Socioeconomic position, family context, and child cognitive development.

Socioeconomic position (SEP) may have different effects on cognitive development and family context could play a role in this association. This work aimed to analyse the role of socioeconomic positions, measured via various indicators collected longitudinally, in cognitive development at 7-11 years of age, evaluating the role of family context as a potential mediator. The study sample included 394 and 382 children from the INMA Gipuzkoa and Valencia cohorts, respectively. SEP indicators were assessed during pregnancy (family social class, parental education, employment, and disposable income) and at 7 (Gipuzkoa) and 11 (Valencia) years of age (At Risk of Poverty or Social Exclusion (AROPE)). Family context and cognitive development were measured with the Haezi-Etxadi Family Assessment Scale 7-11 (HEFAS 7-11) and Raven's Coloured Progressive Matrices (Raven's CPM), respectively. Linear regression models were developed to assess the relationships between (a) SEP-family context, (b) SEP-cognitive development, and (c) family context-cognitive development, adjusting for a priori-selected confounders. Simple and multiple mediation analyses were performed to explore the role of family context in the SEP-cognitive development relationship. Lower SEP was related with a lower cognitive score, this association being particularly robust for family social class. SEP indicators were related to subscales of family context, in particular those regarding cognitive stimulation, parental stress, and parenting. A relationship was also found between these three subscales and child cognitive development, mediating the effect of family social class on child cognition by 5.2, 5.5, and 10.8%, respectively, and 12.0% jointly.    Conclusion: Both family SEP and context contribute to a child's cognitive development. Equalising policies and positive parenting programmes could contribute to improving cognitive development in children. What is Known: • Parental social class, education, and employment status have been widely employed to measure socioeconomic position. What is New: • This work focuses on standard measurements of socioeconomic position but also other economic indicators such as the EHII and AROPE, and their effect on child cognitive development and family context. • Promotion of cognitive and linguistic development, parental stress and conflict, and parental profile fostering child development mediated the effect of family social class on cognitive development.

Associations of Maternal Educational Level, Proximity to Greenspace During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood: A Proof-of-Concept Federated Analysis in 18 Birth Cohorts.

International sharing of cohort data for research is important and challenging. We explored the feasibility of multi-cohort federated analyses by examining associations between three pregnancy exposures (maternal education, exposure to green vegetation and gestational diabetes) with offspring BMI from infancy to 17 years. We used data from 18 cohorts (n=206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13 and 14-17 years. Associations were estimated using linear regression via one-stage IPD meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z-score comparing low with high education age 2-3 years = 0.03 [95% CI 0.00, 0.05], 4-7 years = 0.16 [95% CI 0.14, 0.17], 8-13 years = 0.24 [95% CI 0.22, 0.26]). Gestational diabetes was positively associated with BMI from 8 years (BMI z-score difference = 0.18 [CI 0.12, 0.25]) but not at younger ages; however associations attenuated towards the null when restricted to cohorts which measured GDM via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age one but not at older ages. Opportunities of cross-cohort federated analyses are discussed.

Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.

BACKGROUND: Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming. METHODS: Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings. RESULTS: Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight. CONCLUSIONS: Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.

Cord blood metabolites and rapid postnatal growth as multiple mediators in the prenatal propensity to childhood overweight.

BACKGROUND: The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite. METHODS: Within four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach. RESULTS: Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal. CONCLUSION: Our findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight.

Returning to dialysis after kidney allograft failure: the experience of the Italian Registry of Paediatric Chronic Dialysis.

BACKGROUND: The need for dialysis after kidney allograft failure (DAGF) is among the top five reasons for dialysis initiation, making this an important topic in clinical nephrology. However, data are scarce on dialysis choice after transplantation and clinical outcomes for DAGF in children. METHODS: Patients receiving chronic dialysis < 18 years were recorded from January 1991 to January 2019 by the Italian Registry of Pediatric Chronic Dialysis (IRPCD). We investigated factors influencing choice of dialysis modality, patient outcome in terms of mortality, switching dialysis modality, and kidney transplantation. RESULTS: Among 118 patients receiving DAGF, 41 (35%) were treated with peritoneal dialysis (PD), and 77 (65%) with haemodialysis (HD). Significant predictors for treatment with PD were younger age at dialysis start (OR 0.85 per year increase [95%CI 0.72-1.00]) and PD use before kidney transplantation (OR 8.20 [95%CI 1.82-37.01]). Patients entering DAGF in more recent eras (OR 0.87 per year increase [95%CI 0.80-0.94]) and with more than one dialysis modality before kidney transplantation (OR 0.56 for being treated with PD [0.12-2.59]) were more likely to be initiated on HD. As compared to patients on HD, those treated with PD exhibited increased but non-significant mortality risk (HR 2.15 [95%CI 0.54-8.6]; p = 0.28) and higher prevalence of dialysis-related complications during DAGF (p = 0.002) CONCLUSIONS: Patients entering DAGF in more recent years are more likely to be initiated on HD. In this specific population of children, use of PD seems associated with a more complicated course. A higher resolution version of the Graphical abstract is available as Supplementary information.

