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Purpose: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (D mean,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 D mean,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 (FLOW PAR ) and submandibular/sublingual (FLOW SMSL ) glands, and patient-reported daytime (XER DAY ) and nighttime (XER NIGHT ) 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 (D mean,par ), D mean,SCR , non-SCR parotid gland tissue (D mean,non-SCR ), submandibular glands (D mean,sub ), and oral cavity (D mean,oral ) with salivary flow and xerostomia was analyzed while correcting for known confounders., Results: D mean,SCR proved to be responsible for the effect of D mean,par on FLOW PAR (P ≤ .03), while D mean,non-SCR did not affect FLOW PAR (P ≥ .11). To illustrate, increasing D mean,SCR by 10 Gy at a fixed D mean,non-SCR reduced FLOW PAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOW PAR was observed (0.00 mL/min [4%]). As expected, D mean,sub was significantly associated with FLOW SMSL (P < .001). For example, increasing D mean,sub by 10 Gy reduced FLOW SMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. D mean,SCR and D mean,oral were associated with higher XER DAY scores (P ≤ .05), while D mean,sub increased XER NIGHT scores (P = .01). For example, an increase of 10 Gy in D mean,SCR raised XER DAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in D mean,subs increased XER NIGHT 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, FLOW PAR only influenced XER DAY (P < .001, 10.92 points lower XER DAY per 1 mL/min saliva), while FLOW SMSL affected XER DAY and XER NIGHT (P ≤ .004, 6.69 and 5.74 points lower XER DAY and XER NIGHT , respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, D mean,SCR only increased XER DAY scores via reducing FLOW PAR , whereas the effects of D mean,oral on XER DAY and D mean,sub on XER NIGHT 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Systemic inflammation plays a pivotal role in the development of type 2 diabetes (T2D). Here we hypothesized that circulating levels of calprotectin, a myeloid cell-derived biomarker of inflammation, is associated with the development of new-onset T2D in the general population., Methods: A total of 4,815 initially non-diabetic participants of the Prevention of Renal and Vascular ENd-stage Disease (PREVEND), a prospective population-based cohort study, were assessed for plasma levels of calprotectin at baseline. Circulating levels of calprotectin were investigated for potential associations with the risk of new-onset T2D, defined as a fasting plasma glucose level ≥7.0 mmol/l, a random plasma glucose level ≥11.1 mmol/l, a self-reported physician-based diagnosis of T2D, the use of glucose-lowering drugs, or any combinations thereof., Results: Median plasma calprotectin levels were 0.49 [0.35-0.69] mg/l. Plasma calprotectin levels were significantly associated with the risk of new-onset T2D (hazard ratio [HR] per doubling 1.42 [95% confidence interval: 1.22-1.66], P<0.001). The association remained independent of adjustment for age and sex (HR 1.34 [95%CI: 1.14-1.57], P<0.001), but not after further adjustment for potentially confounding factors (HR 1.11 [95% CI: 0.90-1.37], P=0.326), with adjustment for hyperlipidemia and high-sensitivity C-reactive protein explaining the loss of significance. Stratified analyses showed significant effect modification by hypertension, history of cardiovascular disease and HOMA-IR (Pinteraction≤0.001 for each), with higher HRs in individuals without hypertension, without history of cardiovascular disease and with below-median HOMA-IR., Conclusions: Elevated plasma levels of calprotectin are associated with a higher risk of developing T2D in the general population and may represent a moveable inflammatory biomarker. This association, however, does not represent a direct effect, and seems dependent on hyperlipidemia and systemic inflammation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Systemic inflammation has been associated with chronic kidney disease (CKD). In this study, we aimed to investigate a potential association between the plasma biomarker of inflammation calprotectin and new-onset CKD in a population-based cohort study., Methods: Individuals without CKD at baseline ( n  = 4662) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma calprotectin levels were assessed in samples that had been stored at -80 °C. Occurrence of new-onset CKD was defined as a composite outcome of an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 , urinary albumin excretion (UAE) >30 mg/24h, or both., Results: Baseline median (interquartile range) plasma calprotectin levels were 0.49 (0.35-0.68) mg/l and baseline median eGFR was 95.9 (interquartile range: 85.0-105.7) ml/min per 1.73 m 2 . After median follow-up of 8.3 (7.8-8.9) years, 467 participants developed new-onset CKD. Baseline plasma calprotectin levels were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.28 [95% confidence interval, CI: 1.14-1.44], P  < 0.001), independent of potentially confounding factors (HR 1.14 [95% CI: 1.01-1.29], P  = 0.034), except for baseline high-sensitive C-reactive protein (hs-CRP) (HR 1.05 [0.91-1.21], P  = 0.494). In secondary analyses, the association between plasma calprotectin and occurrence of UAE >30 mg/24h remained significant (HR 1.17 [1.02-1.34], P  = 0.027), but not significantly so for the incidence of eGFR <60 ml/min per 1.73 m 2 as individual outcome (HR 1.15 [0.92-1.43], P  = 0.218)., Conclusion: Higher plasma calprotectin levels are associated with an increased risk of developing CKD in the general population. This association is mitigated after adjustment for hs-CRP, and more pronounced with new-onset CKD defined by UAE., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

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 ( P interaction =0.023) and urinary albumin excretion ( P interaction =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.

