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1.  Breastfeeding, lung volumes and alveolar size at school-age 
BMJ Open Respiratory Research  2015;2(1):e000081.
Background
Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma.
Methods
We analysed data from 111 children and young adults aged 11–21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of 3Helium (3He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1–4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders.
Results
We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels.
Conclusions
Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.
doi:10.1136/bmjresp-2015-000081
PMCID: PMC4499711  PMID: 26180638
Paediatric asthma
2.  Socioeconomic Status and Childhood Leukemia Incidence in Switzerland 
Frontiers in Oncology  2015;5:139.
Socioeconomic status (SES) discrepancies exist for child and adult cancer morbidity and are a major public health concern. In this Swiss population-based matched case–control study on the etiology of childhood leukemia, we selected the cases from the Swiss Childhood Cancer Registry diagnosed since 1991 and the controls randomly from census. We assigned eight controls per case from the 1990 and 2000 census and matched them by the year of birth and gender. SES information for both cases and controls was obtained from census records by probabilistic record linkage. We investigated the association of SES with childhood leukemia in Switzerland, and explored whether it varied with different definitions of socioeconomic status (parental education, living condition, area-based SES), time period, and age. In conditional logistic regression analyses of 565 leukemia cases and 4433 controls, we found no consistent evidence for an association between SES and childhood leukemia. The odds ratio comparing the highest with the lowest SES category ranged from 0.95 (95% CI: 0.71–1.26; Ptrend = 0.73) for paternal education to 1.37 (1.00–1.89; Ptrend = 0.064) for maternal education. No effect modification was found for time period and age at diagnosis. Based on this population-based study, which avoided participation and reporting bias, we assume the potential association of socioeconomic status and childhood leukemia if existing to be small. This study did not find evidence that socioeconomic status, of Switzerland or comparable countries, is a relevant risk factor or strong confounder in etiological investigations on childhood leukemia.
doi:10.3389/fonc.2015.00139
PMCID: PMC4485172  PMID: 26175964
childhood cancer; leukemia; socioeconomic status; risk factor; case–control study
3.  A parent‐completed respiratory questionnaire for 1‐year‐old children: repeatability 
Archives of Disease in Childhood  2007;92(10):861-865.
Background and aims
There are few standardised questionnaires for the assessment of respiratory symptoms in preschool children. We have developed and tested the short‐term repeatability of a postal questionnaire on respiratory symptoms for 1‐year‐old children.
Methods
A newly developed postal questionnaire for the assessment of wheeze and other respiratory symptoms was sent to parents of a population‐based random sample of 4300 children aged 12–24 months. After an interval of 3 months, a random sample of 800 respondents received the questionnaire a second time. The responses were compared using Cohen's kappa (κ) to assess agreement corrected for chance.
Results
The first questionnaire was returned by 3194 (74%) families, the second one by 460/800 (58%). Repeatability was excellent (κ 0.80–0.96) for questions on household characteristics, environmental exposures and family history, good (κ 0.61–0.80) for questions on prevalence, severity and treatment of wheeze, and moderate (κ 0.39–0.66) for chronic cough and upper respiratory symptoms.
Conclusions
This short postal questionnaire designed for use in population‐based studies has excellent repeatability for family and household characteristics and good repeatability for questions on wheeze. Short‐term changes in symptom status might be responsible for variable answers on recent chronic cough and upper respiratory symptoms. Overall, the questionnaire is a valuable instrument for community‐based research on respiratory symptoms in 1 to 2‐year‐old children.
doi:10.1136/adc.2007.117978
PMCID: PMC2083231  PMID: 17502330
preschool; asthma; kappa; repeatability; questionnaire
4.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Summary
Background
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
Methods
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
Findings
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Interpretation
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
Funding
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
doi:10.1016/S1470-2045(14)70265-7
PMCID: PMC4142216  PMID: 24954778
5.  “Attacks” or “Whistling”: Impact of Questionnaire Wording on Wheeze Prevalence Estimates 
PLoS ONE  2015;10(6):e0131618.
Background
Estimates of prevalence of wheeze depend on questionnaires. However, wording of questions may vary between studies. We investigated effects of alternative wording on estimates of prevalence and severity of wheeze, and associations with risk factors.
Methods
White and South Asian children from a population-based cohort (UK) were randomly assigned to two groups and followed up at one, four and six years (1998, 2001, 2003). Parents were asked either if their child ever had “attacks of wheeze” (attack group, N=535), or “wheezing or whistling in the chest” (whistling group, N=2859). All other study aspects were identical, including questions about other respiratory symptoms.
