STN-DBS electrode placement accuracy and motor improvement in Parkinson's disease: systematic review and individual patient meta-analysis.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical treatment for Parkinson's disease. Surgical accuracy is a critical determinant to achieve an adequate DBS effect on motor performance. A two-millimetre surgical accuracy is commonly accepted, but scientific evidence is lacking. A systematic review and meta-analysis of study-level and individual patient data (IPD) was performed by a comprehensive search in MEDLINE, EMBASE and Cochrane Library. Primary outcome measures were (1) radial error between the implanted electrode and target; (2) DBS motor improvement on the Unified Parkinson's Disease Rating Scale part III (motor examination). On a study level, meta-regression analysis was performed. Also, publication bias was assessed. For IPD meta-analysis, a linear mixed effects model was used. Forty studies (1391 patients) were included, reporting radial errors of 0.45-1.86 mm. Errors within this range did not significantly influence the DBS effect on motor improvement. Additional IPD analysis (206 patients) revealed that a mean radial error of 1.13±0.75 mm did not significantly change the extent of DBS motor improvement. Our meta-analysis showed a huge publication bias on accuracy data in DBS. Therefore, the current literature does not provide an unequivocal upper threshold for acceptable accuracy of STN-DBS surgery. Based on the current literature, DBS-electrodes placed within a 2 mm range of the intended target do not have to be repositioned to enhance motor improvement after STN-DBS for Parkinson's disease. However, an indisputable upper cut-off value for surgical accuracy remains to be established. PROSPERO registration number is CRD42018089539.

Motor development in infants with complex congenital heart disease: A longitudinal study.

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.

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

Developmental outcomes after early surgery for complex congenital heart disease: a systematic review and meta-analysis.

AIM: (1) To systematically review the literature on developmental outcomes from infancy to adolescence of children with complex congenital heart disease (CHD) who underwent early surgery; (2) to run a meta-regression analysis on the Bayley Scales of Infant Development, Second Edition Mental Developmental Index and Psychomotor Developmental Index (PDI) of infants up to 24 months and IQs of preschool-aged children to adolescents; (3) to assess associations between perioperative risk factors and outcomes. METHOD: We searched pertinent literature (January 1990 to January 2019) in PubMed, Embase, CINAHL, and PsycINFO. Selection criteria included infants with complex CHD who had primary surgery within the first 9 weeks of life. Methodological quality, including risk of bias and internal validity, were assessed. RESULTS: In total, 185 papers met the inclusion criteria; the 100 with high to moderate methodological quality were analysed in detail. Substantial heterogeneity in the group with CHD and in methodology existed. The outcome of infants with single-ventricle CHD was inferior to those with two-ventricle CHD (respectively: average scores for PDI 77 and 88; intelligence scores 92 and 98). Perioperative risk factors were inconsistently associated with developmental outcomes. INTERPRETATION: The literature on children undergoing surgery in early infancy suggests that infants with a single ventricle are at highest risk of adverse developmental outcomes.

Motor behaviour in infancy is associated with neurological, cognitive, and behavioural function of children born to parents with reduced fertility.

AIM: To evaluate the associations between motor development in infancy and developmental outcomes at school age. METHOD: Participants were 195 children (99 males, 96 females; mean age [SD] 9y 3mo [3mo], range 8y 4mo-10y 11mo) born to couples whose reduced fertility was or was not treated with assisted reproductive technologies. Motor behaviour was assessed at 4, 10, and 18 months with the Infant Motor Profile (IMP). IQ, neurological optimality score (NOS), and behavioural problem scores were measured at 9 years with the Wechsler Abbreviated Scale of Intelligence, minor neurological dysfunction assessment, and the Child Behavior Checklist respectively. RESULTS: Children with a slow developmental trajectory in the IMP-domain adaptability had an IQ 12.6 points lower (95% confidence interval [CI] 4.7-20.4) and an NOS 3.4 points lower (95% CI 0.7-6.2) at 9 years of age than children with typical adaptability development. Children with a slow developmental trajectory in the IMP-domain performance had an IQ 5.0 points lower (95% CI 0.7-9.3) than children with typical performance development. A non-optimal trajectory in IMP-variation and a fluctuating trajectory in IMP-fluency were associated with higher internalizing scores of 3.6 and 5.8 points respectively, than infants with optimal IMP-domain trajectories. INTERPRETATION: In relatively low-risk children, motor behaviour in infancy was associated with neurological, cognitive, and behavioural function at school age.

Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis.

BACKGROUND: The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)-1ß reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1ß secretion increase cardiovascular risk. IL-1ß and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density lipoprotein, and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation. METHODS: To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11. Bone marrow from these mice was transplanted into Ldlr-/- recipients, which were fed a Western-type diet. RESULTS: Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr-/- mice and induced IL-1ß and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1-deficient Ldlr-/- mice. Myeloid Abca1/g1 deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1ß and IL-18 levels. CONCLUSIONS: Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.

Postural control during reaching while sitting and general motor behaviour when learning to walk.

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.

Developmental outcome of 9-year-old children born after PGS: follow-up of a randomized trial.

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.

Cardiovascular health of 9-year-old IVF offspring: no association with ovarian hyperstimulation and the in vitro procedure.

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.

Neurodevelopmental and cardiometabolic outcome in 4-year-old twins and singletons born after IVF.

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.

Development of the quality of reaching in infants with cerebral palsy: a kinematic study.

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.

Subfertility factors rather than assisted conception factors affect cognitive and behavioural development of 4-year-old singletons.

