Assessing the relationship between multimorbidity, NCD configurations, frailty phenotypes, and mortality risk in older adults.

BACKGROUND: Older adults are increasingly susceptible to prolonged illness, multiple chronic diseases, and disabilities, which can lead to the coexistence of multimorbidity and frailty. Multimorbidity may result in various noncommunicable disease (NCD) patterns or configurations that could be associated with frailty and death. Mortality risk may vary depending on the presence of specific chronic diseases configurations or frailty. METHODS: The aim was to examine the impact of NCD configurations on mortality risk among older adults with distinct frailty phenotypes. The population was analyzed from the Costa Rican Longevity and Healthy Aging Study Cohort (CRELES). A total of 2,662 adults aged 60 or older were included and followed for 5 years. Exploratory factor analysis and various clustering techniques were utilized to identify NCD configurations. The frequency of NCD accumulation was also assessed for a multimorbidity definition. Frailty phenotypes were set according to Fried et al. criteria. Kaplan‒Meier survival analyses, mortality rates, and Cox proportional hazards models were estimated. RESULTS: Four different types of patterns were identified: 'Neuro-psychiatric', 'Metabolic', 'Cardiovascular', and 'Mixt' configurations. These configurations showed a higher mortality risk than the mere accumulation of NCDs [Cardiovascular HR:1.65 (1.07-2.57); 'Mixt' HR:1.49 (1.00-2.22); ≥3 NCDs HR:1.31 (1.09-1.58)]. Frailty exhibited a high and constant mortality risk, irrespective of the presence of any NCD configuration or multimorbidity definition. However, HRs decreased and lost statistical significance when phenotypes were considered in the Cox models [frailty + 'Cardiovascular' HR:1.56 (1.00-2.42); frailty + 'Mixt':1.42 (0.95-2.11); and frailty + ≥ 3 NCDs HR:1.23 (1.02-1.49)]. CONCLUSIONS: Frailty accompanying multimorbidity emerges as a more crucial indicator of mortality risk than multimorbidity alone. Therefore, studying NCD configurations is worthwhile as they may offer improved risk profiles for mortality as alternatives to straightforward counts.

Modelling individual infancy growth trajectories to predict excessive gain in BMI z-score: a comparison of growth measures in the ABCD and GECKO Drenthe cohorts.

BACKGROUND: Excessive weight gain during childhood is a strong predictor for adult overweight, but it remains unknown which growth measures in infancy (0-2 years of age), besides predictors known at birth, are the strongest predictors for excessive weight gain between 2 and 5-7 years of age. METHODS: The Amsterdam Born Children and their Development (ABCD) study formed the derivation cohort, and the Groningen Expert Center for Kids with Obesity (GECKO) Drenthe study formed the validation cohort. Change (Δ) in body mass index (BMI) z-score between 2 and 5-7 years was the outcome of interest. The growth measures considered were weight, weight-for-length (WfL), and body mass index (BMI). Formats considered for each growth measure were values at 1, 6, 12, and 24 months, at the BMI peak, the change between aforementioned ages, and prepeak velocity. 10 model structures combining different variable formats and including predictors at birth were derived for each growth measure, resulting in 30 linear regression models. A Parsimonious Model considering all growth measures and a Birth Model considering none were also derived. RESULTS: The derivation cohort consisted of 3139 infants of which 373 (11.9%) had excessive gain in BMI z-score (> 0.67). The validation cohort contained 2201 infants of which 592 (26.9%) had excessive gain. Across the 3 growth measures, 5 model structures which included measures related to the BMI peak and prepeak velocity (derivation cohort area under the curve [AUC] range = 0.765-0.855) achieved more accurate estimates than 3 model structures which included growth measure change over time (0.706-0.795). All model structures which used BMI were superior to those using weight or WfL. The AUC across all models was on average 0.126 lower in the validation cohort. The Parsimonious Model's AUCs in the derivation and validation cohorts were 0.856 and 0.766, respectively, compared to 0.690 and 0.491, respectively, for the Birth Model. The respective false positive rates were 28.2% and 20.1% for the Parsimonious Model and 70.0% and 74.6% for the Birth Model. CONCLUSION: Models' performances varied significantly across model structures and growth measures. Developing the optimal model requires extensive testing of the many possibilities.

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

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

Dairy consumption and incident prediabetes: prospective associations and network models in the large population-based Lifelines Study.

