The PROactive cohort study: rationale, design, and study procedures.

Children with a chronic condition face more obstacles than their healthy peers, which may impact their physical, social-emotional, and cognitive development. The PROactive cohort study identifies children with a chronic disease at high risk of debilitating fatigue, decreased daily life participation and psychosocial problems, as well as children who are resilient and thrive despite the challenges of growing up with a chronic condition. Both groups will teach us how we can best support children, adolescents and parents to adapt to and manage a disease, as well as tailor interventions to their specific needs.This cohort follows a continuous longitudinal design. It is based at the Wilhelmina Children's Hospital (WKZ) in the Netherlands and has been running since December 2016. Children with a chronic condition (e.g. cystic fibrosis, juvenile idiopathic arthritis, chronic kidney disease, or congenital heart disease) as well children with medically unexplained fatigue or pain in a broad age range (2-18 years) are included, as well as their parent(s). Data are collected from parents (of children between 2 and 18 years) and children (8-18 years), as well as data from their electronic health record (EHR). Primary outcome measures are fatigue, daily life participation, and psychosocial well-being, all assessed via patient- and proxy-reported outcome measures. Generic biological/lifestyle, psychological, and social factors were assessed using clinical assessment tools and questionnaires. In the PROactive cohort study the research assessment is an integrated part of clinical care. Children are included when they visit the outpatient clinic and are followed up annually.

Parent-Child Dyadic Coping and Quality of Life in Chronically Diseased Children.

Different forms of dyadic coping are associated with positive outcomes in partner relationships, yet little is known about dyadic coping in parent-child relationships. The current research explored the association between parent-child dyadic coping and children's quality of life in 12-18-year old children with a chronic disease (i.e., cystic fibrosis, autoimmune diseases, and children post-cancer treatment). In a sample of 105 parent-child dyads, self-reported forms of dyadic coping (i.e., stress communication, problem-oriented, emotion-oriented, and negative dyadic coping) and children's quality of life were assessed. Children reported more stress communication and negative dyadic coping than their parents, while parents reported more problem-oriented dyadic coping and emotion-oriented dyadic coping than their children. More stress communication of the child was associated with more emotion-oriented dyadic coping and less negative dyadic coping of the parent. More negative dyadic coping of the child was associated with less stress communication, problem-oriented dyadic coping and emotion-oriented dyadic coping of the parent. Additionally, both children's and parents' negative dyadic coping were associated with lower self-reported pediatric quality of life and parents' emotion-oriented dyadic coping was associated with higher pediatric quality of life. These findings emphasize that children and their parents mutually influence each other and that dyadic coping is associated with children's quality of life. Theoretical and practical implications are discussed.

Role of parents in fatigue of children with a chronic disease: a cross-sectional study.

Objective: As parents majorly impact their child's well-being, and as fatigue is a highly prevalent threat to the well-being of children with a chronic disease, we aimed to explore the association between parental factors and fatigue in children with a chronic disease. Design: Cross-sectional study. Setting: Two Dutch children's hospitals. Population: Children 2-18 years of age with either an autoimmune disease, cystic fibrosis or post-cancer treatment, and one of their parents. Main outcome measures: Paediatric fatigue was measured using the PedsQL Multidimensional Fatigue Scale. Parental factors included parental pain, fatigue and physical symptoms, parental distress, catastrophising thoughts about their child's pain and family empowerment. Multiple linear regressions were used to study associations with paediatric fatigue. A multivariable regression model was used to assess the effect of the different parental factors on paediatric fatigue. All analyses were adjusted for the age and sex of the child. Results: 204 families participated (mean age 11.0±4.3 and 43.5±6.3 years for children and parents, respectively; 69% participation rate). More parental pain, fatigue and physical symptoms, and more parental distress and pain catastrophising were associated with more paediatric fatigue. More parental empowerment was associated with less paediatric fatigue on both subscales. In the multivariable model, only paediatric age remained significantly associated with fatigue. In a separate multivariable model for children 8-18 years old, more parental distress (ß=-1.9, 95% CI -3.7 to -0.1) was also significantly associated with more paediatric fatigue. Conclusions: In a population of children with a chronic disease, parental factors, both physical and psychosocial, were associated with paediatric fatigue. Our study provides evidence that more family empowerment is associated with less paediatric fatigue. This exploratory study adds to our knowledge of associated factors with fatigue in paediatric chronic disease, providing starting points for targeted interventions.