Research on cognitive and behavioural development of children born after assisted conception is inconsistent. This prospective study aimed to explore underlying causal relationships between ovarian stimulation, in-vitro procedures, subfertility components and child cognition and behaviour. Participants were singletons born to subfertile couples after ovarian stimulation IVF (n = 63), modified natural cycle IVF (n = 53), natural conception (n = 79) and singletons born to fertile couples (reference group) (n = 98). At 4 years, cognition (Kaufmann-ABC-II; total IQ) and behaviour (Child Behavior Checklist; total problem T-score) were assessed. Causal inference search algorithms and structural equation modelling was applied to unravel causal mechanisms. Most children had typical cognitive and behavioural scores. No underlying causal effect was found between ovarian stimulation and the in-vitro procedure and outcome. Direct negative causal effects were found between severity of subfertility (time to pregnancy) and cognition and presence of subfertility and behaviour. Maternal age and maternal education acted as confounders. The study concludes that no causal effects were found between ovarian stimulation or in-vitro procedures and cognition and behaviour in childrenaged 4 years born to subfertile couples. Subfertility, especially severe subfertility, however, was associated with worse cognition and behaviour.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part I: multivariable regression analysis.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? SUMMARY ANSWER: Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient. MAIN RESULTS AND THE ROLE OF CHANCE: SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53). LIMITATIONS, REASONS FOR CAUTION: Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach.

STUDY QUESTION: What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children? SUMMARY ANSWER: Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown. STUDY DESIGN, SIZE, DURATION: In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. MAIN RESULTS AND THE ROLE OF CHANCE: Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. LIMITATIONS, REASONS FOR CAUTION: Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Predictive value of General Movements Assessment for developmental delay at 18 months in children with complex congenital heart disease.

BACKGROUND: Infants with complex congenital heart disease are at increased risk of impaired fetal brain growth, brain injury, and developmental impairments. The General Movement Assessment (GMA) is a valid and reliable tool to predict cerebral palsy (CP), especially in preterm infants. Predictive properties of the GMA in infants with complex congenital heart disease (CCHD) are unknown. AIM: To evaluate predictive properties of the GMA to predict developmental outcomes, including cerebral palsy (CP), at 18-months corrected age (CA) in children with CCHD undergoing heart surgery in the first month of life. METHODS: A prospective cohort of 56 infants with CCHD (35 males, 21 females) was assessed with GMA at writhing age (0-6 weeks CA) and fidgety age (7-17 weeks CA) and the Bayley Scales of Infant Development at 18 months. GMA focused on markedly reduced GM-variation and complexity (definitely abnormal (DA) GM-complexity) and fidgety movements. Predictive values of GMA for specific cognitive, language and motor delay (composite scores <85th percentile) and general developmental delay (delay in all domains) were calculated at 18 months. RESULTS: At fidgety age, all infants had fidgety movements and no child was diagnosed with CP. DA GM-complexity at fidgety age predicted general developmental delay at 18 months (71 % sensitivity, 90 % specificity), but predicted specific developmental delay less robustly. DA GM-complexity at writhing age did not predict developmental delay, nor did it improve prediction based on DA GM-complexity at fidgety age. CONCLUSIONS: In infants with CCHD and fidgety movements, DA GM-complexity at fidgety age predicted general developmental delay.

Radiation-induced Xerostomia is Related to Stem Cell Dose-dependent Reduction of Saliva Production.

PURPOSE: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (Dmean,SCR) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and Dmean,SCR is explained by a dose-dependent reduction of saliva production. METHODS AND MATERIALS: In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual (FLOWSMSL) glands, and patient-reported daytime (XERDAY) and nighttime (XERNIGHT) xerostomia were prospectively measured before, at 6 months, and 12 months after RT. Using linear mixed effect models, the relationship of the mean dose to the parotid glands (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub), and oral cavity (Dmean,oral) with salivary flow and xerostomia was analyzed while correcting for known confounders. RESULTS: Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (P ≤ .03), while Dmean,non-SCR did not affect FLOWPAR (P ≥ .11). To illustrate, increasing Dmean,SCR by 10 Gy at a fixed Dmean,non-SCR reduced FLOWPAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 mL/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (P < .001). For example, increasing Dmean,sub by 10 Gy reduced FLOWSMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (P ≤ .05), while Dmean,sub increased XERNIGHT scores (P = .01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores by 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions; ie, FLOWPAR only influenced XERDAY (P < .001, 10.92 points lower XERDAY per 1 mL/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (P ≤ .004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR, whereas the effects of Dmean,oral on XERDAY and Dmean,sub on XERNIGHT were independent of salivary flow. CONCLUSIONS: Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.

Plasma Calprotectin Levels Associate With New-Onset Hypertension in the General Population: A Prospective Cohort Study.

BACKGROUND: Low-grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil-mediated inflammation, is associated with developing new-onset hypertension in the general population. METHODS AND RESULTS: Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective population-based cohort study. Plasma calprotectin levels were studied for associations with the risk of new-onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34-0.66) mg/L, and median systolic blood pressure was 117 (109-126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new-onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21-1.41]; P<0.001), also after adjustment for age and sex (HR, 1.26 [95% CI, 1.16-1.37]; P<0.001), but not after additional adjustment for potentially confounding factors, including baseline systolic blood pressure (HR, 1.00 [95% CI, 0.90-1.11]; P=0.996). Stratified analyses showed significant effect modification by sex (Pinteraction=0.023) and urinary albumin excretion (Pinteraction=0.004), with higher HRs in men (compared with women) and in individuals with higher urinary albumin excretion (>9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). CONCLUSIONS: Higher plasma calprotectin levels are associated with an increased risk of new-onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.