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Oxidative stress plays a pivotal role in cardiovascular (CV) disease, but current biomarkers used to predict CV events are still insufficient. In this study, we comparatively assessed the utility of redox-related biomarkers in predicting the risk of CV events and all-cause mortality in male and female subjects from the general population. Subjects (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) population-based cohort study were included. Blood homocysteine, gamma-GT, HDL cholesterol, bilirubin and protein-adjusted free thiol (R-SH, sulfhydryl groups) levels were quantified at baseline and were prospectively analyzed in association with the risk of CV events and all-cause mortality. After adjustment for potentially confounding factors, protein-adjusted R-SH and homocysteine levels were significantly associated with the risk of CV events in men (HR 0.63 [0.40–0.99], p = 0.045 and HR 1.58 [1.20–2.08], p = 0.001, respectively). Protein-adjusted R-SH and HDL cholesterol levels were significantly associated with the risk of all-cause mortality in men (HR 0.52 [0.32–0.85], p = 0.009 and HR 0.90 [0.85–0.94], p < 0.001, respectively), while the same was observed for bilirubin and homocysteine levels in women (HR 0.68 [0.48–0.98], p = 0.040 and HR 2.30 [1.14–3.76], p < 0.001, respectively). Lower levels of protein-adjusted R-SH were robustly associated with an increased risk of CV events and all-cause mortality in men. Our results highlight the value of R-SH levels in cardiovascular risk assessment and their potential significance as being amenable to therapeutic intervention, while reaffirming the importance of other oxidative stress-related biomarkers, such as homocysteine, HDL cholesterol and bilirubin. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether infants with complex congenital heart disease (CCHD) have an increased risk of impaired quality of motor behavior and delayed motor milestones. Method: A cohort of 69 infants with CCHD (43 males, 26 females) were assessed with the Infant Motor Profile (IMP) at three time periods between 6 to 18 months, mean ages in months (SD): 6.4 (0.7); 12.7 (1.0); 18.5 (0.7) IMP data were available from a reference sample of 300 Dutch infants. Analyses included multivariable logistic regression analysis to estimate differences in IMP scores below the 15th centile between children with CCHD and the reference group, and linear mixed‐effects models to assess the effect of ventricular physiology and systemic oxygen saturation (SpO2) of less than 90% on IMP outcomes. Results: Infants with CCHD had increased risks of total IMP scores below the 15th centile (lowest odds ratio [OR] at 18mo: 6.82 [95% confidence interval {CI} 2.87–16.19]), especially because of lower scores in the domains of variation, adaptability, and performance. Children with single ventricle CCHD scored consistently 3.03% (95% CI 1.00–5.07) lower than those with two ventricle physiology, mainly from contributions of the variation and performance domains. SpO2 of less than 90% was associated with 2.52% (95% CI 0.49–4.54) lower IMP scores. Interpretation: CCHD, especially single ventricle physiology, increases risk of impaired motor development. What this paper adds: Complex congenital heart disease (CCHD) substantially increases risk of impaired motor development.CCHD is associated with motor delay and reduced motor variation and adaptability.Single ventricle physiology increases the risk of impaired motor behavior. [ABSTRACT FROM AUTHOR]

Aim: To study changes in muscular postural strategies and general motor behaviour during the transition to independent walking. Postural control was assessed at its two functional levels: (1) direction specificity, in which dorsal muscles are primarily activated when reaching forward; and (2) fine-tuning of direction specificity.Method: In an explorative longitudinal study, surface electromyograms of the arm, trunk, and neck muscles of 28 typically developing infants were recorded during reaching while sitting. Each infant was assessed in three developmental phases: during pull-to-stand (T0), first independent steps (T1), and 1 month after T1 (T2). Motor behaviour was assessed using the Infant Motor Profile (IMP). The effect on developmental outcome measures (postural parameters and IMP) of the developmental phases (T0, T1, T2) was estimated using linear mixed-effects models.Results: None of the postural parameters changed significantly over time. However, individual developmental trajectories showed infant-specific postural reorganizational changes. Total IMP score decreased between T0 and T1 (mean IMP score 95% and 91% respectively; p<0.001); between T1 and T2 IMP scores did not change (91% and 93%; p=0.073).Interpretation: Typically developing infants do not show consistent patterns of postural reorganization but show individual muscular strategies during the transition to independent walking. However, signs of reorganization of general motor behaviour are present.What This Paper Adds: Infants show signs of reorganization of motor behaviour when learning to walk. Infants show individual strategies of postural reorganization when learning to walk. [ABSTRACT FROM AUTHOR]