Results
Prevalence of wheeze ever was lower in the attack group than in the whistling group for all surveys (32 vs. 40% in white children aged one year, p<0.001). Prevalence of other respiratory symptoms did not differ between groups. Wheeze tended to be more severe in the attack group. The strength of association with risk factors was comparable in the two groups.
Conclusions
The wording of questions on wheeze can affect estimates of prevalence, but has less impact on measured associations with risk factors. Question wording is a potential source of between-study-heterogeneity in meta-analyses.
doi:10.1371/journal.pone.0131618
PMCID: PMC4482591  PMID: 26114296
6.  Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study 
Environmental Health Perspectives  2015;123(6):622-628.
Background
Exposure to medium or high doses of ionizing radiation is a known risk factor for cancer in children. The extent to which low-dose radiation from natural sources contributes to the risk of childhood cancer remains unclear.
Objectives
In a nationwide census-based cohort study, we investigated whether the incidence of childhood cancer was associated with background radiation from terrestrial gamma and cosmic rays.
Methods
Children < 16 years of age in the Swiss National Censuses in 1990 and 2000 were included. The follow-up period lasted until 2008, and incident cancer cases were identified from the Swiss Childhood Cancer Registry. A radiation model was used to predict dose rates from terrestrial and cosmic radiation at locations of residence. Cox regression models were used to assess associations between cancer risk and dose rates and cumulative dose since birth.
Results
Among 2,093,660 children included at census, 1,782 incident cases of cancer were identified including 530 with leukemia, 328 with lymphoma, and 423 with a tumor of the central nervous system (CNS). Hazard ratios for each millisievert increase in cumulative dose of external radiation were 1.03 (95% CI: 1.01, 1.05) for any cancer, 1.04 (95% CI: 1.00, 1.08) for leukemia, 1.01 (95% CI: 0.96, 1.05) for lymphoma, and 1.04 (95% CI: 1.00, 1.08) for CNS tumors. Adjustment for a range of potential confounders had little effect on the results.
Conclusions
Our study suggests that background radiation may contribute to the risk of cancer in children, including leukemia and CNS tumors.
Citation
Spycher BD, Lupatsch JE, Zwahlen M, Röösli M, Niggli F, Grotzer MA, Rischewski J, Egger M, Kuehni CE, for the Swiss Pediatric Oncology Group and the Swiss National Cohort. 2015. Background ionizing radiation and the risk of childhood cancer: a census-based nationwide cohort study. Environ Health Perspect 123:622–628; http://dx.doi.org/10.1289/ehp.1408548
doi:10.1289/ehp.1408548
PMCID: PMC4455589  PMID: 25707026
7.  Intra-Rater and Inter-Rater Reliability of a Medical Record Abstraction Study on Transition of Care after Childhood Cancer 
PLoS ONE  2015;10(5):e0124290.
Background
The abstraction of data from medical records is a widespread practice in epidemiological research. However, studies using this means of data collection rarely report reliability. Within the Transition after Childhood Cancer Study (TaCC) which is based on a medical record abstraction, we conducted a second independent abstraction of data with the aim to assess a) intra-rater reliability of one rater at two time points; b) the possible learning effects between these two time points compared to a gold-standard; and c) inter-rater reliability.
Method
Within the TaCC study we conducted a systematic medical record abstraction in the 9 Swiss clinics with pediatric oncology wards. In a second phase we selected a subsample of medical records in 3 clinics to conduct a second independent abstraction. We then assessed intra-rater reliability at two time points, the learning effect over time (comparing each rater at two time-points with a gold-standard) and the inter-rater reliability of a selected number of variables. We calculated percentage agreement and Cohen’s kappa.
Findings
For the assessment of the intra-rater reliability we included 154 records (80 for rater 1; 74 for rater 2). For the inter-rater reliability we could include 70 records. Intra-rater reliability was substantial to excellent (Cohen’s kappa 0-6-0.8) with an observed percentage agreement of 75%-95%. In all variables learning effects were observed. Inter-rater reliability was substantial to excellent (Cohen’s kappa 0.70-0.83) with high agreement ranging from 86% to 100%.