BACKGROUND: Evidence on associations between dairy consumption and incident prediabetes is inconsistent. One potential explanation for heterogeneity is that health behavior and food intake covary with the consumption of various high-fat and low-fat dairy types. OBJECTIVE: The objective was to investigate the associations of total dairy and dairy types with incident prediabetes and to assess how dairy intake is linked with metabolic risk factors, lifestyle behaviors, and foods, as potential explanations for these associations. METHODS: Overall, 74,132 participants from the prospective population-based Lifelines study were included (mean age, 45.5 ± 12.3 y; 59.7% female). Baseline dairy intake was measured using a validated food frequency questionnaire. Prediabetes at follow-up was defined based on the World Health Organization/International Expert Committee criteria as fasting plasma glucose of 110-125 mg/dL or glycated hemoglobin concentrations of 6.0%-6.5%. Associations were analyzed using Poisson regression models adjusted for social demographics, lifestyle behaviors, family history of diabetes, and food group intake. Interconnections were assessed with mixed graphical model networks. RESULTS: At a mean follow-up of 4.1 ± 1.1 y, 2746 participants developed prediabetes (3.7%). In regression analyses, neutral associations were found for most dairy types. Intake of plain milk and low-fat milk were associated with a higher risk of prediabetes in the top compared with bottom quartiles (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.05, 1.30; P-trend = 0.04 and RR: 1.18; 95% CI: 1.06, 1.31; P-trend =0.01). Strong but nonsignificant effect estimates for high-fat yogurt in relation to prediabetes were found (RRservings/day: 0.80; 95% CI: 0.64, 1.01). The network analysis showed that low-fat milk clustered with energy-dense foods, including bread, meat, and high-fat cheese, whereas high-fat yogurt had no clear link with lifestyle risk factors and food intake. CONCLUSIONS: In this large cohort of Dutch adults, low-fat milk intake was associated with higher prediabetes risk. Heterogeneous associations by dairy type and fat content might partly be attributed to confounding caused by behaviors and food intake related to dairy intake.

A prospective analysis of physical activity and mental health in children: the GECKO Drenthe cohort.

BACKGROUND: Mental health problems in young people have become a global health burden. The positive effects of physical activity on mental health in adults are well known but still not clear in children. The aim of this study was to investigate to what extent physical activity in early childhood would affect mental health in middle childhood. METHODS: From the Dutch GECKO Drenthe birth cohort, 850 children (51.5% boys) were enrolled in this analysis. Physical activity and sedentary time were measured at age 5-6 using ActiGraph GT3X. Mental health was assessed using the Strengths and Difficulties Questionnaire (SDQ) at age 5-6 and age 10-11. Multiple linear regression models were used to estimate the associations between physical activity, sedentary time and SDQ subscales, stratified by gender, adjusting for age, BMI, maternal education level, family size, accelerometer wear time and season, and additionally adjusting for SDQ scores at age 5-6 to take tracking of mental health over time into account. RESULTS: Greater physical activity volume at age 5-6 was associated with lower peer problems scores at age 10-11 in boys and girls. An increase in MVPA was associated with lower peer problems scores in boys (b = -0.445, -0.713 to -0.176) and girls (b = -0.354, -0.601 to -0.107), however, increased sedentary time was linked to higher peer problems scores in boys (b = 1.18, 0.455 to 1.906) and girls (b = 0.870, 0.191 to 1.550). For hyperactivity, higher levels of physical activity volume and MVPA were associated with higher hyperactivity scores in boys. Increased sedentary time was related to lower hyperactivity scores in boys. Further adjustment for SDQ scores at age 5-6 attenuated associations between physical activity and hyperactivity in boys but hardly changed the relationships with peer problems. No significant associations between physical activity and other SDQ subscales or total difficulties scores were observed, neither in boys nor in girls. CONCLUSIONS: Children who are more physically active at age 5-6 have fewer peer problems at age 10-11, and for boys, greater activity levels at age 5-6 could be an indicator of hyperactivity at age 10-11.

Albuminuria and markers for cardiovascular risk in 12-year-olds from the general Dutch population: a cross-sectional study.