COVID-19-like symptoms and their relation to the SARS-CoV-2 epidemic in children and adults of an Italian birth cohort

OBJECTIVES: to estimate the population prevalence of COVID-19-like symptoms in children and adults during the first SARS-CoV-2 epidemic wave hitting Italy in the spring 2020; to assess their geographical correlation with the cumulative number of COVID-19 cases by province; to analyse their clustering within families; to estimate their sensitivity, positive predictive value (PPV) and negative predictive value (NPV) for COVID-19 diagnosis in individuals tested for SARS-CoV-2. DESIGN: cross-sectional study nested within a birth cohort. SETTING AND PARTICIPANTS: mothers participating in an Italian birth cohort (NINFEA) were invited to complete an online questionnaire on COVID-19-like symptoms in their household. MAIN OUTCOME MEASURES: population prevalence of COVID-19-like symptoms in children and adults, geographical correlation of COVID-19-like symptoms with the cumulative number of COVID-19 cases by province, clustering of COVID-19-like symptoms within families, and sensitivity, PPV and NPV of COVID-19-like symptoms for COVID-19 diagnosis in individuals tested for SARS-CoV-2. RESULTS: information was collected on 3,184 households, 6,133 adults, and 5,751 children. In the period March-April 2020, 55.4% of the NINFEA families had at least one member with at least one COVID-19-like symptom. There was a strong geographical correlation between the population cumulative incidence of COVID-19 and the prevalence of muscle pain, fatigue, low-grade fever, and breathing difficulties in adults (Spearman's rho >=0.70). Having at least one family member with a COVID-19 diagnosis, compared with none tested for SARS-CoV-2, was associated with an increased prevalence ratio (PR) of almost all COVID-19-like symptoms in adults, and only of low-grade fever (37-37.5°C; PR 4.54; 95%CI 2.20-9.40) and anosmia/dysgeusia in children. Among adults with COVID-19 diagnosis, fatigue, muscle pain, and fever had a sensitivity >=70%. In individuals tested for SARS-CoV-2, with a 16.6% prevalence of COVID-19, breathing difficulties and nausea/vomiting had the highest PPVs, with point estimates close to 60%, and with NPVs close to 90%. CONCLUSIONS: the geographical prevalence of COVID-19-like symptoms in adults may inform on local disease clusters, while certain symptoms in family members of confirmed COVID-19 cases could help identify the intra-familial spread of the virus and its further propagation in the community. Low-grade fever is frequent in children with at least one household member with COVID-19 and possibly indicates child infection.

Stratification of Major Hepatectomies According to Their Outcome: Analysis of 2212 Consecutive Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To stratify major hepatectomies (MajHs) according to their outcomes. SUMMARY OF BACKGROUND DATA: MajHs are associated with non-negligible operative risks, but they include a wide range of procedures. Detailed depiction of the outcomes of different MajHs is the basis for a new classification of liver resections. METHODS: We retrospectively considered patients that underwent hepatectomy in 17 high-volume centers. Patients with an associated digestive/biliary resection were excluded. We analyzed open MajHs in non-cirrhotic patients. MajHs were classified according to the Brisbane nomenclature. Right hepatectomies (RHs) were reference standards. Outcomes were adjusted for potential confounders, including indication, liver function, preoperative portal vein embolization, and enrolling center. RESULTS: We analyzed a series of 2212 patients. In comparison with RH, left hepatectomy had lower mortality [0.6% vs 2.2%, odds ratio (OR) = 0.25], severe morbidity (11.7% vs 14.4%, OR = 0.62), and liver failure rates (2.1% vs 11.6%, OR = 0.16). Left hepatectomy+Sg1 and mesohepatectomy+/-Sg1 had outcomes similar to RH, except for higher bile leak rate (31.3% and 13.5% vs 6.7%, OR = 4.36 and OR = 2.29). RH + Sg1 had slightly worse outcomes than RH. Right and left trisectionectomies had higher mortality (5.0% and 7.3% vs 2.2%, OR = 2.07 and OR = 2.71) and liver failure rates than RH (19.0% and 22.0% vs 11.6%, OR = 2.03 and OR = 2.21). Left trisectionectomy had even higher severe morbidity (25.6% vs 14.4%, OR = 2.07) and bile leak rates (14.6% vs 6.7%, OR = 2.31). CONCLUSIONS: The term "major hepatectomy" includes resections having heterogeneous outcome. Different MajHs can be stratified according to their mortality, severe morbidity, liver failure, and bile leak rates.