Internet and smartphone-based ecological momentary assessment and personalized advice (PROfeel) in adolescents with chronic conditions: A feasibility study.

OBJECTIVE: Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful. STUDY DESIGN: Feasibility study in fatigued outpatient adolescents 12-18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held. RESULTS: Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good. CONCLUSIONS: PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation.

Fatigue among children with a chronic disease: a cross-sectional study.

Objective: To determine: (1) which biological/lifestyle, psychological and/or social factors are associated with fatigue among children with a chronic disease and (2) how much each of these factors contributes to explaining variance in fatigue. Design and setting: This was a cross-sectional study across two children's hospitals. Patients: We included children aged 8-18 years who visited the outpatient clinic with cystic fibrosis, an autoimmune disease or postcancer treatment. Main outcome measures: Fatigue was assessed using the PedsQL Multidimensional Fatigue Scale. Generic biological/lifestyle, psychological and social factors were assessed using clinical assessment tools and questionnaires. Multiple linear regression analyses were used to test the associations between these factors and fatigue. Finally, a multivariable regression model was used to determine which factor(s) have the strongest effect on fatigue. Results: A total of 434 out of 902 children were included (48% participation rate), with a median age of 14.5 years; 42% were male. Among these 434 children, 21.8% were severely fatigued. Together, all biopsychosocial factors explained 74.6% of the variance in fatigue. More fatigue was uniquely associated with poorer physical functioning, more depressive symptoms, more pressure at school, poorer social functioning and older age. Conclusions: Fatigue among children with a chronic disease is multidimensional. Multiple generic biological/lifestyle, psychological and social factors were strongly associated with fatigue, explaining 58.4%; 65.8% and 50.0% of the variance in fatigue, respectively. Altogether, almost three-quarters of the variance in fatigue was explained by this biopsychosocial model. Thus, when assessing and treating fatigue, a transdiagnostic approach is preferred, taking into account biological, psychological and social factors.

Antenatal exposure to second hand smoke of non-smoking mothers and growth rate of their infants.

OBJECTIVES: There is limited evidence on the effect of exposure to second hand smoke (SHS) in non-smoking pregnant mothers and infant health. We assessed the effects of maternal antenatal exposure to SHS on infant growth rate, and secondarily, on birth weight, birth length and head circumference at birth. METHODS: In this prospective cohort, 305 mother-infant pairs were studied. Mothers filled out questionnaires about exposure to SHS in pregnancy at the 3rd trimester of pregnancy. Infant anthropometry was performed at birth, day 7, and months 1, 2, 4, and 6, postnatally. Linear mixed modeling and linear regression were used to calculate growth rates over the first 6 months. The association between SHS-exposure with growth rate and birth sizes was assessed using multivariate linear regression adjusted for confounders, with SHS as both number of cigarettes and as groups (no exposure, SHS < 23 cigarettes, SHS ≥ 23 cigarettes). RESULTS: Seventy-three mothers were not exposed and 232 were exposed. SHS exposure (per cigarette) was not related to gain in weight, length, head circumference, and weight for length. However, infants born to mothers exposed to ≥ 23 cigarettes/d had lower head circumference gain (-0.32 mm/m, 95% CI -0.60, -0.03) than those born to non-exposed mothers. SHS exposure (per cigarette) was not related to birth weight, length, and head circumference, but exposure to ≥ 23 cigarettes was related to lower head circumference at birth (-11.09 mm, -20.03, -2.16). CONCLUSIONS: Heavy antenatal exposure to SHS in non-smoking mothers results in reduced neonatal head circumference at birth and head circumference gain over the first 6 months of life. Our findings show no clear relations between exposure to SHS during pregnancy and other markers of neonatal growth and birth size.

Fatigue in childhood chronic disease.