In adults, albuminuria represents a risk factor for cardiovascular disease and is associated with hypertension and obesity. Pediatric data from the general population are inconsistent and largely based on randomly collected urine. A possible association between antenatal programming and albuminuria at school age has still to be investigated. The purpose of this study is to assess albuminuria in first morning void urine samples in a population-based pediatric cohort and to investigate cross-sectionally the association with factors related to cardiovascular risk. Moreover, we investigate the possible association of antenatal factors with albuminuria. A first morning void urine sample was collected in the population-based GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort at the age of 12 years. We investigated cross-sectionally associations between albuminuria and body mass index (BMI), waist circumference (WC), blood pressure (BP) and antenatal factors. The prevalence of UACR (urinary albumin-creatinine ratio) ≥ 3 mg/mmol was 3.3% (95%CI 2.3-4.2). In a multivariate linear regression model, UAC was negatively associated with z-BMI (ß-0.08, p = 0.013) and positively with z-systolic BP (ß 0.09, p = 0.006), model significance p = 0.002. UACR was negatively associated with z-BMI (ß - 0.13, p < 0.001) and positively with z-diastolic BP (ß 0.09, p = 0.003), model significance p = 0.001. Albuminuria was not significantly associated with antenatal factors such as gestational age and standardized birth weight. CONCLUSIONS:  Albuminuria in first morning void urine in 12-year-olds has a lower prevalence than previously reported by randomly collected samples. A negative association between albuminuria and BMI is confirmed. A positive association with blood pressure, but no association with antenatal factors was found. WHAT IS KNOWN: • While, in adults, albuminuria is a recognized risk factor for cardiovascular disease and is associated with hypertension and obesity, pediatric data are inconsistent and largely based on randomly collected urine. • A possible association between antenatal programming and albuminuria at school age has still to be investigated. WHAT IS NEW: • In this population study on first morning void urine samples from 12-year-olds of the general population, albuminuria is negatively associated with body mass index, and positively associated with blood pressure, while there is no association with antenatal factors. • The prevalence of albuminuria at 12 years is lower than previously reported in studies based on randomly collected urine samples, probably due to elimination of orthostatic proteinuria.

Lifestyle factors related to prevalent chronic disease multimorbidity: A population-based cross-sectional study.

BACKGROUND: Multimorbidity is associated with poor quality of life, polypharmacy, health care costs and mortality, with those affected potentially benefitting from a healthy lifestyle. We assessed a comprehensive set of lifestyle factors in relation to multimorbidity with major chronic diseases. METHODS: This cross-sectional study utilised baseline data for adults from the prospective Lifelines Cohort in the north of the Netherlands (N = 79,345). We defined multimorbidity as the co-existence of two or more chronic diseases (i.e. cardiovascular disease, cancer, respiratory disease, type 2 diabetes) and evaluated factors in six lifestyle domains (nutrition, physical (in)activity, substance abuse, sleep, stress, relationships) among groups by the number of chronic diseases (≥2, 1, 0). Multinomial logistic regression models were created, adjusted for appropriate confounders, and odds ratios (OR) with 95% confidence intervals (95%CI) were reported. RESULTS: 3,712 participants had multimorbidity (4.7%, age 53.5 ± 12.5 years), and this group tended to have less healthy lifestyles. Compared to those without chronic diseases, those with multimorbidity reported physical inactivity more often (OR, 1.15; 95%CI, 1.06-1.25; not significant for one condition), chronic stress (OR, 2.14; 95%CI, 1.92-2.38) and inadequate sleep (OR, 1.70; 95%CI, 1.41-2.06); as expected, they more often watched television (OR, 1.70; 95%CI, 1.42-2.04) and currently smoked (OR, 1.91; 95%CI, 1.73-2.11), but they also had lower alcohol intakes (OR, 0.66; 95%CI, 0.59-0.74). CONCLUSIONS: Chronic stress and poor sleep, in addition to physical inactivity and smoking, are lifestyle factors of great concern in patients with multimorbidity.

Urinary Copper Excretion Is Associated with Long-Term Graft Failure in Kidney Transplant Recipients.