Marginal Time-Dependent Causal Effects in Mediation Analysis With Survival Data.

The main aim of mediation analysis is to study the direct and indirect effects of an exposure on an outcome. To date, the literature on mediation analysis with multiple mediators has mainly focused on continuous and dichotomous outcomes. However, the development of methods for multiple mediation analysis of survival outcomes is still limited. Here we extend to survival outcomes a method for multiple mediation analysis based on the computation of appropriate weights. The approach considered has the advantages of not requiring specific models for mediators, allowing nonindependent mediators of any nature, and not relying on the assumption of rare outcomes. Simulation studies show good performance of the proposed estimator in terms of bias and coverage probability. The method is further applied to an example from a published study on prostate cancer mortality aimed at understanding the extent to which the effect of DNA methyltransferase 3b (DNMT3b) genotype on mortality was explained by DNA methylation and tumor aggressiveness. This approach can be used to quantify the marginal time-dependent direct and indirect effects carried by multiple indirect pathways, and software code is provided to facilitate its application.

Estimation of Relative and Absolute Risks in a Competing-Risks Setting Using a Nested Case-Control Study Design: Example From the ProMort Study.

In this paper, we describe the Prognostic Factors for Mortality in Prostate Cancer (ProMort) study and use it to demonstrate how the weighted likelihood method can be used in nested case-control studies to estimate both relative and absolute risks in the competing-risks setting. ProMort is a case-control study nested within the National Prostate Cancer Register (NPCR) of Sweden, comprising 1,710 men diagnosed with low- or intermediate-risk prostate cancer between 1998 and 2011 who died from prostate cancer (cases) and 1,710 matched controls. Cause-specific hazard ratios and cumulative incidence functions (CIFs) for prostate cancer death were estimated in ProMort using weighted flexible parametric models and compared with the corresponding estimates from the NPCR cohort. We further drew 1,500 random nested case-control subsamples of the NPCR cohort and quantified the bias in the hazard ratio and CIF estimates. Finally, we compared the ProMort estimates with those obtained by augmenting competing-risks cases and by augmenting both competing-risks cases and controls. The hazard ratios for prostate cancer death estimated in ProMort were comparable to those in the NPCR. The hazard ratios for dying from other causes were biased, which introduced bias in the CIFs estimated in the competing-risks setting. When augmenting both competing-risks cases and controls, the bias was reduced.