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., Competing Interests: Declaration of competing interest Mijna Hadders-Algra has provided courses on the GMA since 1993. She did not get an honorarium, grant, or other form of payment to produce this manuscript. The other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Longer gestation at term and post-term age is associated with increased perinatal mortality. Nonetheless, recent neuroimaging studies indicated that longer gestation is also associated with better functioning of the child's brain., Aims: to assess whether longer gestation in term and post-term (in short: term) singletons is associated with better infant neurodevelopment., Study Design: cross-sectional observational study., Subjects: Participants were all singleton term infants (n = 1563) aged 2-18 months of the IMP-SINDA project that collected normative data for the Infant Motor Profile (IMP) and Standardized Infant NeuroDevelopmental Assessment (SINDA). The group was representative of the Dutch population., Outcome Measures: Total IMP score was the primary outcome. Secondary outcomes were atypical total IMP scores (scores <15th percentile) and SINDA's neurological and developmental scores., Results: Duration of gestation had a quadratic relationship with IMP and SINDA developmental scores. IMP scores were lowest at a gestation of 38·5 weeks, SINDA developmental scores at 38·7 weeks. Next, both scores increased with increasing duration of gestation. Infants born at 41-42 weeks had significantly less often atypical IMP scores (adjusted OR [95 % CI]: 0·571 [0·341-0·957] and atypical SINDA developmental scores (adjusted OR: 0·366 [0·195-0·688]) than infants born at 39-40 weeks. Duration of gestation was not associated with SINDA's neurological score., Conclusions: In term singleton infants representative of the Dutch population longer gestation is associated with better infant neurodevelopment scores suggesting better neural network efficiency. Longer gestation in term infants is not associated with atypical neurological scores., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) have been associated with acute kidney injury and the severity and progression of chronic kidney disease (CKD). This study investigated its potential utility as a biomarker for the risk of new-onset CKD in a population-based cohort study. Individuals without CKD at baseline (n = 4660) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma NGAL concentrations were investigated for their associations with new-onset CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 , urinary albumin excretion (UAE) > 30 mg/24-h, or both. Mean (±SD) plasma NGAL concentrations were 104.0 (±34.7) μg/L and median eGFR was 96 [IQR: 85.3-105.8] mL/min/1.73 m 2 . After median follow-up of 8.3 [IQR: 7.8-8.9] years, 467 participants developed new-onset CKD. Plasma NGAL concentrations were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.35 [95% CI: 1.11-1.63], p = 0.002), even after adjustment for potentially confounding factors (1.37 [1.09-1.73], p = 0.007) except baseline eGFR (1.09 [0.86-1.37], p = 0.490). In secondary analyses, plasma NGAL concentrations were significantly associated with new-onset CKD as defined by eGFR < 60 mL/min/1.73 m 2 alone (adjusted HR per doubling 2.54 [1.69-3.80], p < 0.001), which was abrogated after adjustment for eGFR (1.05 [0.69-1.59], p = 0.828), also when UAE > 30 mg/24-h was set as individual outcome (1.05 [0.82-1.35], p = 0.705). Higher plasma NGAL concentrations are associated with an increased risk of developing CKD in the general population. This association is dependent on renal function, and mainly driven by new-onset CKD as defined by renal function decline.

