of normal weight (P for interaction = 0.06). In 2 large European studies, adults practicing regular physical activity were at lower risk of developing restrictive spirometry pattern over 10 years., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991-1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999-2003, and ECRHS III in 2010-2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21-95) for forced expiratory volume in one second and 83 mL (36-130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding., Competing Interests: The authors have declared that no competing interests exist.

Background: Previous studies have reported an association between weight increase and excess lung function decline in young adults followed for short periods. We aimed to estimate lung function trajectories during adulthood from 20-year weight change profiles using data from the population-based European Community Respiratory Health Survey (ECRHS)., Methods: We included 3673 participants recruited at age 20-44 years with repeated measurements of weight and lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 )) in three study waves (1991-93, 1999-2003, 2010-14) until they were 39-67 years of age. We classified subjects into weight change profiles according to baseline body mass index (BMI) categories and weight change over 20 years. We estimated trajectories of lung function over time as a function of weight change profiles using population-averaged generalised estimating equations., Results: In individuals with normal BMI, overweight and obesity at baseline, moderate (0.25-1 kg/year) and high weight gain (>1 kg/year) during follow-up were associated with accelerated FVC and FEV 1 declines. Compared with participants with baseline normal BMI and stable weight (±0.25 kg/year), obese individuals with high weight gain during follow-up had -1011 mL (95% CI -1.259 to -763) lower estimated FVC at 65 years despite similar estimated FVC levels at 25 years. Obese individuals at baseline who lost weight (<-0.25 kg/year) exhibited an attenuation of FVC and FEV 1 declines. We found no association between weight change profiles and FEV 1 /FVC decline., Conclusion: Moderate and high weight gain over 20 years was associated with accelerated lung function decline, while weight loss was related to its attenuation. Control of weight gain is important for maintaining good lung function in adult life., Competing Interests: Competing interests: JG-A reports personal fees from Esteve, Chiesi and AstraZeneca, outside the submitted work. MJA reports grants from Pfizer, grants from Boehringer-Ingelheim and personal fees from Sanofi, outside the submitted work. PD reports personal fees from ALK, Stallergenes Greer, IQVIA, Chiesi, AstraZeneca, Thermo Fisher Scientific, Menarini, Bausch & Lomb, Mylan, ASIT Biotech, Novartis, Sanofi and Regeneron, outside the submitted work. RJ reports grants from Estonian Research Council (Personal Research Grant no 562) and personal fees from GSK, Boehringer and Novartis, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, but response to medication is variable. Patients with allergic inflammation generally show a better short-term response to ICSs; however, studies on predictors of long-term response are few., Objective: To assess whether allergic sensitization can modify the association between ICS use and lung function decline over 20 years in adult asthma., Methods: We used data from the 3 clinical examinations of the European Community Respiratory Health Survey. We measured ICS use (no use, and use for <1.3, 1.3-8, and >8 years) and FEV 1 decline among subjects with asthma over the 2 periods between consecutive examinations. We conducted a cohort study combining data of the 2 periods (906 observations from 745 subjects) to assess whether the association between ICS use and FEV 1 decline was modified by allergic sensitization (IgE > 0.35 kU/L for any of house-dust mite, timothy grass, cat, or Cladosporium)., Results: FEV 1 decline was similar for non-ICS users, as well as ICS users for less than 1.3 years, with and without allergic sensitization. However, among subjects on ICSs for a longer period, sensitization was associated with an attenuated decline (P interaction  = .006): in the group treated for more than 8 years, FEV 1 decline was on average 27 mL/y (95% CI Bonferroni-adjusted , 11-42) lower for subjects with sensitization compared with nonsensitized subjects., Conclusions: Our study suggests that biomarkers of atopy can predict a more favorable long-term response to ICSs. Randomized controlled studies are needed to confirm these findings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure assessment of air pollution in epidemiologic research remains a challenge. Previous studies showed that magnetic monitoring of strawberry leaves, based on Saturation Isothermal Remnant Magnetization (SIRM), is a valid tool for estimating the concentration of ambient particulate matter (PM). This study uses this assessment method for the first time in epidemiologic research to quantify indoor exposure to PM. In a nested case control study, we evaluated the association between 'waking up by cough' and indoor air pollution measured by SIRM of dust deposition on leaves of strawberry plants located in the bedroom in the general adult population. A multiple logistic regression was used to estimate the association between 'waking up by cough' and exposure to ferromagnetic particles of PM controlling for age, gender and smoking status. A cut-off of 10 µA was decided to define exposure status (high versus low). Using logistic regression, a crude odds ratio (OR) of 1.80 (95% CI: 0.90-3.60) for 'waking up by cough' was found. This association remained approximately the same after controlling for age, gender and smoking status (adjusted OR: 1.76; 95% CI: 0.60-5.30). We found an association between exposure to ferromagnetic particles and 'waking up by cough' in adults; however, it was not statistically significant. This environmental exposure assessment method could be a valuable alternative for expensive personal exposure measurement devices.

Introduction: The fractional exhaled nitric oxide (F E NO) is a marker for type 2 inflammation used in diagnostics and management of asthma. In order to use F E NO as a reliable biomarker, it is important to investigate factors that influence F E NO in healthy individuals. Men have higher levels of F E NO than women, but it is unclear whether determinants of F E NO differ by sex., Objective: To identify determinants of F E NO in men and women without lung diseases., Method: Fractional exhaled nitric oxide was validly measured in 3881 healthy subjects that had answered the main questionnaire of the European Community Respiratory Health Survey III without airways or lung disease., Results: Exhaled NO levels were 21.3% higher in men compared with women P < 0.001. Being in the upper age quartile (60.3-67.6 years), men had 19.2 ppb (95% CI: 18.3, 20.2) higher F E NO than subjects in the lowest age quartile (39.7-48.3 years) P = 0.02. Women in the two highest age quartiles (54.6-60.2 and 60.3-67.6 years) had 15.4 ppb (14.7, 16.2), P = 0.03 and 16.4 ppb (15.6, 17.1), P = <0.001 higher F E NO, compared with the lowest age quartile. Height was related to 8% higher F E NO level in men (P < 0.001) and 5% higher F E NO levels in women (P = 0.008). Men who smoked had 37% lower F E NO levels and women had 30% lower levels compared with never-smokers (P < 0.001 for both). Men and women sensitized to both grass and perennial allergens had higher F E NO levels compared with non-sensitized subjects 26% and 29%, P < 0.001 for both., Conclusion and Clinical Relevance: Fractional exhaled nitric oxide levels were higher in men than women. Similar effects of current smoking, height, and IgE sensitization were found in both sexes. F E NO started increasing at lower age in women than in men, suggesting that interpretation of F E NO levels in adults aged over 50 years should take into account age and sex., (© 2019 John Wiley & Sons Ltd.)

