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Background Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study. Methods The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements. Discussion The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators. Trial registration NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922

Web-based questionnaires have become increasingly popular in health research. However, reported response rates vary and response bias may be introduced. The aim of this study was to evaluate whether sending a mixed invitation (paper-based together with Web-based questionnaire) rather than a Web-only invitation (Web-based questionnaire only) results in higher response and participation rates for female childhood cancer survivors filling out a questionnaire on fertility issues. In addition, differences in type of response and characteristics of the responders and nonresponders were investigated. Moreover, factors influencing preferences for either the Web- or paper-based version of the questionnaire were examined. This study is part of a nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female childhood cancer survivors. The Web-based version of the questionnaire was available for participants through the Internet by means of a personalized user name and password. Participants were randomly selected to receive either a mixed invitation (paper-based questionnaire together with log-in details for Web-based questionnaire, n = 137) or a Web-only invitation (log-in details only, n = 140). Furthermore, the latter group could request a paper-based version of the questionnaire by filling out a form. Overall response rates were comparable in both randomization groups (83% mixed invitation group vs 89% in Web-only invitation group, P = .20). In addition, participation rates appeared not to differ (66% or 90/137, mixed invitation group vs 59% or 83/140, Web-only invitation group, P =.27). However, in the mixed invitation group, significantly more respondents filled out the paper-based questionnaire compared with the Web-only invitation group (83% or 75/90 and 65% or 54/83, respectively, P = .01). The 44 women who filled out the Web-based version of the questionnaire had a higher educational level than the 129 women who filled out the paper-based version (P = .01). Furthermore, the probability of filling out the Web-based questionnaire appeared to be greater for women who were allocated to the Web-only invitation group (OR = 2.85, 95% CI 1.31-6.21), were older (OR = 1.08, 95% CI 1.02-1.15), had a higher educational level (OR high vs low = 0.06, 95% CI 0.01-0.52), or were students (OR employed vs student = 3.25, 95% CI 1.00-10.56). Although overall response as well as participation rates to both types of invitations were similar, adding a paper version of a questionnaire to a Web-only invitation resulted in more respondents filling out the paper-based version. In addition, women who were older, had a higher level of education, or were students, were more likely to have filled out the Web-based version of the questionnaire. Given the many advantages of Web-based over paper-based questionnaires, researchers should strongly consider using Web-based questionnaires, although possible response bias when using these types of questionnaires should be taken into account. Nederlands Trial Register NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922 (Archived by WebCite at http://www.webcitation.org/5zRRdMrDv).

Vegetated ditches and wetlands are important sites for nutrient removal in agricultural catchments. About half of the influx of inorganic nitrogen can be removed from these ecosystems by denitrification. Previous studies have shown that denitrification in aquatic ecosystems is strongly temperature dependent, resulting from temperature-dependent oxygen availability. Here, we study short-term temperature effects on sediment oxygen demand (SOD) and the maximum depth of oxygen penetration into the sediment (Z), in relation to overall denitrification rates. We set up sixteen wetland microcosms at four different temperatures (11–25 °C), in which we determined SOD and Z from sediment oxygen microprofiles. Denitrification rates were measured using 15 N-labeling, analysed by membrane inlet mass spectrometry. Temperature strongly affected sediment oxygen dynamics. SOD exponentially rose with temperature, ranging from 0.37 to 1.53 g m −2 d −1 (Q 10  = 2.4). Correspondingly, warming led to shallower oxygen penetration into the sediment, ranging from 4.12 to 2.08 mm. Denitrification rates increased with warming (Q 10  = 2.6), ranging from 8.4 to 86 μmol N m −2  h −1 . The results of this short-term experiment confirm the potential increase of denitrification with rising temperature, promoted by lower oxygen availability in the top layer of the sediment, which supports the understanding of denitrification variability in freshwaters.

The occurrence of phenotypic differences between monozygotic (MZ) twins is commonly attributed to environmental factors, assuming that MZ twins have a complete identical genetic make-up. Yet, recently several lines of evidence showed that both genetic and epigenetic factors could have a role in phenotypic discordance after all. A high occurrence of copy number variation (CNV) differences was observed within MZ twin pairs discordant for Parkinson's disease, thereby stressing on the importance of post-zygotic mutations as disease-predisposing events. In this study, the prevalence of discrepant CNVs was analyzed in discordant MZ twins of the Esophageal Atresia (EA) and Congenital Diaphragmatic Hernia (CDH) cohort in the Netherlands. Blood-derived DNA from 11 pairs (7 EA and 4 CDH) was screened using high-resolution SNP arrays. Results showed an identical copy number profile in each twin pair. Mosaic chromosome gain or losses could not be detected either with a detection threshold of 20%. Some of the germ-line structural events demonstrated in five out of eleven twin pairs could function as a susceptible genetic background. For example, the 177-Kb loss of chromosome 10q26 in CDH pair-3 harbors the TCF7L2 gene (Tcf4 protein), which is implicated in the regulation of muscle fiber type development and maturation. In conclusion, discrepant CNVs are not a common cause of twin discordancy in these investigated congenital anomaly cohorts.

Abstract Objective To assess the vertebral pattern in a cohort of deceased fetuses and neonates, and to study the possible impact of DNA Copy Number Variations (CNVs) in coding regions and/or disturbing enhancers on the development of the vertebral pattern. Method Radiographs of 445 fetuses and infants, deceased between 2009 and 2015, were assessed. Terminations of pregnancies, stillbirths and neonatal deaths were included. Patients were excluded if the vertebral pattern could not be determined. Copy number profiles of 265 patients were determined using single nucleotide polymorphism array. Results 274/374 patients (73.3%) had an abnormal vertebral pattern. Cervical ribs were present in 188/374 (50.3%) and were significantly more common in stillbirths (69/128 (53.9%)) and terminations of pregnancies (101/188 (53.7%)), compared to live births (18/58, 31.0%, p = 0.006). None of the rare CNVs were recurrent or overlapped candidate genes for vertebral patterning. Conclusion The presence of an abnormal vertebral pattern, particularly in the cervical region, could be a sign of disruption at critical, highly interactive and conserved stages of embryogenesis. The vertebral pattern might provide valuable information regarding fetal and neonatal outcome. CNV analyses did not identify a mutual genetic cause for the occurrence of vertebral patterning abnormalities, indicating genetic heterogeneity. Footnotes * Competing interests: The authors declare no competing interests. * Funding sources: None.