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., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Oxidative stress is known to be involved in the development of hypertension, but accurate redox biomarkers predicting the risk of developing hypertension are scarce. Serum free sulfhydryl groups (R-SH, free thiols) have been shown to accurately reflect systemic oxidative stress in various conditions. In this study, we aimed to investigate associations between serum free thiols and the risk of developing new-onset hypertension in a population-based cohort study., Methods: Subjects (n = 3,575) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of hypertension, defined as a systolic blood pressure (SBP) of at least 140 mmHg, a diastolic blood pressure (DBP) of at least 90 mmHg, or the first usage of antihypertensive medication. Subjects with hypertension at baseline were excluded from the study., Results: Mean protein-adjusted serum free thiols at baseline was 5.16 μmol/g of protein (range: 1.62-8.41 μmol/g). Protein-adjusted serum free thiols were significantly associated with the risk of incident hypertension (hazard ratio [HR] per doubling 0.60 [95% confidence interval [CI]: 0.49-0.72, P < 0.001), also after adjustment for age and sex (HR 0.81 [95% CI: 0.66-0.91], P < 0.05), but not after additional adjustment for relevant confounding factors (HR 0.90 [95% CI: 0.70-1.15], P = 0.382)., Conclusion: Higher levels of serum free thiols, i.e. less oxidative stress, are associated with a decreased risk of developing incident hypertension in subjects from the general population., (Copyright © 2022. Published by Elsevier Inc.)

Background: The Infant Motor Profile (IMP) is an appropriate tool to assess and monitor infant motor behaviour over time. Infants at very high risk (VHR) due to a lesion of the brain generally show impaired motor development. They may grow into or out of their neurodevelopmental deficit., Aims: Evaluate associations between IMP-trajectories, summarised by IMP-scores in early infancy and rates of change, and functional and cognitive outcome at school-age in VHR-children., Study Design: Longitudinal study., Subjects: 31 VHR-children, mainly due to a brain lesion, who had multiple IMP-assessments during infancy, were re-assessed at 7-10 years (school-age)., Outcome Measures: Functional outcome was assessed with the Vineland-II, cognition with RAKIT 2. Associations between IMP-trajectories and outcome were tested by multivariable linear regression analyses., Results: When corrected for sex, maternal education and follow-up age, initial scores of total IMP, variation and performance domains, as well as their rates of change were associated with better functional outcome (unstandardised coefficients [95% CI]): 36.44 [19.60-53.28], 33.46 [17.43-49.49], 16.52 [7.58-25.46], and 513.15 [262.51-763.79], 356.70 [148.24-565.15], and 269 [130.57-407.43], respectively. Positive rates of change in variation scores were associated with better cognition at school-age: 34.81 [16.58-53.03]., Conclusion: Our study indicated that in VHR-children IMP-trajectories were associated with functional outcome at school-age, and to a minor extent also with cognition. Initial IMP-scores presumably reflect the effect of an early brain lesion on brain functioning, whereas IMP rate of change reflects whether infants are able to grow into or out of their initial neurodevelopmental deficit., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the prevalence and development of muscle tone impairments in infants at high risk of developmental disorders, and their associations with cerebral palsy (CP) and cystic periventricular leukomalacia (cPVL)., Method: Longitudinal exploration of muscle tone in 39 infants at high risk of CP (LEARN2MOVE 0-2 project) mostly due to an early lesion of the brain. Muscle tone was assessed ≥4 times between 0 and 21 months corrected age (CA) with the Touwen Infant Neurological Examination. Diagnosis of CP was determined at 21 months CA. Neonatal neuro-imaging was available. Developmental trajectories were calculated using generalized linear mixed effect models., Results: Infants showed atypical muscle tone in three or four body parts in 93% (172/185) of the assessments. The most prevalent muscle tone pattern was hypotonia of neck and trunk with hypertonia of the limbs (28%). From 7 months CA onwards hypertonia of the arms was associated with CP. Asymmetric arm tone during infancy was associated with unilateral CP. At 18-21 months CA ankle hypertonia was associated with CP at 21 months; leg hypertonia in infancy was not associated with CP. Leg hypertonia was associated with cPVL, regardless of age., Interpretation: High-risk infants due to an early lesion of the brain often present with muscle tone impairment. In these infants, hypertonia and asymmetric muscle tone of the arms were from 7 months onwards associated with the diagnosis of CP at 21 months; hypertonia of the legs was not., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study., Methods: Subjects without CKD (n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2 , urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both., Results: Median level of protein-adjusted serum free thiols at baseline was 5.14 μmol/g of protein (interquartile range [IQR]: 4.50-5.75 μmol/g) and median eGFR was 96 mL/min/1.73 m 2 [IQR: 85-106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36-0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47-0.94], P=0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51-0.96], P=0.028)., Conclusion: Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population. Methods: Female participants ( n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events. Results: Postmenopausal women had significantly reduced levels of serum free thiols (4.8 ± 1.0 vs. 5.2 ± 1.0 μmol/g, P < 0.001) compared to reproductive women. In multivariable analyses, serum free thiols were significantly associated with menopausal status (OR 0.70 [0.49-0.98], P = 0.039), even when adjusted for potential confounding factors, except for age ( P = 0.550). Prospectively, serum free thiols were significantly associated with the risk of CV events (HR 0.52 [0.27-0.97], P = 0.040), even with covariate adjustment, although this disappeared when correcting for age. Conclusion: In this study, we revealed serum free thiols to be strongly associated with the female cardiovascular phenotype as well as with female risk of CV events, where the influence of age itself seemed to outweigh that of female menopause. Future studies are warranted to further unravel the clinical utility of serum free thiol levels in the context of female cardiovascular risk management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bourgonje, Bourgonje, Abdulle, Kieneker, la Bastide-van Gemert, Gansevoort, Bakker, Mulder, Pasch, Saleh, Gordijn and van Goor.)