BACKGROUND AND OBJECTIVES: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL). DESIGN AND SETTING: Cross-sectional study in two children's hospitals. PATIENTS: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic. OUTCOME MEASURES: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method. RESULTS: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains. CONCLUSIONS: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.

Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (ß = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (ß = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (ß = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (ß = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (ß = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Antenatal coffee and tea consumption and the effect on birth outcome and hypertensive pregnancy disorders.

BACKGROUND AND OBJECTIVE: Coffee and tea are commonly consumed during pregnancy. While several of their components, like caffeine, have strong pharmacological effects, the effect on the unborn fetus remains unclear. Caffeine intake has been associated with abortion, preterm birth and fetal growth restriction, but a general consensus on caffeine restriction is still lacking. We aimed to investigate antenatal coffee, tea and caffeine consumption and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy. METHODS: A total of 936 healthy pregnancies from the WHISTLER birth cohort with data on coffee and tea consumption were included. Maternal and child characteristics as well as antenatal coffee and tea consumption were obtained through postpartum questionnaires. Reported consumption was validated using available preconceptional data. Caffeine intake was calculated from coffee and tea consumption. Linear and logistic regression was used to assess the association with birth outcome and hypertensive disorders. RESULTS: After adjustment for smoking and maternal age, a daily consumption of more than 300mg of caffeine compared to less than 100mg of caffeine was significantly associated with an increased gestational age (linear regression coefficient = 2.00 days, 95%CI = 0.12-4.21, P = 0.03). Tea consumption was significantly related to a higher risk of pregnancy induced hypertension (OR = 1.13, 95%CI = 1.04-1.23, P = 0.004). No associations concerning coffee consumption or birth weight and birth length were observed. CONCLUSIONS: Daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research. For most outcomes, we found no significant associations with coffee or tea intake.

Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study.

BACKGROUND: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. METHODS: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. RESULTS: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. CONCLUSION: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

The relationship between vitamin K and peripheral arterial disease.

BACKGROUND AND AIMS: A high dietary intake of vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) is thought to decrease cardiovascular disease risk by reducing vascular calcification. The objective of this study is to explore if there is a relationship between phylloquinone and menaquinones intake and risk of PAD. METHODS: We investigated the association between intake of phylloquinone and menaquinones with PAD in a prospective cohort with 36,629 participants. Occurrence of PAD was obtained by linkage to national registries. Baseline intake of phylloquinone and menaquinones was estimated using a validated food-frequency questionnaire. Multivariate Cox regression was used to estimate adjusted hazard ratio's for the association. RESULTS: During 12.1 years (standard deviation 2.1 years) of follow-up, 489 incident cases of PAD were documented. Menaquinones intake was associated with a reduced risk of PAD with a hazard ratio (HR) of 0.71, 95% CI; 0.53-0.95 for the highest versus lowest quartile. A stronger association was observed (p interaction 0.0001) in participants with hypertension (HRQ4 versus Q1 0.59; 95% CI 0.39-0.87) or diabetes (HRQ4 versus Q1 0.56; 95% CI 0.18-1.91), though confidence intervals were wide in the small (n = 530) diabetes stratum. Phylloquinone intake was not associated with PAD risk. CONCLUSIONS: High intake of menaquinones was associated with a reduced risk of PAD, at least in hypertensive participants. High intake of phylloquinone was not associated with a reduced risk of PAD.

The relationship between fermented food intake and mortality risk in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.