Conclusions
Our study showed that data abstracted from medical records are reliable. Investigating intra-rater and inter-rater reliability can give confidence to draw conclusions from the abstracted data and increase data quality by minimizing systematic errors.
doi:10.1371/journal.pone.0124290
PMCID: PMC4441480  PMID: 26001046
9.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Background
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
Objectives
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
Methods
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Results
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Conclusion
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
doi:10.1016/j.jaci.2013.12.1082
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
10.  Copy Number Variation of the Beta-Defensin Genes in Europeans: No Supporting Evidence for Association with Lung Function, Chronic Obstructive Pulmonary Disease or Asthma 
PLoS ONE  2014;9(1):e84192.
Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02–1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72–1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.
doi:10.1371/journal.pone.0084192
PMCID: PMC3880289  PMID: 24404154
11.  Catch-up Alveolarization in Ex-Preterm Children. Evidence from 3He Magnetic Resonance 
Rationale: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair.
Objectives: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance.
Methods: We recruited schoolchildren aged 10–14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37–42 wk; n = 61); (2) mild preterm (32–36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance.
Measurements and Main Results: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm2/second (95% confidence interval, 0.089–0.095) in the term group. Corresponding values were 0.096 (0.091–0.101), 0.090 (0085–0.095), and 0.089 (0.083–0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders.
Conclusions: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.
doi:10.1164/rccm.201210-1850OC
PMCID: PMC3734619  PMID: 23491406
alveolar structure; lung acinus; bronchopulmonary dysplasia; neonatal chronic lung disease
12.  Domestic Radon Exposure and Risk of Childhood Cancer: A Prospective Census-Based Cohort Study 
Environmental Health Perspectives  2013;121(10):1239-1244.
Background: In contrast with established evidence linking high doses of ionizing radiation with childhood cancer, research on low-dose ionizing radiation and childhood cancer has produced inconsistent results.
Objective: We investigated the association between domestic radon exposure and childhood cancers, particularly leukemia and central nervous system (CNS) tumors.
Methods: We conducted a nationwide census-based cohort study including all children < 16 years of age living in Switzerland on 5 December 2000, the date of the 2000 census. Follow-up lasted until the date of diagnosis, death, emigration, a child’s 16th birthday, or 31 December 2008. Domestic radon levels were estimated for each individual home address using a model developed and validated based on approximately 45,000 measurements taken throughout Switzerland. Data were analyzed with Cox proportional hazard models adjusted for child age, child sex, birth order, parents’ socioeconomic status, environmental gamma radiation, and period effects.
Results: In total, 997 childhood cancer cases were included in the study. Compared with children exposed to a radon concentration below the median (< 77.7 Bq/m3), adjusted hazard ratios for children with exposure ≥ the 90th percentile (≥ 139.9 Bq/m3) were 0.93 (95% CI: 0.74, 1.16) for all cancers, 0.95 (95% CI: 0.63, 1.43) for all leukemias, 0.90 (95% CI: 0.56, 1.43) for acute lymphoblastic leukemia, and 1.05 (95% CI: 0.68, 1.61) for CNS tumors.
Conclusions: We did not find evidence that domestic radon exposure is associated with childhood cancer, despite relatively high radon levels in Switzerland.
Citation: Hauri D, Spycher B, Huss A, Zimmermann F, Grotzer M, von der Weid N, Weber D, Spoerri A, Kuehni C, Röösli M, for the Swiss National Cohort and the Swiss Paediatric Oncology Group (SPOG). 2013. Domestic radon exposure and risk of childhood cancer: a prospective census-based cohort study. Environ Health Perspect 121:1239–1244; http://dx.doi.org/10.1289/ehp.1306500
doi:10.1289/ehp.1306500
PMCID: PMC3801468  PMID: 23942326
13.  Effect of Mannitol Dry Powder Challenge on Exhaled Nitric Oxide in Children 
PLoS ONE  2013;8(1):e54521.
Background
Fractional exhaled nitric oxide (FENO), a non-invasive marker of eosinophilic airway inflammation, is increasingly used for diagnostic and therapeutic decisions in adult and paediatric asthma. Standardized guidelines for the measurement of FENO recommend performing FENO measurements before rather than after bronchial provocation tests.
Objective
To investigate whether FENO levels decrease after a Mannitol dry powder (MDP) challenge in a clinical setting, and whether the extent of the decrease is influenced by number of MDP manoeuvres, baseline FENO, atopy and doctor diagnosed asthma.
Methods
Children aged 6–16 years, referred for possible reactive airway disease to a respiratory outpatient clinic, performed an MDP challenge (Aridol®, Pharmaxis, Australia). FENO was measured in doublets immediately before and after the challenge test using the portable NIOX MINO® device (Aerocrine, Stockholm, Sweden). We analysed the data using Kruskal-Wallis rank tests, Wilcoxon signed rank tests and multivariable linear regressions.