This longitudinal study investigated whether smoking bans influence passive smoking at work and/or at home in the same subjects. Passive smoking at work and/or at home was investigated in random population samples (European Community Respiratory Health Survey) in 1990-1995, with follow-up interviews in 1998-2003 and 2010-2014. National smoking bans were classified as partial (restricted to public workplaces) or global (extended to private workplaces). Multivariable analysis was accomplished by three-level logistic regression models, where level-1, level-2, and level-3 units were, respectively, questionnaire responses, subjects, and centers. Passive smoking at work was reported by 31.9% in 1990-1995, 17.5% in 1998-2003, and 2.5% in 2010-2014. Concurrently, passive smoking at home decreased from 28.9% to 18.2% and 8.8%. When controlling for sex, age, education, smoking status, and ECHRS wave, the odds of passive smoking at work was markedly reduced after global smoking bans (OR = 0.45, 95% CI 0.25-0.81), particularly among non-smokers, while the protective effect of global smoking bans on passive smoking at home was only detected in non-smokers. Smoking bans both in public and private workplaces were effective in reducing passive smoking at work in Europe. However, given the inefficacy of smoking bans in current smokers' dwellings, better strategies are needed to avoid smoking indoors., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Chronic bronchitis (CB) is an important chronic obstructive pulmonary disease (COPD)-related phenotype, with distinct clinical features and prognostic implications. Occupational exposures have been previously associated with increased risk of CB but few studies have examined this association prospectively using objective exposure assessment. We examined the effect of occupational exposures on CB incidence in the European Community Respiratory Health Survey., Methods: Population samples aged 20-44 were randomly selected in 1991-1993, and followed up twice over 20 years. Participants without chronic cough or phlegm at baseline were analysed. Coded job histories during follow-up were linked to the ALOHA Job Exposure Matrix, generating occupational exposure estimates to 12 categories of chemical agents. Their association with CB incidence over both follow-ups was examined with Poisson models using generalised estimating equations., Results: 8794 participants fulfilled the inclusion criteria, contributing 13 185 observations. Only participants exposed to metals had a higher incidence of CB (relative risk (RR) 1.70, 95% CI 1.16 to 2.50) compared with non-exposed to metals. Mineral dust exposure increased the incidence of chronic phlegm (RR 1.72, 95% CI 1.43 to 2.06). Incidence of chronic phlegm was increased in men exposed to gases/fumes and to solvents and in women exposed to pesticides., Conclusions: Occupational exposures are associated with chronic phlegm and CB, and the evidence is strongest for metals and mineral dust exposure. The observed differences between men and women warrant further investigation., Competing Interests: Competing interests: DJ reports grants from European Commission during the conduct of the study. VS reports grants from the Wood Dust Foundation (Project No 444508795) during the conduct of the study. IP reports non-financial support and other from Novartis, personal fees and other from Astra Zeneca, non-financial support and other from Chiesi, outside the submitted work. PD reports personal fees from ALK, Stallergènes Greer, Chiesi, Thermo Fisher Scientific, Ménarini, Bausch&Lomb and Mylan, outside the submitted work. RJ reports grants from Estonian Research Council (personal research grant number 562) during the conduct of the study, personal fees and non-financial support from GSK, personal fees from Novartis and Boehringer, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Breast cancer has, due its high incidence, the highest mortality of cancer in women. The most common molecular variety of breast cancer is luminal subtype that expresses estrogen and progesterone receptors. Estrogen receptor alpha (ERα), encoded by the estrogen receptor1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and hormonal therapy represents a major treatment modality in all stages of ER positive breast cancers. Acquired mutations in the ligand-binding domain (LBD) of ERα, referred as ESR1 mutation, result in resistance to different endocrine therapies leading to disease progression or recurrence. Recent studies reviled that these ESR1 mutations lead to constitutive activity of the estrogen receptor ER, meaning that the receptor is active in absence of its ligand conferring resistance against endocrine therapy and tumor growth. Published studies have not yet been able to determine the exact prevalence rate of ESR1 mutations, but set the outer boundaries between 11-55%., Purpose: The goal of the present study is to determine the frequency rate of ESR1 mutations in ER positive recurrent breast cancer by using digital droplet PCR (ddPCR) technique., Materials and Methods: This retrospective study was conducted in the Multidisciplinary Breast Clinic of Antwerp University Hospital. The seven most common ESR1mutations (c.1138G>C (p. (E380Q)), c.1610A>G (p.(Y537C)), c.1613A>G (p.(p.D538G)), c.1607T>G (p.(L536R)), c.1387T>C (p.S463R)), c.16410A>C (p.(Y537S)), c.609T>A (p.(Y537N)) were assessed in available baseline plasma samples of 21 patients with ER positive recurrent breast cancer. Inclusion criteria for study participation were: female, age above 18 years, ER positive breast cancer, 5years adjuvant hormonal therapy of primary disease, and disease recurrence or metastasis during or after stop of endocrine therapy. ESR1 mutations were analyzed in cell-free DNA (cfDNA) by using digital droplet PCR (ddPCR)., Results: cfDNA was obtained from 21 patients with recurrent breast cancer. ESR1 mutations were found in 4/21 (19%; 95% CI, 5%-42%). The test sensitivity was lower than the targeted value <0.1% in 29% of patients (6/21). No significant statistical difference in baseline clinical characteristics was observed in patients with wild-type and mutant ER (p>0.05). Adjuvant endocrine therapy for primary disease was Tamoxifen (TAM) for 57% of patients (12 of 21) of whom 8 patients had received aromatase inhibitor (AI) after two years, while 43% of patients (9 of 21) had received AI as first line adjuvant hormonal therapy. All the patients had received aromatase inhibitor AI therapy in first or second line therapy with initially a variable period of good response., Conclusion: ESR1 mutation analysis could be determined in archived plasma samples using simple non-invasive methods. In the future, screening for mutation status could improve the therapeutic strategies in controlling ER signaling before the occurrence of wide spread disease metastasis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Restrictive spirometry pattern is an under-recognised disorder with a poor morbidity and mortality prognosis. We compared physical activity levels between adults with a restrictive spirometry pattern and with normal spirometry., Methods: Restrictive spirometry pattern was defined as a having post-bronchodilator FEV 1 /FVC ≥ Lower Limit of Normal and a FVC<80% predicted in two population-based studies (ECRHS-III and SAPALDIA3). Physical activity was measured using the International Physical Activity Questionnaire. The odds of having low physical activity (<1st study-specific tertile) was evaluated using adjusted logistic regression models., Results: Subjects with a restrictive spirometry pattern (n = 280/4721 in ECRHS, n = 143/3570 in SAPALDIA) reported lower levels of physical activity than those with normal spirometry (median of 1770 vs 2253 MET·min/week in ECRHS, and 3519 vs 3945 MET·min/week in SAPALDIA). Subjects with a restrictive spirometry pattern were more likely to report low physical activity (meta-analysis odds ratio: 1.41 [95%CI 1.07-1.86]) than those with a normal spirometry. Obesity, respiratory symptoms, co-morbidities and previous physical activity levels did not fully explain this finding., Conclusion: Adults with a restrictive spirometry pattern were more likely to report low levels of physical activity than those with normal spirometry. These results highlight the need to identify and act on this understudied but prevalent condition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Occupational exposures have been associated with an increased risk of COPD. However, few studies have related objectively assessed occupational exposures to prospectively assessed incidence of COPD, using postbronchodilator lung function tests. Our objective was to examine the effect of occupational exposures on COPD incidence in the European Community Respiratory Health Survey., Methods: General population samples aged 20-44 were randomly selected in 1991-1993 and followed up 20 years later (2010-2012). Spirometry was performed at baseline and at follow-up, with incident COPD defined using a lower limit of normal criterion for postbronchodilator FEV1/FVC. Only participants without COPD and without current asthma at baseline were included. Coded job histories during follow-up were linked to a Job-Exposure Matrix, generating occupational exposure estimates to 12 categories of agents. Their association with COPD incidence was examined in log-binomial models fitted in a Bayesian framework., Findings: 3343 participants fulfilled the inclusion criteria; 89 of them had COPD at follow-up (1.4 cases/1000 person-years). Participants exposed to biological dust had a higher incidence of COPD compared with those unexposed (relative risk (RR) 1.6, 95% CI 1.1 to 2.3), as did those exposed to gases and fumes (RR 1.5, 95% CI 1.0 to 2.2) and pesticides (RR 2.2, 95% CI 1.1 to 3.8). The combined population attributable fraction for these exposures was 21.0%., Interpretation: These results substantially strengthen the evidence base for occupational exposures as an important risk factor for COPD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Very few studies have examined whether a long-term beneficial effect of physical activity on lung function can be influenced by living in polluted urban areas., Objective: We assessed whether annual average residential concentrations of nitrogen dioxide (NO 2 ) and particulate matter with aerodynamic diameters < 2.5 μm (PM 2.5 ) and <10 μm (PM 10 ) modify the effect of physical activity on lung function among never- (N = 2801) and current (N = 1719) smokers in the multi-center European Community Respiratory Health Survey., Methods: Associations between repeated assessments (at 27-57 and 39-67 years) of being physically active (physical activity: ≥2 times and ≥1 h per week) and forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were evaluated using adjusted mixed linear regression models. Models were conducted separately for never- and current smokers and stratified by residential long-term NO 2 , PM 2.5 mass and PM 10 mass concentrations (≤75th percentile (low/medium) versus >75th percentile (high))., Results: Among current smokers, physical activity and lung function were positively associated regardless of air pollution levels. Among never-smokers, physical activity was associated with lung function in areas with low/medium NO 2 , PM 2.5 mass and PM 10 mass concentrations (e.g. mean difference in FVC between active and non-active subjects was 43.0 mL (13.6, 72.5), 49.5 mL (20.1, 78.8) and 49.7 mL (18.6, 80.7), respectively), but these associations were attenuated in high air pollution areas. Only the interaction term of physical activity and PM 10 mass for FEV 1 among never-smokers was significant (p-value = 0.03)., Conclusions: Physical activity has beneficial effects on adult lung function in current smokers, irrespective of residential air pollution levels in Western Europe. Trends among never-smokers living in high air pollution areas are less clear., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Mothers' smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers' smoking may have a similar effect, and biological plausibility that fathers' smoking during adolescence may influence offspring's health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma., Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents' (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines., Results: Fathers' smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01-2.01] and mothers' smoking during pregnancy (RRR = 1.27, 95% CI: 1.01-1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers' smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55)., Conclusions: Fathers' smoking during early adolescence and grandmothers' and mothers' smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception., Funding: European Union (Horizon 2020, GA-633212).