Minor Hepatectomies: Focusing a Blurred Picture: Analysis of the Outcome of 4471 Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To elucidate minor hepatectomy (MiH) outcomes. SUMMARY BACKGROUND DATA: Liver surgery has moved toward a parenchyma-sparing approach, favoring MiHs over major resections. MiHs encompass a wide range of procedures. METHODS: We retrospectively evaluated consecutive patients who underwent open liver resections in 17 high-volume centers. EXCLUSION CRITERIA: cirrhosis and associated digestive/biliary resections. Resections were classified as (Brisbane nomenclature): limited resections (LR); (mono)segmentectomies/bisegmentectomies (Segm/Bisegm); right anterior and right posterior sectionectomies (RightAnteriorSect/RightPosteriorSect). Additionally, we defined: complex LRs (ComplexLR = LRs with exposed vessels); postero-superior segmentectomies (PosteroSuperiorSegm = segment (Sg)7, Sg8, and Sg7+Sg8 segmentectomies); and complex core hepatectomies (ComplexCoreHeps = Sg1 segmentectomies and combined resections of Sg4s+Sg8+Sg1). Left lateral sectionectomies (LLSs, n = 442) and right hepatectomies (RHs, n = 1042) were reference standards. Outcomes were adjusted for potential confounders. RESULTS: Four thousand four hundred seventy-one MiHs were analyzed. Compared with RHs, MiHs had lower 90-day mortality (0.5%/2.2%), severe morbidity (8.6%/14.4%), and liver failure rates (2.4%/11.6%, P < 0.001), but similar bile leak rates. LR and LLS had similar outcomes. ComplexLR and Segm/Bisegm of anterolateral segments had higher bile leak rates than LLS rates (OR = 2.35 and OR = 3.24), but similar severe morbidity rates. ComplexCoreHeps had higher bile leak rates than RH rates (OR = 1.94); the severe morbidity rate approached that of RH. PosteroSuperiorSegm, RightAnteriorSect, and RightPosteriorSect had severe morbidity and bile leak rates similar to RH rates. MiHs had low liver failure rates, except RightAnteriorSect (vs LLS OR = 4.02). CONCLUSIONS: MiHs had heterogeneous outcomes. Mortality was low, but MiHs could be stratified according to severe morbidity, bile leak, and liver failure rates. Some MiHs had postoperative outcomes similar to RH.

Differentially methylated DNA regions in early childhood wheezing: An epigenome-wide study using saliva.

BACKGROUND: Epigenetics may play a role in wheezing and asthma development. We aimed to examine infant saliva DNA methylation in association with early childhood wheezing. METHODS: A case-control study was nested within the NINFEA birth cohort with 68 cases matched to 68 controls by sex, age (between 6 and 18 months, median: 10.3 months) and season at saliva sampling. Using a bumphunting region-based approach, we examined associations between saliva methylome measured using Illumina Infinium HumanMethylation450k array and wheezing between 6 and 18 months of age. We tested our main findings in independent publicly available data sets of childhood respiratory allergy and atopic asthma, with DNA methylation measured in different tissues and at different ages. RESULTS: We identified one wheezing-associated differentially methylated region (DMR) spanning ten sequential CpG sites in the promoter-regulatory region of PM20D1 gene (family-wise error rate < 0.05). The observed associations were enhanced in children born to atopic mothers. In the publicly available data sets, hypermethylation in the same region of PM20D1 was consistently found at different ages and in all analysed tissues (cord blood, blood, saliva and nasal epithelia) of children with respiratory allergy/atopic asthma compared with controls. CONCLUSION: This study suggests that PM20D1 hypermethylation is associated with early childhood wheezing. Directionally consistent epigenetic alteration observed in cord blood and other tissues at older ages in children with respiratory allergy and atopic asthma provides suggestive evidence that a long-term epigenetic modification, likely operating from birth, may be involved in childhood atopic phenotypes.

Questionnaire Breakoff and Item Nonresponse in Web-Based Questionnaires: Multilevel Analysis of Person-Level and Item Design Factors in a Birth Cohort.

BACKGROUND: Web-based questionnaires are increasingly used in epidemiologic studies, as traditional methods are facing a decrease in response rates and an increase in costs. However, few studies have investigated factors related to the level of completion of internet-based epidemiologic questionnaires. OBJECTIVE: Our objective was to identify person-level characteristics and item design factors associated with breakoff (not finishing the questionnaire) and item nonresponse in a Web-based questionnaire. METHODS: This study was a cross-sectional analysis of the baseline questionnaire, applied from 2005 to 2016, of the Italian NINFEA (Nascita e Infanzia: gli Effetti dell'Ambiente) birth cohort. The baseline questionnaire was administered to enrolled women, who could register at any time during pregnancy. We used logistic regression to analyze the influence of person-level factors on questionnaire breakoff, and a logistic multilevel model (first level: items of the questionnaire; second level: sections of the questionnaire; third level: study participants) to analyze the influence of person-level and item design factors on item nonresponse. Since the number of applicable items depended on the respondent's characteristics and breakoff, we used inverse probability weighting to deal with missing by design. RESULTS: Of 5970 women, 519 (8.69%) did not finish the questionnaire. Older age (adjusted odds ratio 1.40, 95% CI 1.05-1.88), lower educational level (adjusted odds ratio [OR] 1.53, 95% CI 1.23-1.90), and earlier stage of pregnancy (adjusted OR 3.01, 95% CI 2.31-3.92) were positively associated with questionnaire breakoff. Of the 1,062,519 applicable items displayed for the participants, 22,831 were not responded to (overall prevalence of item nonresponse 2.15%). Item nonresponse was positively associated with older age (adjusted OR 1.25, 95% CI 1.14-1.38), being in the first trimester of pregnancy (adjusted OR 1.18, 95% CI 1.06-1.31), and lower educational level (adjusted OR 1.23, 95% CI 1.14-1.33). Dropdown menu items (adjusted OR 1.77, 95% CI 1.56-2.00) and items organized in grids (adjusted OR 1.69, 95% CI 1.49-1.91) were positively associated with item nonresponse. CONCLUSIONS: It is important to use targeted strategies to keep participants motivated to respond. Item nonresponse in internet-based questionnaires is affected by person-level and item design factors. Some item types should be limited to reduce item nonresponse.