Results
One hundred and seven children completed both tests (mean±SD age 11.5±2.8 years). Overall, median (interquartile range) FENO decreased slightly by −2.5 ppb (−7.0, −0.5), from 18.5 ppb (10.5, 45.5) before the MDP challenge to 16.5 ppb thereafter (8.5, 40.5; p<0.001). In all participants, the change in FENO was smaller than one standard deviation of the baseline mean. The % fall in FENO was smaller in children with less MDP manoeuvres (e.g. higher bronchial responsiveness; p = 0.08) but was not influenced by levels of baseline FENO (p = 0.68), atopy (p = 0.84) or doctor diagnosed asthma (p = 0.93).
Conclusion
MDP challenge test influences FENO values but differences are small and clinically barely relevant.
doi:10.1371/journal.pone.0054521
PMCID: PMC3548778  PMID: 23349918
14.  Follow-Up Programs for Childhood Cancer Survivors in Europe: A Questionnaire Survey 
PLoS ONE  2012;7(12):e53201.
Background
For many childhood cancer survivors follow-up care is important long after treatment completion. We aimed to describe the availability and characteristics of long-term follow-up programs (LTFU) across Europe, their content and aims, their problems, and to assess opinions on different models of LTFU.
Methodology/Principal Findings
We asked 179 pediatric oncology institutions in 20 European countries to complete an online survey on LTFU available at their institution. Of 110 respondents (62% response), 66% reported having LTFU for pediatric survivors, 38% for adult survivors of childhood cancer. Availability varied widely across European regions, from 9% of institutions in Northern Europe reporting LTFU for adult survivors to 83% of institution on the British Isles reporting LTFU for pediatric survivors. Pediatric and adult LTFU were usually located in pediatric hospitals and run by pediatric oncologists. Content of follow-up included screening for adverse outcomes and health education. Important problems included lack of time, personnel and funding. Most institutions without LTFU reported that they would like to offer a program (86%).
Conclusion/Significance
Despite general agreement on the need of follow-up care, there is still a lack of well-organized LTFU for survivors of childhood cancer across Europe.
doi:10.1371/journal.pone.0053201
PMCID: PMC3534070  PMID: 23300889
15.  Physical Performance Limitations in Adolescent and Adult Survivors of Childhood Cancer and Their Siblings 
PLoS ONE  2012;7(10):e47944.
Purpose
This study investigates physical performance limitations for sports and daily activities in recently diagnosed childhood cancer survivors and siblings.
Methods
The Swiss Childhood Cancer Survivor Study sent a questionnaire to all survivors (≥16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976–2003 aged <16 years. Siblings received similar questionnaires. We assessed two types of physical performance limitations: 1) limitations in sports; 2) limitations in daily activities (using SF-36 physical function score). We compared results between survivors diagnosed before and after 1990 and determined predictors for both types of limitations by multivariable logistic regression.
Results
The sample included 1038 survivors and 534 siblings. Overall, 96 survivors (9.5%) and 7 siblings (1.1%) reported a limitation in sports (Odds ratio 5.5, 95%CI 2.9-10.4, p<0.001), mainly caused by musculoskeletal and neurological problems. Findings were even more pronounced for children diagnosed more recently (OR 4.8, CI 2.4–9.6 and 8.3, CI 3.7–18.8 for those diagnosed <1990 and ≥1990, respectively; p = 0.025). Mean physical function score for limitations in daily activities was 49.6 (CI 48.9–50.4) in survivors and 53.1 (CI 52.5–53.7) in siblings (p<0.001). Again, differences tended to be larger in children diagnosed more recently. Survivors of bone tumors, CNS tumors and retinoblastoma and children treated with radiotherapy were most strongly affected.
Conclusion
Survivors of childhood cancer, even those diagnosed recently and treated with modern protocols, remain at high risk for physical performance limitations. Treatment and follow-up care should include tailored interventions to mitigate these late effects in high-risk patients.
doi:10.1371/journal.pone.0047944
PMCID: PMC3474773  PMID: 23082232
16.  Alveolarization Continues during Childhood and Adolescence 
Rationale: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals.
Objectives: We reexamined the current hypothesis using helium-3 (3He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent.
Methods: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7–21 years. Using 3HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of 3He at FRC (n = 109), and average diffusion distance of helium (Xrms¯) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization.