Objectives: To develop a guideline on Responsible Epidemiologic Research Practice that will increase value and transparency, increase the accountability of the epidemiologists, and reduce research waste., Setting: A working group of the Netherland Epidemiological Society was given the task of developing a guideline that would meet these objectives. Several publications about the need to prevent Detrimental Research Practices triggered this work. Among these were a series in the Lancet on research waste and a subsequent series on transparency in the Journal of Clinical Epidemiology. The reputation and trust in epidemiologic research is still high, and the Netherlands Epidemiological Society wishes to keep it that way. The guideline deals with how epidemiologic research should be conducted, archived, and disclosed. It does not deal with the more technical aspects, such as required sample size, choice of study design, and so forth. The guideline describes each step in the process of conducting an epidemiologic study, from the first idea to the ultimate publication and beyond., Methods: The working group reviewed the literature on responsible research conduct, including the various existing codes of conduct. It applied the general principles from these codes to the elements of an epidemiologic study and formulated specific recommendations for each of these. Next step was to draft the guideline. Preceding the 2016 annual national epidemiology conference in Wageningen, a preconference was organized to discuss the draft guideline and to assess support. Support was clearly present, and the provided recommendations were incorporated into the draft guideline. In March 2017, a draft version of the guideline was sent to all 1,100 members of the society with the request to review and provide comments. All received responses were positive, and some minor additions were made. The Responsible Epidemiologic Research Practice guideline has now been approved by the board of the Netherlands Epidemiological Society., Conclusion: With the Responsible Epidemiologic Research Practice guideline, we hope to contribute to better research practices in epidemiology but perhaps also in adjacent disciplines., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We assessed associations between physical activity and lung function, and its decline, in the prospective population-based European Community Respiratory Health Survey cohort., Methods: FEV 1 and FVC were measured in 3912 participants at 27-57 years and 39-67 years (mean time between examinations=11.1 years). Physical activity frequency and duration were assessed using questionnaires and used to identify active individuals (physical activity ≥2 times and ≥1 hour per week) at each examination. Adjusted mixed linear regression models assessed associations of regular physical activity with FEV 1 and FVC., Results: Physical activity frequency and duration increased over the study period. In adjusted models, active individuals at the first examination had higher FEV 1 (43.6 mL (95% CI 12.0 to 75.1)) and FVC (53.9 mL (95% CI 17.8 to 89.9)) at both examinations than their non-active counterparts. These associations appeared restricted to current smokers. In the whole population, FEV 1 and FVC were higher among those who changed from inactive to active during the follow-up (38.0 mL (95% CI 15.8 to 60.3) and 54.2 mL (95% CI 25.1 to 83.3), respectively) and who were consistently active, compared with those consistently non-active. No associations were found for lung function decline., Conclusion: Leisure-time vigorous physical activity was associated with higher FEV 1 and FVC over a 10-year period among current smokers, but not with FEV 1 and FVC decline., Competing Interests: Competing interests: PD reports consulting fees from ALK, Stallergènes Greer, Circassia, Chiesi, Thermofisher Scientific and Ménarini, and AGC reports grants from Chiesi Farmaceutici and from GlaxoSmithKline Italy, during the conduct of the study. Other authors declare no competing interests related to this work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Change in the prevalence of asthma-like symptoms in populations of ageing adults is likely to be influenced by smoking, asthma treatment and atopy., Methods: The European Community Respiratory Health Survey collected information on prevalent asthma-like symptoms from representative samples of adults aged 20-44 years (29 centres in 13 European countries and Australia) at baseline and 10 and 20 years later (n=7844). Net changes in symptom prevalence were determined using generalised estimating equations (accounting for non-response through inverse probability weighting), followed by meta-analysis of centre level estimates., Findings: Over 20 years the prevalence of 'wheeze' and 'wheeze in the absence of a cold' decreased (-2.4%, 95% CI -3.5 to -1.3%; -1.5%, 95% CI -2.4 to -0.6%, respectively) but the prevalence of asthma attacks, use of asthma medication and hay fever/nasal allergies increased (0.6%, 95% CI 0.1 to 1.11; 3.6%, 95% CI 3.0 to 4.2; 2.7%, 95% CI 1.7 to 3.7). Changes were similar in the first 10 years compared with the second 10 years, except for hay fever/nasal allergies (increase seen in the first 10 years only). Decreases in these wheeze-related symptoms were largely seen in the group who gave up smoking, and were seen in those who reported hay fever/nasal allergies at baseline., Interpretation: European adults born between 1946 and 1970 have, over the last 20 years, experienced less wheeze, although they were more likely to report asthma attacks, use of asthma medication and hay fever. Decrease in wheeze is largely attributable to smoking cessation, rather than improved treatment of asthma. It may also be influenced by reductions in atopy with ageing., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect., Objective: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period., Methods: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse., Results: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts., Conclusion: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Our objective was to test the hypothesis of a short-term late-promoting effect of ultraviolet (UV) exposure on the development of cutaneous melanoma as an explanation for the summer peak in melanoma incidence. Therefore, we studied seasonal variation in melanoma incidence in relation to recent UV levels by direct UV measurements. Data from the Belgian Cancer Registry on invasive cutaneous melanoma diagnosed during 2006-2011 were used for analysis. Daily data on UV measurements in Belgium were obtained from the Royal Meteorological Institute. Simple and multiple negative binomial regression models were used to investigate the influence of recent UV levels on melanoma incidence. The sum of the mean UV doses in the 2 months before diagnosis was used as a proxy for recent UV exposure in the population. To include variable sunburn risks during the year, the categorical variable 'semester' was created. The incidence of melanoma in Belgium shows a distinct seasonal variation, with peaks in June or July. We found that part of this variation could be explained by the variation in dermatologic activity and, therefore, used this as an offset in our models. We found a linear relationship between melanoma incidence and UV dose in the 2 months preceding the diagnosis. UV levels had more impact in the first semester. The effect of UV levels was not modified by sex nor age. The interaction between anatomical site and UV levels was significant (P=0.002) and showed a higher effect on the upper and lower limbs compared with the head and neck and trunk.