INTRODUCTION: In chronic kidney disease, proteinuria increases urinary copper excretion, inducing oxidative tubular damage and worsening kidney function. We investigated whether this phenomenon occurred in kidney transplant recipients (KTRs). In addition, we studied the associations of urinary copper excretion with the biomarker of oxidative tubular damage urinary liver-type fatty-acid binding protein (u-LFABP) and death-censored graft failure. METHODS: This prospective cohort study was performed in the Netherlands between 2008 and 2017, including outpatient KTR with a functioning graft for longer than 1 year, who were extensively phenotyped at baseline. Twenty-four-hour urinary copper excretion was measured by inductively coupled plasma mass spectrometry. Multivariable linear and Cox regression analyses were performed. RESULTS: In 693 KTR (57% men, 53 ± 13 years, estimated glomerular filtration rate [eGFR] 52 ± 20 mL/min/1.73 m2), baseline median urinary copper excretion was 23.6 (interquartile range 11.3-15.9) µg/24 h. Urinary protein excretion was positively associated with urinary copper excretion (standardized ß = 0.39, p < 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized ß = 0.29, p < 0.001). During a median follow-up of 8 years, 109 (16%) KTR developed graft failure. KTR with relatively high copper excretion were at higher risk of long-term graft failure (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.32-1.86 per log2, p < 0.001), independent of multiple potential confounders like eGFR, urinary protein excretion, and time after transplantation. A dose-response relationship was observed over increasing tertiles of copper excretion (HR: 5.03, 95% CI: 2.75-9.19, tertile 3 vs. 1, p < 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p < 0.001). CONCLUSION: In KTR, urinary protein excretion is positively correlated with urinary copper excretion. In turn, higher urinary copper excretion is associated with an independent increased risk of kidney graft failure, with a substantial mediating effect through oxidative tubular damage. Further studies are warranted to investigate whether copper excretion-targeted interventions could improve kidney graft survival.

Correction: Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].

Low selenium intake is associated with risk of all-cause mortality in kidney transplant recipients.

BACKGROUND: Deficiency of the essential trace element selenium is common in kidney transplant recipients (KTR), potentially hampering antioxidant and anti-inflammatory defence. Whether this impacts the long-term outcomes of KTR remains unknown. We investigated the association of urinary selenium excretion, a biomarker of selenium intake, with all-cause mortality; and its dietary determinants. METHODS: In this cohort study, outpatient KTR with a functioning graft for longer than 1 year were recruited (2008-11). Baseline 24-h urinary selenium excretion was measured by mass spectrometry. Diet was assessed by a 177-item food frequency questionnaire, and protein intake was calculated by the Maroni equation. Multivariable linear and Cox regression analyses were performed. RESULTS: In 693 KTR (43% men, 52 ± 12 years), baseline urinary selenium excretion was 18.8 (interquartile range 15.1-23.4) µg/24-h. During a median follow-up of 8 years, 229 (33%) KTR died. KTR in the first tertile of urinary selenium excretion, compared with those in the third, had over a 2-fold risk of all-cause mortality [hazard ratio 2.36 (95% confidence interval 1.70-3.28); P < .001], independent of multiple potential confounders including time since transplantation and plasma albumin concentration. The most important dietary determinant of urinary selenium excretion was protein intake (Standardized ß 0.49, P < .001). CONCLUSIONS: Relatively low selenium intake is associated with a higher risk of all-cause mortality in KTR. Dietary protein intake is its most important determinant. Further research is required to evaluate the potential benefit of accounting for selenium intake in the care of KTR, particularly among those with low protein intake.

Differences in birth weight between immigrants' and natives' children in Europe and Australia: a LifeCycle comparative observational cohort study.

OBJECTIVE: Research on adults has identified an immigrant health advantage, known as the 'immigrant health paradox', by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives? SETTING: Western Europe and Australia. PARTICIPANTS: We use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants' children: Etude Longitudinale Française depuis l'Enfance-France (N=12 494), the Raine Study-Australia (N=2283), Born in Bradford-UK (N=4132), Amsterdam Born Children and their Development study-Netherlands (N=4030) and the Generation R study-Netherlands (N=4877). We include male and female babies born to immigrant and native parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0-1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad. RESULTS: Two patterns in children's birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, p<0.10) and Australia (+40 g, p<0.10) and lower birth weight among children of immigrants in the UK (-82 g, p<0.05) and the Netherlands (-80 g and -73 g, p<0.001) compared with natives' children. Smoking during pregnancy emerged as a mechanism explaining some of the birth weight gaps between children of immigrants and natives. CONCLUSION: The immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries.

Plasma Copper Concentration Is Associated with Cardiovascular Mortality in Male Kidney Transplant Recipients.