[Effects decomposition in mediation analysis: a numerical example]. / Scomposizione degli effetti nell'analisi di mediazione: un esempio numerico.

Mediation analysis aims to decompose the total effect of the exposure on the outcome into a direct effect (unmediated) and an indirect effect (mediated by a mediator). When the interest also lies on understanding whether the exposure effect differs in different sub-groups of study population or under different scenarios, the mediation analysis needs to be integrated with interaction analysis. In this setting it is necessary to decompose the total effect not only into two components, the direct and indirect effects, but other two components linked to interaction. The interaction between the exposure and the mediator in their effect on the outcome could indeed act through the effect of the exposure on the mediator or through the mediator when the mediator is not totally explained by the exposure. We describe options for decomposition, proposed in literature, of the total effect and we illustrate them through a hypothetical example of the effect of age at diagnosis of cancer on survival, mediated and unmediated by the therapeutical approach, and a numerical example.

[Communicating data of the Italian NINFEA birth cohort]. / Comunicare i dati della coorte italiana di nuovi nati NINFEA.

"In March 2016, the website of the NINFEA project (an Internet-based cohort set up to investigate the effects of exposures acting early in life) was enriched with the section «Data¼, which reports aggregated data for selected variables of the cohort. This article discusses the rationale for this new section, available data and their possible uses are described, and some results are compared with figures accessible from surveillance studies. The Italian birth cohort NINFEA includes 7,500 pregnant women, recruited through the Internet from 2005 to June 2016, and of their children, followed up with repeated questionnaires. Thus, the «Data¼ section is based on a selected population. Currently, this new section includes information on maternal lifestyles/characteristics in pregnancy (e.g., alcohol, smoking, use of medications), child health (e.g., obesity, asthma symptoms, growth) and behaviours (e.g., sleeping patterns, being breastfed). Up to December 18th, 2017, its pages were visited 12,620 times. Prevalences for selected variables (e.g., prepregnancy body mass index, breast feeding, infant sleeping position) are similar to those reported by surveillance studies. Aggregated exposure and outcome data from large cohorts can be systematically made publicly available. These data may be of interest to the participants, to population subgroups whose characteristics are similar to the study participants, and to researchers and policy makers, whenever similar data are not available from population-based surveillance systems."

Postnatal risk factors for testicular cancer: The EPSAM case-control study.

Testicular cancer is considered to originate from an impaired differentiation of fetal germ cells, but puberty could represent another time window of susceptibility. Our study aimed at investigating the association between environmental exposures acting during puberty/adolescence (13-19 years of age) and the risk of testicular cancer. We used data of the EPSAM study, a case-control study on germ-cell testicular cancer conducted in the province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Histologically confirmed cases (n = 255) and controls (n = 459) completed a postal questionnaire focusing in particular on the pubertal period (namely age 13 years) with questions on physical activity (competitive sports, gardening), lifestyle (alcohol consumption, smoking), occupational history and medical conditions. All analyses were adjusted for the matching variables, cryptorchidism and educational level. Having done at least one competitive sport during puberty (odds ratio [OR]: 0.72, 95% confidence interval: 0.52-1.00), gardening activities during puberty (OR: 0.62, 0.42-0.94) and having a lower weight than peers during puberty (OR: 0.64, 0.42-0.97) were all inversely associated with the risk of testicular cancer. No evidence of association between smoking or alcohol consumption during puberty and the risk of testicular cancer was observed. Regarding agriculture-related occupations, we found an association with the risk of testicular cancer both for occasional jobs during puberty (OR: 2.40, 95% CI: 1.08-5.29) and ever employment in adolescence (OR: 2.59, 95% CI: 0.83-8.10). Our results suggest that postnatal exposures could play a role in testicular cancer aetiology, at least when acting in puberty or adolescence.