Study Question: Does Day-3 cleavage-stage PGS affect neurodevelopment of 9-year-old IVF offspring?Summary Answer: We did not find evidence of adverse consequences of Day-3 cleavage-stage PGS on neurodevelopment of 9-year-old IVF offspring, although children born after IVF with or without PGS often had a non-optimal neurological condition.What Is Known Already: Knowledge on long-term sequelae for development and health of children born following PGS is lacking. This is striking as evidence accumulates that IVF itself is associated with increased risk for impaired health and development in the offspring.Study Design Size, Duration: This prospective, assessor-blinded, multicentre, follow-up study evaluated development and health of 9-year-old IVF children born to women who were randomly assigned to IVF with PGS (PGS group) or without PGS (control group). The follow-up examination at 9 years took place between March 2014 and May 2016.Participants/materials, Setting, Methods: In total, 408 women were included and randomly assigned to IVF with or without Day-3 cleavage-stage PGS. This resulted in 52 ongoing pregnancies in the PGS group and 74 in the control group. In the PGS group, 59 children were born alive; in the control group, 85 children were born alive. At the age of 9 years, 43 children born after PGS and 56 control children participated in the study. Our primary outcome was the neurological optimality score, a sensitive measure of neurological condition assessed with a standardized, age-specific test (Touwen test). Secondary outcomes were adverse neurological condition (neurologically abnormal and the complex form of minor neurological dysfunction), cognitive development (intelligence quotient and specific domains), behaviour (parental and teacher's questionnaires), blood pressure and anthropometrics.Main Results and the Role Of Chance: Neurodevelopmental outcome of PGS children did not differ from that of controls; the neurological optimality scores (mean values [(95% CI]: PGS children 51.5 [49.3; 53.7], control children 53.1 [50.5; 55.7]) were not significantly different. The prevalences of adverse neurological outcome (in all but one child implying the presence of the complex form of minor neurological dysfunction) did not differ between the groups (PGS group 17/43 [40%], control group 19/56 [34%]), although the prevalence of complex minor neurological dysfunction in both groups was rather high. Also intelligence quotient scores of the two groups were not significantly different (PGS group 114 [108; 120]); control group 117 [109; 125]), and the behaviour, blood pressure and anthropometrics of both groups did not differ. Mean blood pressures of both groups were above the 60th percentile.Limitations Reasons For Caution: The power analysis of the study was not based on the number of children needed for the follow-up study, but on the number of women who were needed to detect an increase in ongoing pregnancy rates after PGS. In addition, our study evaluated embryo biopsy in the form of PGS at cleavage stage (Day-3 embryo biopsy), while currently PGS at blastocyst stage (Day-5 embryo biopsy) is recommended and increasingly being used.Wider Implications Of the Findings: Our findings indicate that PGS in cleavage stage embryos is not associated with adverse effects on neurological, cognitive and behavioural development, blood pressure and anthropometrics of offspring at 9 years. This is a reassuring finding as embryo biopsy in the forms of PGS and PGD is increasingly applied. However, both groups of IVF offspring showed high prevalences of the clinically relevant form of minor neurological dysfunction, which is a point of concern for the IVF community. In addition, our study confirms findings of others that IVF offspring may be at risk of an unfavourable cardiovascular outcome. These findings are alarming and highlight the importance of research on the underlying mechanisms of unfavourable neurodevelopmental and cardiovascular outcomes in IVF offspring.Study Funding/competing Interest(s): The randomized controlled trial was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (Grant number 945-03-013). The follow-up was financially supported by the University Medical Center Groningen (Grant number: 754510), the Cornelia Foundation, and the graduate schools BCN and Share, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest.Trial Registration Number: ISRCTN76355836. [ABSTRACT FROM AUTHOR]