Kidney transplant recipients (KTR) are at increased risk of cardiovascular mortality. We investigated whether, in KTR, post-transplantation copper status is associated with the risk of cardiovascular mortality and potential effect modification by sex. In this cohort study, plasma copper was measured using mass spectrometry in extensively-phenotyped KTR with a functioning allograft >1-year. Cox regression analyses with the inclusion of multiplicative interaction terms were performed. In 660 KTR (53 ± 13 years old, 56% male), the median baseline plasma copper was 15.42 (IQR 13.53-17.63) µmol/L. During a median follow-up of 5 years, 141 KTR died, 53 (38%) due to cardiovascular causes. Higher plasma copper was associated with an increased risk of cardiovascular mortality in the overall KTR population (HR 1.37; 95% CI, 1.07-1.77 per 1-SD, p = 0.01). Sex was a significant effect modifier of this association (Pinteraction = 0.01). Among male KTR, higher plasma copper concentration was independently associated with a two-fold higher risk of cardiovascular mortality (HR 2.09; 95% CI, 1.42-3.07 per 1-SD, p < 0.001). Among female KTR, this association was absent. This evidence offers a rationale for considering a sex-specific assessment of copper's role in cardiovascular risk evaluation. Further studies are warranted to elucidate whether copper-targeted interventions may decrease cardiovascular mortality in male KTR.

Longitudinal relationship between albuminuria in infancy and childhood.

BACKGROUND: Mildly increased albuminuria is common in the general adult population and is a strong predictor for cardiovascular events, even in otherwise healthy individuals. The underlying pathophysiological process could be endothelial dysfunction. Previously, we reported that increased albuminuria can also be found in 2-year-olds from the general population. We hypothesized that some individuals have constitutionally higher levels of albuminuria, possibly as an expression of early or inborn endothelial dysfunction. The aim of this study is to evaluate longitudinal persistence of albuminuria from infancy into school age. METHODS: In the population-based GECKO (Groningen Expert Center for Kids with Obesity) cohort, urine was collected from 816 children at the age of 2 years as well as 12 years (random urine and first morning void urine, respectively). We evaluated prevalence and persistence of increased albuminuria (UACR ≥ 3 mg/mmol) at the two time points. RESULTS: The prevalence of UACR ≥ 3 mg/mmol at 2 and 12 years of age was 31.9% (95% CI 28.7-35.2) and 3.1% (95% CI 2.0-4.5), respectively. UACR < 3 mg/mmol at both 2 and 12 years of age was present in 540 children (66.2%). Only 9 children (3.5%) of the 260 children with an UACR ≥ 3 mg/mmol at 2 years had an UACR ≥ 3 mg/mmol at 12 years (p < 0.001). CONCLUSION: Albuminuria in 2-year-olds does largely not persist until the age of 12, indicating that albuminuria at 2 years of age is not a marker for constitutional endothelial dysfunction in this cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effect of vitamin K supplementation on serum calcification propensity and arterial stiffness in vitamin K-deficient kidney transplant recipients: A double-blind, randomized, placebo-controlled clinical trial.

Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 µg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs. TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. CONCLUSIONS: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.

Measures of Early-life Behavior and Later Psychopathology in the LifeCycle Project - EU Child Cohort Network: A Cohort Description.

BACKGROUND: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. METHODS: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. RESULTS: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. CONCLUSION: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Hand dexterity, daily functioning and health-related quality of life in kidney transplant recipients.

Impaired interplay between sensory and motor function may be an important, often overlooked cause of the decreased daily functioning and impaired health-related quality of life (HRQoL) of kidney transplant recipients (KTR). We assessed this interplay using a hand dexterity test, and investigated its potential associations with daily functioning and HRQoL among KTR enrolled at the TransplantLines Biobank and Cohort Study. A total of 309 KTR (58% male, mean age 56 ± 13 years) at median 4 [IQR: 1-11] years after transplantation were included. Impaired hand dexterity, as defined by a test performance slower than the 95th percentile of an age- and sex-specific reference population, was observed in 71 (23%) KTR. Worse hand dexterity was independently associated with worse performance on almost all measures of physical capacity, activities of daily living and societal participation. Finally, hand dexterity was independently associated with physical HRQoL (standardized beta - 0.22, 95%CI - 0.34 to - 0.09, P < 0.001). In conclusion, impaired interplay between sensory and motor function, as assessed by hand dexterity, is prevalent among KTR. In addition, poor hand dexterity was associated with impaired daily functioning and limited physical HRQoL. Impaired interplay between sensory and motor function may be therefore an important, hitherto overlooked, phenomenon in KTR.