The aim of this study was to evaluate the frequency of electrocardiographic (ECG) abnormalities in the acute phase of severe traumatic brain injury (TBI) and the association with brain injury severity and outcome. In contrast to neurovascular diseases, sparse information is available on this issue. Data of adult patients with severe TBI admitted to the Intensive Care Unit (ICU) for intracranial pressure monitoring of a level-1 trauma center from 2002 till 2018 were analyzed. Patients with a cardiac history were excluded. An ECG recording was obtained within 24 h after ICU admission. Admission brain computerized tomography (CT)-scans were categorized by Marshall-criteria (diffuse vs. mass lesions) and for location of traumatic lesions. CT-characteristics and maximum Therapy Intensity Level (TILmax) were used as indicators for brain injury severity. We analyzed data of 198 patients, mean (SD) age of 40 ± 19 years, median GCS score 3 [interquartile range (IQR) 3-6], and 105 patients (53%) had thoracic injury. In-hospital mortality was 30%, with sudden death by cardiac arrest in four patients. The incidence of ECG abnormalities was 88% comprising ventricular repolarization disorders (57%) mostly with ST-segment abnormalities, conduction disorders (45%) mostly with QTc-prolongation, and arrhythmias (38%) mostly of supraventricular origin. More cardiac arrhythmias were observed with increased grading of diffuse brain injury ( p = 0.042) or in patients treated with hyperosmolar therapy (TILmax) (65%, p = 0.022). No association was found between ECG abnormalities and location of brain lesions nor with thoracic injury. Multivariate analysis with baseline outcome predictors showed that cardiac arrhythmias were not independently associated with in-hospital mortality ( p = 0.097). Only hypotension ( p = 0.029) and diffuse brain injury ( p = 0.017) were associated with in-hospital mortality. In conclusion, a high incidence of ECG abnormalities was observed in patients with severe TBI in the acute phase after injury. No association between ECG abnormalities and location of brain lesions or presence of thoracic injury was present. Cardiac arrhythmias were indicative for brain injury severity but not independently associated with in-hospital mortality. Therefore, our findings likely suggest that ECG abnormalities should be considered as cardiac mimicry representing the secondary effect of traumatic brain injury allowing for a more rationale use of neuroprotective measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lenstra, Kuznecova-Keppel Hesselink, la Bastide-van Gemert, Jacobs, Nijsten, van der Horst and van der Naalt.)

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., (© 2020 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Purpose: Evidence for efficacy of early intervention in infants at high risk of cerebral palsy (CP) is limited. We compared outcome of infants at very high risk of CP after receiving the family centered program COPing with and CAring for infants with special needs (COPCA) or typical infant physiotherapy. Materials and methods: Forty-three infants were randomly assigned before the corrected age of 9 months to 1 year of COPCA ( n  = 23) or typical infant physiotherapy ( n  = 20). Neuromotor development, cognition, and behavior was assessed until 21 months corrected age. Video-recorded physiotherapy sessions were quantitatively analyzed for further process analyses. Outcome was evaluated with nonparametric tests and linear mixed effect models. Results: During and after the interventions, infant outcome in both intervention groups was similar [primary outcome Infant Motor Profile: COPCA 82 (69-94), typical infant physiotherapy 81 (69-89); Hodges Lehman estimate of the difference 0 (confidence interval -5;4)]. Outcome was not associated with contents of intervention. Conclusions: One year of COPCA and 1 year of typical infant physiotherapy in infants at high risk of CP resulted in similar neurodevelopmental outcomes. It is conceivable that combinations of active ingredients from different approaches are needed for effective early intervention.IMPLICATIONS FOR REHABILITATIONFor infants at very high risk of cerebral palsy, 1 year of intervention with the family-centred programme Coping with and Caring for infants with special needs resulted in similar infant outcome as 1 year of typical infant physiotherapy.Infant's neuromotor, cognitive, and behavioural outcome was not associated with specific interventional elements, implying that the various elements may have a similar effect on developmental outcome.We suggest that a specific mix of ingredients of different approaches may work best, resulting in comprehensive care including both infant and family needs.