Malnutrition is a known problem in hospitals and nursing homes. This study aims to evaluate the prevalence of being at risk of malnutrition in community living adults receiving homecare nursing and to determine factors independently associated with this risk of malnutrition. Furthermore, it also aimed to describe aspects of current nutritional nursing care. Patients (n = 100) are screened with the Malnutrition Universal Screening Tool to evaluate their risk of malnutrition. A patient survey was used to analyse associated factors. In this population, 29% are at risk for malnutrition. Following a multivariate logistic regression analysis, 'loss of appetite' proved the most important factor. A survey for nurses (n = 61) revealed low awareness, poor knowledge, poor communication between stakeholders and a moderate approach of malnutrition. These findings should encourage homecare nurses to use a recommended screening tool for malnutrition and to actively observe and report loss of appetite to initiate the prescription of individual tailored interventions. Belgian homecare nurses' management does not yet fully comply with international recommendations. Additional training in nutritional nursing care and screening methods for malnutrition is needed. Systematic screening should be further developed and evaluated in this at-risk population., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background and Aim: Decreased left ventricular mass index in anorexia nervosa is amply reported. The aim of this study is to identify non-burdensome predictors of reduced left yentricular mass/height (cLVM) in a cohort of adolescent restrictive anorexic girls., Methods: This is a retrospective study of all anorexic girls of the restrictive type referred to our tertiary eating disorder unit between September 2002 and December 2012, for somatic assessment of weig ht loss. All subjects fulfilled DMS-IV criteria, without a family history of cardiac or cardiovascular diseases., Results: In all, 283 restrictive anorexic girls (age: 14.63 +/- 1.65 y; body mass index: 15.72 +/- 1.81 kg/m2) were included. Ferritin and body mass index were independent, statistically significant predictors of the corrected left ventricular mass (P <0.05)., Conclusion: Decreased cLVM is very common in anorexia nervosa of the restrictive type. Two factors predicted decreased cLVM in our population: ferritin and BMI.

Purpose: To describe the documentation of nutrition-related data and wards referral to dieticians in a Belgian university hospital., Method: Retrospective analysis of 506 nursing records., Findings: Body weight and height are documented in 22%. "Feeding assistance" and "usual food intake pattern" are documented in 68% of all cases, and in 71% it is marked whether the patient is on a diet. Eight percent of the patients are referred to a dietician, but the indications for these referrals are not clear., Conclusion: Given the poor documentation, most likely these patients are not adequately screened for malnutrition as recommended., Implications for Nursing Practice: Nurses' documentation of nutrition-related data should be improved to facilitate treatment of malnutrition with tailored multidisciplinary interventions., (© 2013 NANDA International, Inc.)

Nocturnal gastro-oesophageal reflux (nGOR) is associated with asthma and obstructive sleep apnoea (OSA). Our aim was to investigate whether nGOR is a risk factor for onset of asthma and onset of respiratory and OSA symptoms in a prospective population-based study. We invited 2640 subjects from Iceland, Sweden and Belgium for two evaluations over a 9-year interval. They participated in structured interviews, answered questionnaires, and underwent spirometries and methacholine challenge testing. nGOR was defined by reported symptoms. Subjects with persistent nGOR (n=123) had an independent increased risk of new asthma at follow-up (OR 2.3, 95% CI 1.1-4.9). Persistent nGOR was independently related to onset of respiratory symptoms (OR 3.0, 95% CI 1.6-5.6). The risk of developing symptoms of OSA was increased in subjects with new and persistent nGOR (OR 2.2, 95% CI 1.3-1.6, and OR 2.0, 95% CI 1.0-3.7, respectively). No significant association was found between nGOR and lung function or bronchial responsiveness. Persistent symptoms of nGOR contribute to the development of asthma and respiratory symptoms. New onset of OSA symptoms is higher among subjects with symptoms of nGOR. These findings provide evidence that nGOR may play a role in the genesis of respiratory symptoms and diseases.