Abdominal adiposity is not a mediator of the protective effect of Mediterranean diet on colorectal cancer.

Adherence to the Mediterranean diet (MD) has a preventive effect on colorectal cancer (CRC). Several biological mechanisms have been hypothesized to explain this effect, but the involvement of clinical mediators has not been experimentally proven. We examined the role of abdominal adiposity (i.e., waist-to-hip ratio, WHR) as a potential mediator of the relationship between the MD and CRC in the Italian centres of the European Prospective Investigation into Cancer and Nutrition. We evaluated the effect of the Italian Mediterranean Index (IMI) on WHR and of WHR on CRC risk. We then estimated the natural indirect effect (NIE, mediated by WHR) and the pure direct effect (PDE, unmediated) of IMI on CRC risk using mediation analyses, considering age, sex, education, physical activity, smoking and EPIC centre as confounders. Increased IMI was associated with significantly decreased odds of high WHR (odds ratio [OR] for an IMI of 6-11 vs. 0-1: 0.88, 95% confidence interval [CI]: 0.81-0.97). There was a positive relationship between WHR and CRC (hazard ratio [HR] for high vs. low WHR: 1.34, 95%CI: 1.09-1.66). The total effect of IMI was protective on CRC risk and was mainly explained by the PDE (HR for an IMI of 6-11 vs. 0-1: 0.51, 95%CI: 0.31-0.83), whereas the NIE was 1.00 (95%CI: 0.94-1.10). In this Mediterranean cohort, the protective effect of the MD on the development of CRC was not mediated by abdominal adiposity. Since this is the first study to investigate the mediating effect of abdominal obesity, other studies are needed to replicate this result.

Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts.

Evidence on the association between mode of delivery and asthma at school age is inconclusive. We assessed the associations between specific modes of delivery and asthma in children from 9 European birth cohorts that enrolled participants between 1996 and 2006. Cohort-specific crude and adjusted risk ratios for asthma at ages 5-9 years were calculated using Poisson regression models and pooled. A sensitivity analysis was carried out in children born at term to reduce confounding due to perinatal factors. The study included 67,613 participants. Cohort-specific rates of cesarean delivery varied from 9.4% to 37.5%. Cesarean delivery, as opposed to vaginal delivery, was associated with an increased risk of asthma (adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.02, 1.46). Compared with spontaneous vaginal delivery, the adjusted risk ratio was 1.33 (95% CI: 1.02, 1.75) for elective cesarean delivery, 1.07 (95% CI: 0.94, 1.22) for emergency cesarean delivery, and 0.97 (95% CI: 0.84, 1.12) for operative vaginal delivery. In children born at term, the associations were strengthened only for elective cesarean delivery (aRR = 1.49, 95% CI: 1.13, 1.97). The large sample size allowed analysis of the associations between specific modes of delivery and asthma at school age. The increased risk of asthma associated with elective cesarean delivery, especially among children born at term, is relevant in counteracting the increasing use of this procedure, which is often performed without a clear medical indication.

Prenatal exposure to antibiotics and wheezing in infancy: a birth cohort study.

The role of prenatal antibiotic exposure in the development of childhood wheezing is debated. We evaluated whether this association could potentially be explained by confounding factors.Antibiotic use in the first and third trimester of pregnancy, wheezing in children aged ≤18 months and confounding factors were assessed in singletons participating in the NINFEA (Nascita e Infanzia: gli Effetti dell'Ambiente) birth cohort (n=3530 for first-trimester exposure and n=3985 for third-trimester exposure).There was no evidence of an association between antibiotic exposure in the first trimester of pregnancy and ever-wheezing (adjusted risk ratio (RR) 1.02, 95% CI 0.80-1.30) or recurrent wheezing (RR 0.99, 95% CI 0.54-1.82). For the third-trimester exposure, the crude RRs (95% CI) of ever-wheezing and recurrent wheezing were 1.34 (1.10-1.64) and 2.72 (1.80-4.11), respectively, which decreased to 1.12 (0.90-1.39) and 2.09 (1.32-3.29) after adjustment. The RRs of wheezing after genitourinary infections during pregnancy were increased independently of antibiotic treatment.In conclusion, the association between prenatal antibiotic exposure and infant wheezing could be largely explained by confounding factors, in particular respiratory infections during pregnancy. An excess risk of wheezing after antibiotic exposure during the third trimester of pregnancy remains after adjustment.