Regional variation in lifestyle patterns and BMI in young children: the GECKO Drenthe cohort.

BACKGROUND: A better understanding of lifestyle behaviours of children < 7 years and the relation with childhood overweight is needed. The aim of our prospective study was to examine how lifestyle patterns in young children are associated with the development of childhood overweight. As ecological models suggest focusing on not only the child as an individual, but also their environment, we also considered the role of socio-economic status (SES) and spatial clustering of lifestyle and body mass index (BMI). METHODS: In 1792 children (aged 3-6 years) participating in the GECKO Drenthe cohort, diet, screen time, outdoor play and sleep were assessed by questionnaires and moderate-to-vigorous physical activity and sedentary time by accelerometry (Actigraph GT3X). At 10-11 years, height and weight were measured to calculate age- and sex-specific standardized BMI z-scores (zBMI). Lifestyle patterns were identified using principal component analysis. To assess spatial clustering for the lifestyle patterns and zBMI, we calculated the Global Moran's I statistic. Linear- and logistic regression models, taking into account SES, were performed to examine the association between the lifestyle patterns and the development of overweight. For the spatial analyses, we added spatial terms for the determinants, the outcome, and the error term. RESULTS: Three lifestyle patterns were identified: (1) 'high activity', (2) 'low screen time, high sleep and healthy diet', and (3) 'high outdoor play'. No associations were observed between the 'high activity' or 'high outdoor play' patterns at young age with the development of childhood overweight (all p > 0.05). In contrast, children who adhered to the 'low screen time, high sleep and healthy diet' pattern had lower odds to become overweight and a lower zBMI at 10-11 years (odds ratio [95% CI] = 0.766 [0.65; 0.90]). These findings remained similar after taking SES into account. Regarding the spatial analyses, we found spatial clustering of zBMI, but no spatial clustering of the lifestyle patterns. CONCLUSIONS: Low screen time, high sleep duration and a healthy diet cluster into a pattern that seems favourable in the prevention of childhood overweight, independent of individual SES. The spatial analyses suggest that there are likely other neighbourhood factors that contribute to the spatial clustering of childhood overweight.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Ultra-processed foods and risk of all-cause mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTRs) have a 6-fold higher risk of mortality than age- and sex-matched controls. Whether high consumption of ultra-processed foods is associated with survival in RTRs is unknown. OBJECTIVES: We aimed to study the association between high consumption of ultra-processed foods and all-cause mortality in stable RTRs. METHODS: We conducted a prospective cohort study in adult RTRs with a stable graft. Dietary intake was assessed using a validated 177-item FFQ. Food items were categorized according to the NOVA classification system and the proportion ultra-processed foods comprised of total food weight per day was calculated. RESULTS: We included 632 stable RTRs (mean ± SD age: 53.0 ± 12.7 y, 57% men). Mean ± SD consumption of ultra-processed foods was 721 ± 341 g/d (28% of total weight of food intake), whereas the intake of unprocessed and minimally processed foods, processed culinary ingredients, and processed foods accounted for 57%, 1%, and 14%, respectively. During median follow-up of 5.4 y [IQR: 4.9-6.0 y], 129 (20%) RTRs died. In Cox regression analyses, ultra-processed foods were associated with all-cause mortality (HR per doubling of percentage of total weight: 2.13; 95% CI: 1.46, 3.10; P < 0.001), independently of potential confounders. This association was independent from the quality of the overall dietary pattern, expressed by the Mediterranean Diet Score (MDS) or Dietary Approaches to Stop Hypertension (DASH) score. When analyzing ultra-processed foods by groups, only sugar-sweetened beverages (HR: 1.21; 95% CI: 1.05, 1.39; P = 0.007), desserts (HR: 1.24; 95% CI: 1.02, 1.49; P = 0.03), and processed meats (HR: 1.87; 95% CI: 1.22, 2.86; P = 0.004) were associated with all-cause mortality. CONCLUSIONS: Consumption of ultra-processed foods, in particular sugar-sweetened beverages, desserts, and processed meats, is associated with a higher risk of all-cause mortality after renal transplantation, independently of low adherence to high-quality dietary patterns, such as the Mediterranean diet and the DASH diet.This trial was registered at clinicaltrials.gov as NCT02811835.