Background: The causal link between body mass index (BMI) or obesity and asthma in children is still being debated. Analyses of large longitudinal studies with a sufficient number of incident cases and in which the time-dependent processes of both excess weight and asthma development can be validly analyzed are lacking., Objective: We sought to investigate whether the course of BMI predicts incident asthma in childhood., Methods: Data from 12,050 subjects of 8 European birth cohorts on asthma and allergies were combined. BMI and doctor-diagnosed asthma were modeled during the first 6 years of life with latent growth mixture modeling and discrete time hazard models. Subpopulations of children were identified with similar standardized BMI trajectories according to age- and sex-specific "World Health Organization (WHO) child growth standards" and "WHO growth standards for school aged children and adolescents" for children up to age 5 years and older than 5 years, respectively (BMI-SDS). These types of growth profiles were analyzed as predictors for incident asthma., Results: Children with a rapid BMI-SDS gain in the first 2 years of life had a higher risk for incident asthma up to age 6 years than children with a less pronounced weight gain slope in early childhood. The hazard ratio was 1.3 (95% CI, 1.1-1.5) after adjustment for birth weight, weight-for-length at birth, gestational age, sex, maternal smoking in pregnancy, breast-feeding, and family history of asthma or allergies. A rapid BMI gain at 2 to 6 years of age in addition to rapid gain in the first 2 years of life did not significantly enhance the risk of asthma., Conclusion: Rapid growth in BMI during the first 2 years of life increases the risk of asthma up to age 6 years., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objectives: Recent studies suggest adverse health effects after low exposure to cadmium (Cd). Brazing with Cd-containing solder exposes workers to Cd. The purpose of this study was to assess: (1) indicators of Cd exposure in blood (Cd-B)/ urine (Cd-U); (2) the association between Cd-B, Cd-U and renal and oxidative stress biomarkers., Methods: In this cross-sectional study Cd-B, Cd-U, renal (ie, N-acetyl-β-D-glucosaminidase/urinary intestinal alkaline phosphatase (IAP)/microalbumin/beta-2-microglobulin/retinol binding protein and oxidative stress markers (ie, derivatives of reactive oxygen metabolites/glutathione peroxidase/superoxide dismutase (SOD)/ advanced oxidation protein products/8-hydroxy-2'-deoxyguanosin/8-isoprostanes) were determined in 36 solderers., Results: Multiple linear regression analysis adjusting for age and pack-years of smoking show that IAP is statistically significantly associated with Cd-B (B=0.24; SE=0.11) and Cd-U (B=0.15; SE=0.07). Also SOD is statistically significantly associated with Cd-B (B=62.96; SE=29.62). The association between SOD and Cd-U is of borderline statistical significance (B=37.69; SE=19.59)., Conclusions: While there is still some debate as whether the Cd-induced tubular effects are reversible or not, IAP and SOD appear as sensitive and potentially useful early biomarkers for the health surveillance of workers exposed to low levels of Cd.

Screening patients' nutritional status on admission to hospital is recommended by evidence-based guidelines on malnutrition. In practice, self-reported values for body weight and height are often used by nurses and dieticians. This study assessed the accuracy of self-reported body weight and height and whether these self-reported values might be influenced by the nature of the health-care worker involved. Patients (n = 611) on admission reported their body weight and height to a nurse and a dietician. Reported values were analysed and compared with the measured values. Self-reported values for body weight and height on admission are not always accurate. Patients do report different values to different health-care workers. Self-reported values for body weight to nurses were more accurate as compared with dieticians. Self-reported values for body weight and height are subject to observer bias and should be used with caution in nutritional screening and multi-professional nutritional care., (© 2012 Wiley Publishing Asia Pty Ltd.)

Background: Industrial composting is a relatively new and expanding activity. Several studies indicate that compost workers are at risk to develop health symptoms. The aim of this study was to assess the prevalence of work-related health symptoms among compost workers compared with control subjects., Methods: A questionnaire was distributed among 62 workers (31 exposed and 31 non-exposed workers). Data were analyzed using simple and multiple logistic regression analyses., Results: Workers exposed to organic dust reported significantly more often respiratory, irritation (e.g., eyes, nose and throat), gastrointestinal, and skin symptoms than the non-exposed group. Moreover, all work-related symptoms were significantly more often reported by exposed than non-exposed workers. After adjustment for smoking status and age, the associations between exposure and respiratory, gastrointestinal, and skin symptoms remained statistically significant, in particular if these symptoms were work-related., Conclusions: This study confirms that workers at compost facilities are at risk to develop occupational health problems, most likely related to organic dust exposure.

Background: Anastomotic leakage (AL) is the most feared complication of colorectal surgery. Atherosclerosis is suggested to have a detrimental effect on anastomotic healing. This study aimed to analyze the calcium score, a measure for atherosclerosis, as a risk factor for AL., Study Design: The calcium scores of colorectal patients operated on in 2 Dutch university medical centers were determined using a computed tomography scan and calcium scoring software. The aorta, common iliac arteries, internal and external iliac arteries were studied. Additionally, patient- and operation-related factors were scored., Results: A total of 122 patients were included. In patients with AL, calcium scores were significantly higher in the left common iliac artery (561.4 vs 156.0, P = .028), right common iliac artery (542.0 vs 144.4, P = .041), both common iliac arteries together (1,103.3 vs 301.9, P = .046), and the left internal iliac artery (716.3 vs 35.3, P = .044)., Conclusions: Patients with higher calcium scores in the iliacal arteries have an increased leakage risk., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Surgical resection of lung metastases is a widely accepted procedure but 5-year survival rates remain low and vary between 20% and 50%. Isolated lung perfusion (ILuP) is an experimental technique to deliver a high dose of chemotherapy to the lung, without systemic toxicity. Long-term survival of ILuP has not been reported yet and was determined in a phase I clinical trial., Methods: From May 2001 to December 2004, a phase I clinical trial was conducted to define the maximum tolerated dose (MTD) of ILuP with melphalan. Twenty-nine procedures were performed in 23 patients. The primary tumour was colorectal in 10 patients, renal in eight, sarcoma in four and salivary gland in one. Toxicity results were previously reported and the MTD of melphalan was determined at 45 mg when given at 37°C. Follow-up was updated and long-term survival is reported., Results: Follow-up was complete, except for one patient who was lost to follow-up after 8 months. After a median follow-up of 62 months, 6 out of 23 patients were alive and free of recurrent disease. One patient died after a subsequent operation. Sixteen patients developed recurrent disease, of whom 11 died. Nine patients had intrathoracic recurrent disease only, one intra- and extrathoracic recurrences each and five extrathoracic only. In one patient, the location of recurrence was not known. Overall- and disease-free 5-year survival rates were 54.8 ± 10.6% and 27.5 ± 9.5%, respectively with an overall median survival time (MST) of 84 months (95% confidence interval (CI): 41-128) and disease-free MST of 19 months (95% CI: 4-34). Lung function and diffusion capacity initially dropped 1 month after perfusion, slightly improving afterwards. Radiographic follow-up with chest computed tomography showed no long-term toxicity from ILuP., Conclusion: ILuP can be applied without major long-term pulmonary toxicity. Five-year survival rate, overall and disease-free MST in this phase I clinical trial are promising. This is another incentive to perform further studies with ILuP., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Objectives: Classification of non-small-cell lung cancer (NSCLC) into growth patterns is based on the following question: What does the tumour do with normal lung parenchyma? There are only three possible ways according to which a tumour can behave: (1) preservation of lung tissue and use of its microenvironment for further growth, (2) destruction of lung tissue and formation of new microenvironment for continued expansion and (3) preservation of lung tissue and formation of new microenvironment (modulation). The aim of the current study is to test the prognostic value of growth-pattern classification along with other clinical, pathological and immunohistochemical factors., Methods: Clinicopathological factors of 239 patients operated for NSCLC were retrospectively reviewed. Preoperative smoking status was determined based on two prospectively independent questionnaires. Co-morbidity was determined based on Charlson co-morbidity index (CCI). Haematoxylin-eosin tissue sections were analysed for the determination of tumour growth patterns, histological types, grading, necrosis and desmoplasia. Tumour cell proliferation, endothelial cell proliferation and microvessel density were determined based on double immunostaining with CD34 and Ki67 antibodies. Follow-up data were updated in 2008., Results: According to the growth-pattern classification, 161 patients (67.4%) had a destructive, 33 (13.8%) a papillary and 45 (18.8%) an alveolar growth pattern. Multiple Cox regression analysis showed that older age (p<0.001), lymph node metastasis (p<0.001), growth-pattern classification (p=0.036) and current smokers (p=0.027) were independent prognostic factors for overall survival. Similar results were obtained for disease-specific and disease-free survival. Papillary (hazard ratio=1.658 and confidence interval=1.001-2.748, p=0.050) and alveolar (hazard ratio=2.056 and confidence interval=1.305-3.237, p=0.002) growth patterns were independent predictors of early recurrence., Conclusions: Growth-pattern classification remains a significant prognostic factor in NSCLC providing a possible explanation for survival differences in the same disease stage., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate cardiac, biochemical and endocrine differences between female adolescents with anorexia nervosa (AN) with and without pericardial effusions. We studied 128 female adolescents (9.8-17.7 years) with anorexia nervosa (AN) diagnosed according to DSM-IV (American Psychiatric Association, 1994) criteria. They all underwent an echocardiographic evaluation. In 29 patients (22.2 %) a pericardial effusion (ranging between >or= 0.35-2.5 cm) was noted. None of the patients were clinically symptomatic. After 3 months of refeeding, the effusions disappeared in 18/29 patients while in 7/29 patients a pericardial effusion > 0.3 cm persisted. Risk factors for development of effusions were a BMI or= 25% and IGF-1-level

Background: There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor associated antigens possibly inducing a cellular anti-tumor immune response. It is well recognized that cytotoxic lymphocytes constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in colorectal cancer remains controversial. Aim of the study was to examine infiltration of CD3+ and CD8+ lymphocytes in colorectal cancer and their prognostic potential.Two-hundred-fifteen colorectal cancer cases, previously analyzed for microsatellite instability (MSI), were selected for immunohistochemical detection of CD3+, CD8+ infiltration and the expression of granzyme B. Prognostic relevance was assessed by survival analysis., Results: Strong correlations were found between the infiltration of lymphocytes and several clinicopathological variables. Survival analysis revealed that intra-epithelial infiltration of CD3+ and CD8+ T lymphocytes and stromal infiltration of CD3+ lymphocytes had a major impact on the patients' overall survival in the univariate analysis, however independent of their association with MSI-status. In addition, it was also demonstrated that there was an important disease specific survival advantage for patients with microsatellite stable (MSS) tumors containing intraepithelial CD8+ tumor infiltrating lymphocytes. When samples were analyzed for colon cancer and rectal cancer separately, the results of the overall population were confirmed in colon cancer only. When entered into a multiple Cox regression analysis adjusting for other possible important confounding factors, the strong impact of lymphocyte infiltration on overall survival was not maintained. Only early stage and young age (borderline significant for overall population only) were associated with a better overall survival (early disease with disease-free survival also)., Conclusions: In conclusion our results suggest a role for infiltrating CD3+ and CD8+ T lymphocytes in colorectal cancer whereby tumor infiltration could reflect a general principle of antitumor immunity, irrespective of the MSI-status.

Background: The significance of borderline magnetic resonance (MR) findings that are equivocal for a tear of the knee meniscus remains uncertain. Given their higher signal-to-noise ratio (SNR) and greater spatial resolution, these equivocal meniscal tears could be expected to be less frequent using a 3.0T MR system., Purpose: To investigate the prevalence of equivocal meniscal tears using 3.0T MR, and to study their impact on MR accuracy compared with arthroscopy in the detection of meniscal tears., Material and Methods: The medical records of 100 patients who underwent 3.0T MR imaging and subsequent arthroscopy of the knee were retrospectively reviewed. Two observers interpreted MR images in consensus, and menisci were diagnosed as torn (abnormality on two or more images), equivocal for a tear (abnormality on one image), or intact, using arthroscopy as the standard of reference. The prevalence of equivocal meniscal tears was assessed, and MR accuracy was calculated as follows: first, considering both torn menisci and equivocal diagnoses as positive for a tear; and second, considering only torn menisci as positive for a tear., Results: Evidence of meniscal tears on MR images was equivocal in 12 medial (12%) and three lateral (3%) menisci. Of these equivocal MR diagnoses, tears were found at arthroscopy in eight medial and one lateral meniscus. In our study, the specificity and positive predictive value increased for both the medial and lateral meniscus when only menisci with two or more abnormal images were considered to be torn: from 80% and 89% to 91% and 94% for the medial meniscus, and from 91% and 73% to 93% and 78% for the lateral meniscus, respectively., Conclusion: Subtle findings that are equivocal for a tear of the knee meniscus still make MR diagnosis difficult, even at 3.0T. We recommend that radiologists should rather be descriptive in reporting subtle or equivocal MR findings, alerting the clinician of possible meniscal tear.