Study Question: Are the in vitro procedure, ovarian hyperstimulation or a combination of these two associated with blood pressure (BP) of 9-year-old IVF children born to subfertile couples?Summary Answer: Our study demonstrates that ovarian hyperstimulation and the in vitro procedure are not associated with BP values in 9-year-old children born to subfertile couples.What Is Known Already: Possible long-term effects of IVF on child health and development have been studied relatively little. This is surprising, as it is known that environmental conditions may influence embryonic and foetal development which may result in health related problems in later life. Some studies suggested that IVF is associated with higher BP at pre-school age. Yet, it is unclear whether this may be also true for older children and if so, which component of IVF, i.e. the ovarian hyperstimulation, the embryo culture or a combination of these, attributes to this potentially less favourable BP.Study Design, Size, Duration: The Groningen Assisted Reproductive Technology cohort-study is a prospective assessor-blinded study of children followed from before birth onwards. In total, 170 children were assessed at the age of 9 years. The attrition rate up until the 9-year-old assessment was 21%.Participants/materials, Setting, Methods: We evaluated cardiovascular health, focusing on BP (in mmHg and the internationally recognized percentiles of the US National High BP Education Program), heart rate and anthropometrics of 57 children born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI); 47 children born after modified natural cycle-IVF/ICSI (MNC-IVF/ICSI); and 66 children who were conceived naturally by subfertile couples (Sub-NC). Cardiovascular parameters were measured multiple times on one day. In addition, anthropometric data, including BMI and skinfold thickness, were collected.Main Results and the Role Of Chance: Systolic BP in mmHg did not differ between the COH-IVF/ICSI (mean 106.9, SD 6.7), MNC-IVF/ICSI (mean 104.8, SD 5.9) and Sub-NC (mean 106.3, SD 5.3) groups. In addition, systolic BP percentiles did not differ between the groups: COH-IVF/ICSI (mean 62.4, SD 20.2); MNC-IVF/ICSI (mean 56.3, SD 19.3); and Sub-NC (mean 62.3, SD17.8). Also, after adjustment for confounders BP in the three groups was similar. Heart rate and anthropometric values in the three groups did not differ. For instance, BMI values in the COH-IVF/ICSI-children were 16.3 (median value, range 13.0-24.7), in MNC-IVF/ICSI-children 16.1 (range 12.7-22.5) and in Sub-NC children 16.3 (range 12.7-24.0).Limitations, Reasons For Caution: The size of our study groups does not allow for pertinent conclusions on the effect of ovarian hyperstimulation and the in vitro procedure. The lack of a fertile control group may be regarded as another limitation.Wider Implications Of the Findings: Our study suggests that ovarian hyperstimulation and in vitro procedures are not associated with cardiovascular health in 9-year-old. Yet, BP percentiles of the three groups were higher than the expected 50th percentile. This might indicate that children of subfertile couples have a higher BP than naturally conceived children.Study Funding/competing Interest(s): The study was financially supported by the University Medical Center Groningen (UMCG), the two graduate schools of the UMCG, BCN, SHARE and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Aim: To assess development of reaching and head stability in infants at very high risk (VHR-infants) of cerebral palsy (CP) who did and did not develop CP.Method: This explorative longitudinal study assessed the kinematics of reaching and head sway in sitting in 37 VHR-infants (18 CP) one to four times between 4.7 months and 22.6 months corrected age. Developmental trajectories were calculated using linear mixed effect models. Motor function was evaluated with the Infant Motor Profile (IMP) around 13 months corrected age.Results: Throughout infancy, VHR-infants with CP had a worse reaching quality than infants