Measurements and Main Results: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13–0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31–0.52). Similarly, increase of (Xrms¯) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64–2.30) across the age range studied.
Conclusions: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.
doi:10.1164/rccm.201107-1348OC
PMCID: PMC3410735  PMID: 22071328
growth and development; lung development; alveolarization
17.  Health-Related Quality of Life in Long-Term Survivors of Relapsed Childhood Acute Lymphoblastic Leukemia 
PLoS ONE  2012;7(5):e38015.
Background
Relapses occur in about 20% of children with acute lymphoblastic leukemia (ALL). Approximately one-third of these children can be cured. Their risk for late effects is high because of intensified treatment, but their health-related quality of life (HRQOL) was largely unmeasured. Our aim was to compare HRQOL of ALL survivors with the general population, and of relapsed with non-relapsed ALL survivors.
Methodology/Principal Findings
As part of the Swiss Childhood Cancer Survivor Study (SCCSS) we sent a questionnaire to all ALL survivors in Switzerland who had been diagnosed between 1976–2003 at age <16 years, survived ≥5 years, and were currently aged ≥16 years. HRQOL was assessed with the Short Form-36 (SF-36), which measures four aspects of physical health and four aspects of mental health. A score of 50 corresponded to the mean of a healthy reference population. We analyzed data from 457 ALL survivors (response: 79%). Sixty-one survivors had suffered a relapse. Compared to the general population, ALL survivors reported similar or higher HRQOL scores on all scales. Survivors with a relapse scored lower in general health perceptions (51.6) compared to those without (55.8;p=0.005), but after adjusting for self-reported late effects, this difference disappeared.
Conclusion/Significance
Compared to population norms, ALL survivors reported good HRQOL, even after a relapse. However, relapsed ALL survivors reported poorer general health than non-relapsed. Therefore, we encourage specialists to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects. This will help to improve patients’ HRQOL.
doi:10.1371/journal.pone.0038015
PMCID: PMC3360640  PMID: 22662262
18.  Daily Physical Activities and Sports in Adult Survivors of Childhood Cancer and Healthy Controls: A Population-Based Questionnaire Survey 
PLoS ONE  2012;7(4):e34930.
Background
Healthy lifestyle including sufficient physical activity may mitigate or prevent adverse long-term effects of childhood cancer. We described daily physical activities and sports in childhood cancer survivors and controls, and assessed determinants of both activity patterns.
Methodology/Principal Findings
The Swiss Childhood Cancer Survivor Study is a questionnaire survey including all children diagnosed with cancer 1976–2003 at age 0–15 years, registered in the Swiss Childhood Cancer Registry, who survived ≥5years and reached adulthood (≥20years). Controls came from the population-based Swiss Health Survey. We compared the two populations and determined risk factors for both outcomes in separate multivariable logistic regression models. The sample included 1058 survivors and 5593 controls (response rates 78% and 66%). Sufficient daily physical activities were reported by 52% (n = 521) of survivors and 37% (n = 2069) of controls (p<0.001). In contrast, 62% (n = 640) of survivors and 65% (n = 3635) of controls reported engaging in sports (p = 0.067). Risk factors for insufficient daily activities in both populations were: older age (OR for ≥35years: 1.5, 95CI 1.2–2.0), female gender (OR 1.6, 95CI 1.3–1.9), French/Italian Speaking (OR 1.4, 95CI 1.1–1.7), and higher education (OR for university education: 2.0, 95CI 1.5–2.6). Risk factors for no sports were: being a survivor (OR 1.3, 95CI 1.1–1.6), older age (OR for ≥35years: 1.4, 95CI 1.1–1.8), migration background (OR 1.5, 95CI 1.3–1.8), French/Italian speaking (OR 1.4, 95CI 1.2–1.7), lower education (OR for compulsory schooling only: 1.6, 95CI 1.2–2.2), being married (OR 1.7, 95CI 1.5–2.0), having children (OR 1.3, 95CI 1.4–1.9), obesity (OR 2.4, 95CI 1.7–3.3), and smoking (OR 1.7, 95CI 1.5–2.1). Type of diagnosis was only associated with sports.
Conclusions/Significance
Physical activity levels in survivors were lower than recommended, but comparable to controls and mainly determined by socio-demographic and cultural factors. Strategies to improve physical activity levels could be similar as for the general population.
doi:10.1371/journal.pone.0034930
PMCID: PMC3323587  PMID: 22506058
19.  European Birth Cohorts for Environmental Health Research 
Background: Many pregnancy and birth cohort studies investigate the health effects of early-life environmental contaminant exposure. An overview of existing studies and their data is needed to improve collaboration, harmonization, and future project planning.