Purpose: To compare family and functional outcome in infants at very high risk of cerebral palsy, after receiving the family centred programme "Coping with and Caring for infants with special needs (COPCA)" or typical infant physiotherapy. Materials and methods: Forty-three infants at very high risk were included before 9 months corrected age and randomly assigned to one year COPCA ( n  = 23) or typical infant physiotherapy ( n  = 20). Family and infant outcome were assessed before and during the intervention. Physiotherapy intervention sessions were analysed quantitatively for process analysis. Outcome was evaluated with non-parametric tests and linear mixed-effect models. Results: Between-group comparisons revealed no differences in family and infant outcomes. Within-group analysis showed that family's quality of life improved over time in the COPCA-group. Family empowerment was positively associated with intervention elements, including "caregiver coaching." Conclusions: One year of COPCA or typical infant physiotherapy resulted in similar family and functional outcomes. Yet, specific intervention elements, e.g., coaching, may increase empowerment of families of very high risk infants and may influence quality of life, which emphasizes the importance of family centred services.Implications for rehabilitationOne year of the family centred programme "Coping with and a Caring for infants with special needs" compared with typical infant physiotherapy resulted in similar family outcome and similar functional outcome for the infants at very high risk for cerebral palsy.Specific contents of intervention, such as caregiver coaching, are associated with more family empowerment and increased quality of life.Emphasis on family needs is important in early intervention for infants at very high risk for cerebral palsy.

Background: The Alberta Infant Motor Scale (AIMS) has been developed in Canada in the 90ies. The AIMS and its Canadian norms are frequently used across the world to monitor infants' gross motor development. Currently, it is disputed whether the Canadian norms are valid for non-Canadian infants., Aims: To compare scores on the AIMS of Dutch infants with that of the Canadian norms, to compare the sequence of motor milestones in Dutch and Canadian infants, and to establish Dutch AIMS norms., Study Design: Cross-sectional study., Subjects: 1697 infants, aged 2-18 months, representative of the Dutch population (gestational age 39.7 weeks (27-42))., Outcome Measure: AIMS assessments, based on standardized video. Perinatal and social information was obtained by questionnaire and medical records. To create Dutch reference values quantile regression with polynomial splines was used., Results: 1236 Dutch infants (73%) scored below the 50th (P50) percentile of the Canadian norms, 653 (38%) below the P10 and 469 (28%) below the P5. In infants aged 6 to 12 months these values were: 567 infants (81%) < P50, 288 infants (41%) < P10, 201 infants (29%) < P5. The sequence of achievement of motor milestones of Dutch and Canadian infants was similar. Dutch norm-reference values of the AIMS were calculated., Conclusions and Implications: Gross motor development of Dutch infants is considerably slower than that of the Canadian AIMS norms sample. To prevent overdiagnosis of developmental delay and overreferral to paediatric physiotherapy Dutch AIMS norms are required. The paper introduces these norms, including percentile ranks., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: To evaluate the effect of 15° forward (FW) seat inclination and foot-support in children with cerebral palsy (CP) on postural adjustments during reaching., Design: Observational study repeated-measures design; step two of two-step-project., Setting: Laboratory unit within University Hospital and two special education schools., Participants: 19 children (ten unilateral spastic CP (US-CP); nine bilateral spastic CP (BS-CP); Gross Motor Function Classification System levels I-III; 6-12 years old). Participants were able to take part for one one-hour session., Intervention: Reaching while sitting in four seating conditions (FW or horizontal seat; with or without foot-support) applied in randomized order., Outcome Measures: Simultaneously, surface electromyography (EMG) of neck, trunk and arm muscles and kinematics of head and reaching arm (step one of two-step-project) were recorded. Primary outcome parameters were the ability to modulate EMG-amplitudes at baseline and during reaching (phasic muscle activity). Other EMG-parameters were direction-specificity (1st control level), and 2nd level of control parameters: recruitment order, and anticipatory postural activity. Motor behaviour measures: ability to modulate EMG-amplitudes to kinematic characteristics of reaching and head stability., Results: Only foot-support was associated with increased tonic background EMG-amplitudes and decreased phasic EMG-amplitudes of the trunk extensors in children with US-CP and BS-CP (mixed-models analyses; p-values <0.01). The foot-support effect was also associated with better kinematics of reaching (Spearman's Rho; p-values <0.01)., Conclusion: In terms of postural adjustments during forward reaching, foot-support enhanced the children's capacity to modulate trunk extensor activity, which was associated with improved reaching quality. FW-tilting did not affect postural muscle activity., (Copyright © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2019. Published by Oxford University Press.)