Early exposure to solid foods in infancy has been associated with the development of allergic diseases. However, scientific evidence for this is conflicting. The aim of this study was to examine the association between early exposure to solid foods in the infant's diet and the development of eczema up to 4 years of age. We conducted an etiologic case-control study nested in the PIPO cohort (Prospective Cohort on the Influence of Perinatal Factors on the Occurrence of Asthma and Allergies). In this cohort data on nutrition, environmental exposures and parent-reported eczema were collected prospectively starting from 5 months pregnancy by means of questionnaires administered during two home visits and semi-annual postal questionnaires. In addition, detailed information on the timing of introduction of solid foods at individual food item level was collected at 1 year of age. Adjusted odds ratios and 95% confidence intervals were computed using logistic regression analysis as a measure of association between eczema and the timing of exposure to solid foods. Early introduction (within the first 4 months) of solid foods was inversely associated with eczema up to 4 years of age (adj OR: 0.49; 95% CI: 0.32-0.74). Moreover, we found that early exposure to solid foods was associated with a reduced risk for eczema only among children with allergic parents (adj OR: 0.35; 95% CI: 0.20-0.63), whereas no significant effect was found among children with non-allergic parents (adj OR: 0.69; 95% CI: 0.37-1.29). The results of this study show that early exposure to solid foods is associated with less parent-reported eczema in children, particularly among children with allergic parents. Therefore, the current study does not support a delayed introduction of solid foods for the prevention of eczema in childhood., ((c) 2009 John Wiley & Sons A/S)

Background: Concomitant chemotherapy and radiotherapy (chemoradiation; CRT) is the standard treatment for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). CRT improves local control and overall survival (OS) when compared to radiotherapy (RT) alone. Induction chemotherapy (IC) reduces the risk of distant metastases (DM) and improves OS by 5% with the use of cisplatin/infusional 5 fluorouracil (PF) in meta-analysis. Adding a taxane to PF in the IC regimen confers a better outcome. Sequential treatment (ST) of IC followed by CRT is therefore under active investigation in multiple phase III trials., Methods: We compared the outcome of two cohorts of patients (pts) with LA-SCCHN treated at our institution with CRT (n = 27) or ST (n = 31), respectively. CRT consisted of GEM 100 mg/m2 weekly + conventional RT (70 Gy); ST consisted of the same CRT preceded by platinum-based IC., Results: Response to IC: complete 8 (26%), partial 20 (65%), stable 1, progressive 1, not evaluable 1. Median follow up of the surviving pts: for CRT 73 months, for ST 51 months. Median time to distant metastasis (TDM) was for CRT 23.6 months, for ST not reached. Median OS was for CRT 20.2 months, for ST 40.2 months. Cox regression analysis, taking into account age, T and N stage and tumor site, showed a hazard ratio with ST of 1.190 for time to locoregional failure (p = 0.712), 0.162 for TDM (p = 0.002), and 0.441 for overall survival (OS) (p = 0.026)., Conclusion: TDM and OS were found significantly longer in the ST cohort without a reduced locoregional control. Notwithstanding the limitations of a non-randomized single-center comparison, the results are in line with very preliminary data of randomized comparisons suggesting an improved outcome with ST.

Ductal carcinoma in situ (DCIS) is a heterogeneous malignant condition of the breast with an excellent prognosis. Until recently mastectomy was the standard treatment. As the results of the National Surgical Adjuvant Breast and Bowel Project-17 trial and the introduction of the Van Nuys Prognostic Index (VNPI) less radical therapies are used. Objectives are to identify clinicopathologic and biologic factors that may predict outcome. Cases of DCIS diagnosed in two Belgian University Centers were included. Paraffin-embedded material and Hematoxylin and Eosin stained slides of DCIS cases were reviewed and tumor size, margin width, nuclear grade, and comedo necrosis were assessed. Molecular markers (estrogen receptor, progesterone receptor, HER1-4, Ki67, and c-myc) were assayed immunohistochemically. Applied treatment strategies were correlated with the prospective use of the VNPI score. Kaplan-Meier survival plots were generated with log-rank significance and multiple regression analysis was carried out using Cox proportional hazards regression analysis; 159 patients were included with a median age of 54 years (range 29-78); 141 had DCIS and 18 DCIS with microinvasion. The median time of follow-up was 54 months (range 5-253). Twenty-three patients developed a recurrence (14.5%). The median time to recurrence was 46 months (range 5-253). Before the introduction of the VNPI, 37.5% of the DCIS patients showed a recurrence while thereafter 6.7% recurred (p < 0.005). Two recurrences occurred in the VNPI group I (7.1%); seven in the VNPI group II (8.5%) (median time to recurrence 66.3 months) and 14 in the VNPI group III (28.5%) (median time to recurrence 40.2 months) (disease-free survival [DFS]: p < 0.05). A Cox proportional hazards regression analysis indicated that tumor size, margin width, pathologic class, and age were independent predictors of recurrence, but none of the studied molecular markers showed this. Overexpression of HER4 in the presence of HER3 was found to be associated with a better DFS (p < 0.05). This study confirms the value of the VNPI score and questions the benefit of an aggressive approach in the low-risk DCIS lesions. Independent predictors for recurrence included size, margin width, pathologic class, and age, but none of the molecular markers were part of it. Overexpression of HER4 in the presence of HER3 was associated with a better DFS.

Introduction: Several studies have been performed to assess the prognostic value of early neurological and neurophysiological findings in patients with postanoxic coma, but they have not led to precise, generally accepted, prognostic rules. This study was performed to assess whether it is possible to create a prognostic outcome table, using a combination of clinical variables and the electroencephalogram (EEG)., Methods: Clinical variables and EEG were registered on admission, at day 1-5, day 6-14, and day 15-42, and were related to the Glasgow outcome scale (GOS) at 30 and 180 days. The EEG abnormalities were categorized using the EEG classification system proposed by Synek (J Clin Neurophysiol 5:161-174, 1988) and Young et al. (Can J Neurol Sci 24:320-325, 1997). These EEG classifications were then further divided into prognostic categories., Results: Age was a significant predictor of outcome. The early recorded clinical variables were the most predictive and the GCS showed a limited prognostic value. The first EEG registration proved to be the most predictive. The Synek-classification was divided into three prognostic categories: "benign," "malignant," and "fatal" and the Young-classification into four: "benign," "intermediate," "malignant," and "fatal." An outcome prediction table is proposed using the Young-classification stratified for age., Conclusion: Age is an important variable determining the prognostic value of the EEG and should always be taken into consideration. The prognostic categories, especially when derived from the Young-classification, showed a good prognostic value. Although this is a pilot study, we believe that the revised prognostic categories have a good prognostic value in predicting outcome and are worth further investigation and validation.

Aims: To evaluate, in a randomized controlled way, the use of a daytime wetting alarm in a day-care center during three consecutive weeks in healthy children., Methods: Thirty-nine healthy young children, between 18 and 30 months old, were selected at random for a wetting alarm diaper training (n = 27) or control wearing a placebo alarm (n = 12). Toilet behavior was observed during a period of 10 hr by independent observers before, at the end of, and 2 weeks after training. Children were defined as completing daytime toilet training when the child wore undergarments, showed awareness of a need to void, initiated the toileting without prompts or reminder from the trainer and had maximum one leakage accident per day., Results: Children in the wetting alarm diaper training group achieved independent bladder control in 51.9% and did significantly better than in the control group (8.3%) (P = 0.013). The results were sustained during the following 14 days (P = 0.013)., Conclusion: The wetting alarm diaper training is an effective option for toilet training young healthy children in a day-care center. It offers day-care providers clear guidelines and limits the time to complete toilet training in many children without putting too much burden on the child and the day-care center activities., ((c) 2008 Wiley-Liss, Inc.)