Objectives: Our goal was to create a comprehensive overview of European birth cohorts with environmental exposure data.
Methods: Birth cohort studies were included if they a) collected data on at least one environmental exposure, b) started enrollment during pregnancy or at birth, c) included at least one follow-up point after birth, d) included at least 200 mother–child pairs, and e) were based in a European country. A questionnaire collected information on basic protocol details and exposure and health outcome assessments, including specific contaminants, methods and samples, timing, and number of subjects. A full inventory can be searched on www.birthcohortsenrieco.net.
Results: Questionnaires were completed by 37 cohort studies of > 350,000 mother–child pairs in 19 European countries. Only three cohorts did not participate. All cohorts collected biological specimens of children or parents. Many cohorts collected information on passive smoking (n = 36), maternal occupation (n = 33), outdoor air pollution (n = 27), and allergens/biological organisms (n = 27). Fewer cohorts (n = 12–19) collected information on water contamination, ionizing or nonionizing radiation exposures, noise, metals, persistent organic pollutants, or other pollutants. All cohorts have information on birth outcomes; nearly all on asthma, allergies, childhood growth and obesity; and 26 collected information on child neurodevelopment.
Conclusion: Combining forces in this field will yield more efficient and conclusive studies and ultimately improve causal inference. This impressive resource of existing birth cohort data could form the basis for longer-term and worldwide coordination of research on environment and child health.
doi:10.1289/ehp.1103823
PMCID: PMC3261945  PMID: 21878421
birth cohorts; child health; environmental exposures; Europe; review
20.  Childhood cancer and nuclear power plants in Switzerland: a census-based cohort study 
Background Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland.
Methods We computed person-years at risk for children aged 0–15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5–10 km and 10–15 km from the nearest NPP with children born >15 km away, using Poisson regression models.
Results We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0–4 and 0–15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0–4 and 0–15 year olds were 1.20 (0.60–2.41) and 1.05 (0.60–1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61–1.54) and 0.89 (0.63–1.27). There was no evidence of a dose–response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results.
Conclusions This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.
doi:10.1093/ije/dyr115
PMCID: PMC3204210  PMID: 21750009
Childhood; cancer; leukaemia; ionizing radiation; nuclear power plants; population based; cancer registry
21.  A Disease Model for Wheezing Disorders in Preschool Children Based on Clinicians' Perceptions 
PLoS ONE  2009;4(12):e8533.
Background
Wheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult.
Methodology/Principal Findings
The aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children.
Conclusions/Significance
While there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.
doi:10.1371/journal.pone.0008533
PMCID: PMC2795203  PMID: 20046874
22.  Lung Volume, Breathing Pattern and Ventilation Inhomogeneity in Preterm and Term Infants 
PLoS ONE  2009;4(2):e4635.
Background
Morphological changes in preterm infants with bronchopulmonary dysplasia (BPD) have functional consequences on lung volume, ventilation inhomogeneity and respiratory mechanics. Although some studies have shown lower lung volumes and increased ventilation inhomogeneity in BPD infants, conflicting results exist possibly due to differences in sedation and measurement techniques.
Methodology/Principal Findings
We studied 127 infants with BPD, 58 preterm infants without BPD and 239 healthy term-born infants, at a matched post-conceptional age of 44 weeks during quiet natural sleep according to ATS/ERS standards. Lung function parameters measured were functional residual capacity (FRC) and ventilation inhomogeneity by multiple breath washout as well as tidal breathing parameters. Preterm infants with BPD had only marginally lower FRC (21.4 mL/kg) than preterm infants without BPD (23.4 mL/kg) and term-born infants (22.6 mL/kg), though there was no trend with disease severity. They also showed higher respiratory rates and lower ratios of time to peak expiratory flow and expiratory time (tPTEF/tE) than healthy preterm and term controls. These changes were related to disease severity. No differences were found for ventilation inhomogeneity.
Conclusions
Our results suggest that preterm infants with BPD have a high capacity to maintain functional lung volume during natural sleep. The alterations in breathing pattern with disease severity may reflect presence of adaptive mechanisms to cope with the disease process.
doi:10.1371/journal.pone.0004635
PMCID: PMC2645689  PMID: 19247491

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