Risk of congenital malformations among offspring of mothers and fathers with celiac disease: a nationwide cohort study.

BACKGROUND & AIMS: Many patients with celiac disease experience malabsorption, weight loss, and anemia; undiagnosed celiac disease during pregnancy has been linked with adverse outcomes. Studies of celiac disease and congenital malformations in offspring have been underpowered. We investigated the risk of congenital malformations among the offspring of parents with celiac disease. METHODS: We performed a nationwide cohort study of data from linked health care registers in Sweden from 1973 through 2009. We collected histopathology data from 28 pathology departments in Sweden to identify individuals with celiac disease (based on the presence of villous atrophy). We estimated the risks of malformations in the offspring of mothers and fathers with and without celiac disease. Logistic regression was used to estimate adjusted prevalence odds ratios (aPORs) with 95% confidence intervals (CIs). RESULTS: Among 11,382 offspring of mothers with celiac disease, there were 672 cases (5.9%) of malformation compared with 2098 cases (5.1%) among 40,922 offspring of mothers without celiac disease. Similarly, 352 (5.9%) of 6002 offspring of fathers with celiac disease and 1009 (5.1%) of 19,600 offspring of fathers without celiac disease had a malformation. In adjusted analyses, the offspring of mothers or fathers with celiac disease had a slightly increased risk of having children with malformations (for those with mothers with celiac disease: aPOR, 1.15; 95% CI, 1.05-1.26; for those with fathers with celiac disease: aPOR, 1.14; 95% CI, 1.00-1.29). However, these excess risks decreased or vanished entirely when we restricted our data to births since 2000 (for those with mothers with celiac disease: aPOR, 1.11; and 95% CI, 0.79-1.56; for those with fathers with celiac disease: aPOR, 1.01; 95% CI, 0.81-1.26). CONCLUSIONS: In a nationwide study, we found an increased risk for malformation among the offspring of mothers or fathers with celiac disease. However, the excess risk is small; the upper limits of the CIs for malformation indicate a 29% maximum relative increase.

Regression discontinuity design for the study of health effects of exposures acting early in life.

Regression discontinuity design (RDD) is a quasi-experimental approach to study the causal effect of an exposure on later outcomes by exploiting the discontinuity in the exposure probability at an assignment variable cut-off. With the intent of facilitating the use of RDD in the Developmental Origins of Health and Disease (DOHaD) research, we describe the main aspects of the study design and review the studies, assignment variables and exposures that have been investigated to identify short- and long-term health effects of early life exposures. We also provide a brief overview of some of the methodological considerations for the RDD identification using an example of a DOHaD study. An increasing number of studies investigating the effects of early life environmental stressors on health outcomes use RDD, mostly in the context of education, social and welfare policies, healthcare organization and insurance, and clinical management. Age and calendar time are the mostly used assignment variables to study the effects of various early life policies and programs, shock events and guidelines. Maternal and newborn characteristics, such as age, birth weight and gestational age are frequently used assignment variables to study the effects of the type of neonatal care, health insurance, and newborn benefits, while socioeconomic measures have been used to study the effects of social and welfare programs. RDD has advantages, including intuitive interpretation, and transparent and simple graphical representation. It provides valid causal estimates if the assumptions, relatively weak compared to other non-experimental study designs, are met. Its use to study health effects of exposures acting early in life has been limited to studies based on registries and administrative databases, while birth cohort data has not been exploited so far using this design. Local causal effect around the cut-off, difficulty in reaching high statistical power compared to other study designs, and the rarity of settings outside of policy and program evaluations hamper the widespread use of RDD in the DOHaD research. Still, the assignment variables' cut-offs for exposures applied in previous studies can be used, if appropriate, in other settings and with additional outcomes to address different research questions.