Pathological stage is currently the most important determinant of colorectal cancer prognosis. Hence, identification of additional prognostic markers is warranted. This study aimed to analyse the prognostic relevance of microsatellite instability (MSI) in 241 colon and 90 rectal tumours, using a mononucleotide loci multiplex PCR assay and immunohistochemistry. Thirty (12.4%) colon tumours and one rectal tumour showed MSI. Although MSI was associated with proximal location and poor differentiation, no survival benefit was observed. The prognostic value of stage and differentiation was confirmed in this study. Analysis by stage revealed a longer overall (stage II/III) and disease free survival (stage II) for patients with well differentiated tumours. In addition, age and distal localisation were related to longer overall survival in stage II tumours. In conclusion, our findings show an association of MSI in sporadic colon tumours and certain clinical features; however, they do not suggest a survival benefit for MSI tumours.

Objective: To study the recurrence of breast cancer among patients who were using the levonorgestrel-releasing intrauterine system (LNG IUS)., Design: A retrospective, controlled cohort analysis., Setting: Six Belgian hospitals., Patient(s): We identified 79 breast cancer patients who used the LNG IUS, and we selected a control group of 120 patients with no history of LNG IUS use and who were closely matched for age at diagnosis, tumor stage, tumor grade, and treatment modalities. Two subgroups were identified: [1] breast cancer patients who continued using the LNG IUS after diagnosis and [2] breast cancer patients who began using an LNG IUS after treatment for breast cancer., Intervention(s): Patient's data were collected and survival analysis was performed., Main Outcome Measure(s): Breast cancer recurrence rate., Result(s): There was a recurrence rate of 21.5% (17/79) among LNG IUS users and of 16.6% (20/120) among the control group (adjusted hazard ratio, 1.86; 95% confidence interval, 0.86-4.00; no statistically significant difference). Subgroup analysis showed that women using the LNG IUS (n = 38) at the time of breast cancer diagnosis (and who continued its use) had a statistically significantly increased risk of recurrence (adjusted hazard ratio, 3.39; 95% confidence interval, 1.01-11.35) compared with patients in the control group. There was 47.4% (18/38) nodal involvement in this subgroup, and all patients who recurred had metastatic disease., Conclusion(s): Overall, we did not find an increased risk of breast cancer recurrence associated with use of the LNG-IUS. However, in a subgroup analysis of women who developed breast cancer while using an LNG IUS and who continued to use the LNG IUS, we found a higher risk of recurrence of borderline statistical significance. Additional research is needed to confirm or refute these findings.

Objective: Toilet training (TT) is important for every child, but there is no agreement on what is the best training method. We evaluated in a randomized way the comprehensive use of a daytime wetting alarm at home for 5 days in healthy children and compared it with timed potty training., Methods: Thirty-nine children, between 20 and 36 months of age, were randomized to wetting alarm diaper training (WAD-T; n = 20) or timed potty training (TP-T; n = 19). Toilet behavior was observed by parents and independent observers before, at the end, and after 2 weeks of training. Late evaluation at 1 month was done by telephone., Results: The WAD-T group did significantly better than the TP-T group at the end training (p = .041), at 14 days (p = .027), and 1 month after training (p = .027). Independent bladder control was achieved in 88.9% of the WAD-T group., Conclusions: The WAD-T method is a structured, child-friendly, highly effective option for TT young healthy children. It offers the parents clear guidelines, a limited time needed to complete TT, a high success rate, and minor emotional conflicts. Results must now be confirmed in a larger sample size.

Background: Gastric restrictive procedures such as laparoscopic gastric banding or vertical banded gastroplasty show, at longer follow up, more and more failures and complications. This study focuses on the results of Roux-en-Y gastric bypass procedure (RYGBP) done as a re-do procedure, both after a technically failed restrictive procedure or when the restrictive procedure failed to obtain substantial weight loss., Methods: We reviewed data concerning the postoperative complications and weight loss of 36 patients undergoing re-do surgery for failed restrictive procedures., Results: Over a period of two years, 36 patients with a mean age of 40.9 years were converted to a RYGBP. Median time to conversion was 4.9 years, median follow up after conversion was 6.6 months. Early postoperative complications (less than 30 days postoperatively) were noted in 11 patients (30%). A greater number of early complications were noticed in group A (technical complications) compared to group B (insufficient weight loss) (39% vs. 22%). Late postoperative complications were seen in six patients (16%). In this relatively short follow up period we noticed a drop in body mass index (BMI) from a mean of 38.8kg/m(2) to 30.9 kg/m(2) with a mean excess body weight loss (EBWL) of 33.1% after the re-do procedure. Body mass index decreased from a mean preoperative value of 37.6kg/m(2) to 28.9 kg/m(2) in group A patients with an EBWL 36%, while group B patients had a change in BMI from 40.1kg/m(2) to 32.9 kg/m(2) with a mean EBWL of 30%., Conclusion: Based on the literature, we can presume that restrictive surgery for morbidly obese patients will require many reoperations in the future. The standard operation of choice is RYGBP. In our study this procedure showed a higher, but not significantly early morbidity rate when the indication for re-do surgery was a technical complication of the initial procedure.

Background: We have recently shown the prognostic value of growth pattern classification in non-small cell lung cancer. The aim of this study is to validate the hypothesis that these growth patterns have a distinct angiogenic and proliferative profile., Methods: Hematoxylin-eosin stained tissue sections of 239 patients with non-small cell lung cancer were classified into growth patterns. One representative tissue section per patient was double immunostained with CD34 and Ki-67 antibodies. Endothelial cell proliferation fraction, tumor cell proliferation fraction, microvessel density, and Chalkley count were assessed at the invading front and the center of the selected tumor section., Results: According to the growth pattern classification, 161 patients (67.4%) had a destructive, 33 (13.8%) a papillary, and 45 (18.8%) an alveolar growth pattern. There were significant differences in endothelial cell proliferation fraction (p < 0.001), tumor cell proliferation fraction (p < 0.001), microvessel density (p < 0.001), and Chalkley count (p < 0.001) between the growth patterns. Multiple Cox regression analysis showed that a low endothelial cell proliferation fraction was consistently an independent prognostic factor for overall poor (hazard ratio = 0.93; confidence interval: 0.88 to 0.97, p = 0.002) and disease-free survival (hazard ratio = 0.94; confidence interval: 0.89 to 0.98, p = 0.007)., Conclusions: Growth patterns have a distinct angiogenic and proliferative profile. In non-small cell lung cancer, a low degree of angiogenesis (a low endothelial cell proliferation fraction) is associated with poor prognosis.