without CP, reflected for example by more movement units (factor 1.52, 95% CI 1.16-1.99) and smaller transport movement units (factor 1.86, 95% CI 1.20-2.90). Total head sway of infants with and without CP was similar, but infants with CP used more head movement units to achieve stability. The rate of developmental change in infants with and without CP was similar. Around 13 months, head control and reaching quality were interrelated; both were associated with IMP-scores.Interpretation: Infants with CP showed a worse kinematic reaching quality and head stability throughout infancy from early age onwards than VHR-infants without CP, implying that kinematically they do not grow into a deficit, but exhibit deficits from early infancy on.What This Paper Adds: Reaching quality improves throughout infancy in all infants at high risk (VHR-infants). Infants with cerebral palsy (CP) show a worse reaching quality than VHR-infants without CP. Infants with CP achieve head stability differently from infants without CP. Infants with CP exhibit kinematic reaching problems from early age onwards. [ABSTRACT FROM AUTHOR]

Background: We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood.Methods: First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR) < 0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring's sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis.Results: We found 35 differentially methylated CpGs (FDR < 0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P < 1 × 10(-7)). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P < 0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12-19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity.Conclusions: Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system. [ABSTRACT FROM AUTHOR]

Background: Development of postural problems in Cerebral Palsy (CP) is largely unknown. Postural muscle activity is organized into two levels: 1) direction-specificity; 2) fine-tuning of direction-specific activity.Aim: To study development of postural control until 21 months corrected age in subgroups of infants at very high-risk (VHR) of CP: a) with and without CP at 21 months; b) with and without cystic periventricular leukomalacia (cPVL), the brain lesion with highest risk of CP.Methods and Procedures: Longitudinal electromyography recordings of postural muscles during reaching were made in 38 VHR-infants (severe brain lesion or clear neurological signs) between 4.7 and 22.6 months (18 CP, of which 8 with cPVL). Developmental trajectories were calculated using linear mixed effect models.Outcomes and Results: VHR-infants with and without CP showed virtually similar postural development throughout infancy. The subgroup of VHR-infants with cPVL improved performance in direction-specificity with increasing age, while they performed throughout infancy worse in fine-tuning of postural adjustments than infants without cPVL.Conclusions and Implications: VHR-infants with and without CP have a similar postural development that differs from published trajectories of typically developing infants. Infants with cPVL present from early age onwards dysfunctions in fine-tuning of postural adjustments; they focus on direction-specificity. [ABSTRACT FROM AUTHOR]

This prospective cohort study evaluated whether the cognitive development, neurological condition, anthropometrics and blood pressure of 4-year-old IVF twins differed from those of 4-year-old IVF singletons; 103 IVF singletons and 48 IVF twins born after conventional IVF treatment were included. Primary outcome was total intelligence quotient (IQ). Secondary outcomes were minor neurological dysfunction, anthropometrics and blood pressure. Unadjusted analyses found that the total IQ score of twins was lower than that of singletons, with a mean difference of −5.4 (–9.7 to −1.0). Weight (singletons: 18.6 [18.1 to 19.1] kg; twins: 16.9 [16.0 to 17.9] kg) and height (singletons: 108.8 [107.9 to 109.8] cm; twins: 105.9 [104.0 to 107.7] cm) of twins were lower than those of singletons (mean values [95% CI]). All differences disappeared after adjusting for mediators and confounders. Neurological outcome, systolic and diastolic blood pressure of twins and singletons were similar. Four-year-old IVF twins had a lower total IQ (−5.4 points), lowerbodyweight (−1.7 kg) and were shorter (−2.9 cm) than 4-year-old IVF singletons. After adjustment, the adverse twin effect disappeared, implying that increased risk for impaired health and development in twins also holds true for IVF twins, and is not altered by IVF. [ABSTRACT FROM AUTHOR]