The objective of the present study was to investigate the relationship between total and subtypes of bacterial fermented food intake (dairy products, cheese, vegetables and meat) and mortality due to all causes, total cancer and CVD. From the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort, 34 409 Dutch men and women, aged 20-70 years who were free from CVD or cancer at baseline, were included. Baseline intakes of total and subtypes of fermented foods were measured with a validated FFQ. Data on the incidence and causes of death were obtained from the national mortality register. Cox proportional hazards models were used to analyse mortality in relation to the quartiles of fermented food intake. After a mean follow-up of 15 (sd 2·5) years, 2436 deaths occurred (1216 from cancer and 727 from CVD). After adjustment for age, sex, total energy intake, physical activity, education level, hypertension, smoking habit, BMI, and intakes of fruit, vegetables and alcohol, total fermented food intake was not found to be associated with mortality due to all causes (hazard ratio upper v. lowest quartile (HR(Q4 v. Q1)) 1·00, 95% CI 0·88, 1·13), cancer (HR(Q4 v. Q1) 1·02, 95% CI 0·86, 1·21) or CVD (HR(Q4 v. Q1) 1·04, 95 % CI 0·83, 1·30). Bacterial fermented foods mainly consisted of fermented dairy foods (78 %) and cheese (16%). None of the subtypes of fermented foods was consistently related to mortality, except for cheese which was moderately inversely associated with CVD mortality, and particularly stroke mortality (HR(Q4 v. Q1) 0·59, 95% CI 0·38, 0·92, P trend= 0·046). In conclusion, the present study provides no strong evidence that intake of fermented foods, particularly fermented dairy foods, is associated with mortality.

Intake of phytosterols from natural sources and risk of cardiovascular disease in the European Prospective Investigation into Cancer and Nutrition-the Netherlands (EPIC-NL) population.

BACKGROUND: Phytosterols (PSs) are known to lower low-density lipoprotein cholesterol (LDL-C), an established risk factor for cardiovascular disease (CVD). Whether a high intake of PS reduces CVD risk is unknown. This observational study aimed to investigate the associations between intake of naturally occurring PSs, blood lipids and CVD risk. METHODS: The study included 35,597 Dutch men and women, participating in the European Prospective Investigation into Cancer and Nutrition-the Netherlands (EPIC-NL) study. At baseline, intakes of naturally occurring PSs were estimated with a validated food frequency questionnaire and non-fasting blood lipids were measured. Occurrence of CVD, coronary heart disease (CHD) and myocardial infarction (MI) was determined through linkage with registries. RESULTS: The average energy-adjusted PS intake at baseline was 296 mg/d (range: 83-966 mg/d). During 12.2 years of follow-up, 3047 CVD cases (8.6%) were documented. After adjustment for confounders, PS intake was not associated with risk of CVD, CHD or MI (p-value trend > 0.05); hazard ratios ranged from 0.90-0.99 for CVD, from 0.83-0.90 for CHD and from 0.80-0.95 for MI risk across quintiles of PS intake and were almost all non-significant. Higher PS intake was associated with lower total cholesterol (-0.06 mmol/l per 50 mg/d; p-value = 0.038) and lower LDL-C (-0.07 mmol/l; p-value = 0.007), particularly among men. In mediation analysis, LDL-C did not materially affect the association between PS intake and CVD risk. CONCLUSIONS: In this population with a relatively narrow range of low naturally occurring PS intakes, intake of PS was not associated with reduced CVD risk despite lower LDL-C concentrations in men.

Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women.

Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification. Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). In high-risk populations, high total uncarboxylated MGP (t-ucMGP) was associated with decreased CAC, while high non-phosphorylated uncarboxylated MGP (dp-ucMGP) was associated with a poor vitamin K status. This cross-sectional study investigated the association of MGP species with CAC, vitamin K status among 200 healthy women. Circulating dp-ucMGP, t-ucMGP and, non-phosphorylated carboxylated MGP (dp-cMGP) levels were measured by ELISA techniques and Agatston score by multi-detector computed tomography. The ratio of uncarboxylated to carboxylated osteocalcin was used as proxy of vitamin K status. A borderline significant (P=.06) association between higher circulating dp-ucMGP levels and high CAC was observed (ß=0.091, 95% CI-0.01; 0.19). In the entire study population, high t-ucMGP levels tended to be associated (P=.09) with lower CAC (ß=-0.36, 95% CI:-0.78; 0.06). This association strengthened amongst women with CAC to a significant relation between high t-ucMGP levels and lower CAC (ß=-0.55, 95% CI-1.01;-0.10). Dp-cMGP was not associated with CAC. Low vitamin K-status was associated with high dp-ucMGP concentrations (ß=0.138, 95% CI 0.09; 0.19) but not with other MGP species. These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed.