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Introduction: Patients participating in randomized controlled trials (RCTs) are susceptible to a wide range of different adverse events (AE) during the RCT. MedDRA® is a hierarchical standardization terminology to structure the AEs reported in an RCT. The lowest level in the MedDRA hierarchy is a single medical event, and every higher level is the aggregation of the lower levels. Method: We propose a multi-stage Bayesian hierarchical Poisson model for estimating MedDRA-coded AE rate ratios (RRs). To deal with rare AEs, we introduce data aggregation at a higher level within the MedDRA structure and based on thresholds on incidence and MedDRA structure. Results: With simulations, we showed the effects of this data aggregation process and the method's performance. Furthermore, an application to a real example is provided and compared with other methods. Conclusion: We showed the benefit of using the full MedDRA structure and using aggregated data. The proposed model, as well as the pre-processing, is implemented in an R-package: BAHAMA.

Background and aims: Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. In clinical practice, Lp(a) is mostly measured only once assuming that it does not change with age nor vary within individuals. This is mainly based on adult data and data on Lp(a) levels during childhood is scarce. Therefore, we evaluated whether Lp(a) levels changed with age and determined the intra-individual variation of Lp(a) in a large cohort of children. Methods: We collected all Lp(a) measurements of children referred to the pediatric lipid clinic of the Amsterdam UMC between 1989 and 2017. The association between Lp(a) and age, as well as the intra-individual variation of Lp(a), was assessed using mixed models. We stratified for lipid-lowering medication use. Results: In total, we included 2740 children. From the age of 8 years onwards, mean Lp(a) increased with 22% in children that reached adulthood without lipid-lowering medication (n = 2254). In statin-users (n = 418) and children that used ezetimibe additionally (n = 65), Lp(a) increased with 43% and 9%, respectively. The intra-individual variation of Lp(a) was 70%. Conclusions: Lp(a) levels increase with age and exhibit considerable variation within children referred to a lipid clinic. Measuring Lp(a) only once during childhood might therefore lead to substantial over- or underestimation and possibly result in over- or under treatment in the future. Thus, to more accurately assess the Lp(a) level, we suggest measuring Lp(a) more than once during childhood and to repeat this in adulthood if a patient only has childhood assessment of Lp(a).

Background: Statins are the primary therapy in patient with heterozygous familial hypercholesterolemia (HeFH). Non-adherence to statin therapy is associated with increased cardiovascular risk. Objective: We constructed a dynamic prediction model to predict statin adherence for an individual HeFH patient for each upcoming statin prescription. Methods: All patients with HeFH, identified by the Dutch Familial Hypercholesterolemia screening program between 1994 and 2014, were eligible. National pharmacy records dated between 1995 and 2015 were linked. We developed a dynamic prediction model that estimates the probability of statin adherence (defined as proportion of days covered >80%) for an upcoming prescription using a mixed effect logistic regression model. Static and dynamic patient-specific predictors, as well as data on a patient's adherence to past prescriptions were included. The model with the lowest AIC (Akaike Information Criterion) value was selected. Results: We included 1094 patients for whom 21,171 times a statin was prescribed. Based on the model with the lowest AIC, age at HeFH diagnosis, history of cardiovascular event, time since HeFH diagnosis and duration of the next statin prescription contributed to an increased adherence, while adherence decreased with higher untreated LDL-C levels and higher intensity of statin therapy. The dynamic prediction model showed an area under the curve of 0.63 at HeFH diagnosis, which increased to 0.85 after six years of treatment. Conclusion: This dynamic prediction model enables clinicians to identify HeFH patients at risk for non-adherence during statin treatment. These patients can be offered timely interventions to improve adherence and further reduce cardiovascular risk.

Background Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms. Methods Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity. Results Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R2 = 0.05, p = 0.04, CpG 32: pseudo-R2 = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R2 = 0.03, p = 0.00, CpG 24: pseudo-R2 = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R2 = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R2: 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations. Conclusions This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms.

INTRODUCTION: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations.METHODS: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites.RESULTS: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = -0.3, p < 0.01), depression (rs = -0.3, p < 0.01) and fatigue (rs = -0.2, p = 0.04).CONCLUSION: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.

Background Milk feeding type (exclusive breastfeeding [EBF], formula feeding or mixed feeding) and timing of complementary feeding (CF) have been associated with infant growth. However, studies evaluating their combined role, and the role of ethnicity, are scarce. We examined associations of feeding patterns (milk feeding type combined with timing of CF) with infant body mass index (BMI) trajectories and potential ethnic-specific associations. Methods Infant feeding and BMI data during the 1st year of life from 3524 children (Dutch n = 2880, Moroccan n = 404 and Turkish n = 240) from the Amsterdam Born Children and their Development (ABCD) cohort were used. Six feeding patterns were defined: EBF/earlyCF, EBF/lateCF (reference), formula/earlyCF, formula/lateCF, mixed/earlyCF and mixed/lateCF. A covariate adjusted latent class mixed model was applied to simultaneously model BMI trajectories and associations with feeding patterns. Potential ethnic differences in the associations were studied in a separate model where interactions between ethnicity and feeding patterns were included. Results Four distinct BMI trajectories (low, mid-low, mid-high and high) were identified. Feeding pattern of formula/earlyCF was associated with lower odds for low (OR: 0.43; 95% CI: 0.25, 0.76) or mid-high (0.28; 0.16, 0.51) (ref: high) trajectory compared with EBF/lateCF pattern (ref). An ethnic-specific model revealed that among Dutch infants, formula/earlyCF pattern was associated with lower odds for low trajectory (0.46; 0.24, 0.87), whereas among Turkish/Moroccan infants almost all feeding patterns were associated with lower odds for the low trajectory (ref: high). Conclusion Infant feeding patterns are associated with early BMI trajectories with specific ethnic differences. Future studies should take the role of ethnicity into account in the associations between infant feeding and growth.

Background: Evidence on long-term dupilumab treatment for atopic dermatitis in daily practice is lacking. Objective: To investigate patient characteristics, treatment aspects, effectiveness, and safety of up to 84 weeks of dupilumab treatment. Methods: An observational prospective cohort study was conducted of patients with atopic dermatitis starting dupilumab in routine clinical care. Results: Of the 221 included patients, 103 used systemic therapy at baseline. At 84 weeks, we found a change of −15.2 (SE, 1.7) for the Eczema Area and Severity Index, −16.9 (SE, 1.4) for the Patient-Oriented Eczema Measure, and −17.2 (SE, 1.6) for the Dermatology Life Quality Index. We found a trend for improvement over time for the Investigator Global Assessment and Numerical Rating Scale for pruritus. Severe (n = 79) including serious (n = 11) adverse events were observed in 69 patients. Eye complaints were most frequently reported (n = 46). Twenty-one patients adjusted the regular dosing schedule, and 14 patients discontinued treatment, mainly due to ineffectiveness (n = 7). Limitations: Only adverse events of severe and serious nature were registered for feasibility reasons. Conclusion: Daily practice dupilumab treatment of up to 84 weeks is generally well-tolerated, apart from the reporting of eye complaints. It can be considered a long-term effective treatment for atopic dermatitis in combination with topical and initial concomitant systemic treatment, showing a sustained improvement of signs, symptoms, and quality of life.

Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.

Background Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited success is the selection of participants. Studies generally include sporadically long-lived individuals, i.e. individuals with the longevity phenotype but without a genetic predisposition for longevity. The inclusion of these individuals causes phenotype heterogeneity which results in power reduction and bias. A way to avoid sporadically long-lived individuals and reduce sample heterogeneity is to include family history of longevity as selection criterion using a longevity family score. A main challenge when developing family scores are the large differences in family size, because of real differences in sibship sizes or because of missing data. Methods We discussed the statistical properties of two existing longevity family scores: the Family Longevity Selection Score (FLoSS) and the Longevity Relatives Count (LRC) score and we evaluated their performance dealing with differential family size. We proposed a new longevity family score, the mLRC score, an extension of the LRC based on random effects modeling, which is robust for family size and missing values. The performance of the new mLRC as selection tool was evaluated in an intensive simulation study and illustrated in a large real dataset, the Historical Sample of the Netherlands (HSN). Results Empirical scores such as the FLOSS and LRC cannot properly deal with differential family size and missing data. Our simulation study showed that mLRC is not affected by family size and provides more accurate selections of long-lived families. The analysis of 1105 sibships of the Historical Sample of the Netherlands showed that the selection of long-lived individuals based on the mLRC score predicts excess survival in the validation set better than the selection based on the LRC score . Conclusions Model-based score systems such as the mLRC score help to reduce heterogeneity in the selection of long-lived families. The power of future studies into the genetics of longevity can likely be improved and their bias reduced, by selecting long-lived cases using the mLRC.

STUDY QUESTION Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228–338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84–117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with ‘male factor’ as treatment indication (compared to ‘tubal factor’). LIMITATIONS, REASONS FOR CAUTION Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER N/A.

IntroductionPeople of South Asian origin are at high risk of type 2 diabetes (T2D), but the underpinning mechanisms are not fully understood. We determined ethnic differences in acylcarnitine, amino acid and sphingolipid concentrations and determined the associations with T2D.Research design and methodsAssociations between these metabolites and incident T2D among Dutch and South-Asian Surinamese were determined in participants from the Healthy Life in an Urban Setting (HELIUS) study (Amsterdam, the Netherlands) using Prentice-weighted Cox regression. The HELIUS study includes 95 incident T2D cases and a representative subcohort of 700 people from a cohort of 5977 participants with a mean follow-up of 4 years.ResultsConcentrations of acylcarnitines were comparable between both ethnic groups. Amino acid and lactosylceramide concentrations were higher among South-Asian Surinamese than Dutch (eg, isoleucine 65.7 (SD 16.3) vs 60.7 (SD 15.6) µmol/L). Ceramide concentrations were lower among South-Asian Surinamese than Dutch (eg, Cer d18:1 8.48 (SD 2.04) vs 9.08 (SD 2.29) µmol/L). Metabolic dysregulation preceded T2D without evidence for a multiplicative interaction by ethnicity. Most amino acids and (dihydro)ceramides were associated with increased risk (eg, Cer d18:1 HR 2.38, 95% CI 1.81 to 3.12) while acylcarnitines, glycine, glutamine and lactosylceramides were associated with decreased risk for T2D (eg, LacCer d18:2 HR 0.56, 95% CI 0.42 to 0.77).ConclusionsOverall, these data suggest that the disturbances underlying amino acid and sphingolipid metabolism may be predictive of T2D risk in populations of both South Asian and European background. These observations may be used as starting point to unravel the underlying metabolic disturbances.

Our aim was to identify whether low-grade inflammation, reflected by C-reactive protein (CRP), explains the higher risk for incident type 2 diabetes (T2D) among ethnic minorities. We included 837 Dutch, 712 South-Asian Surinamese, 797 African Surinamese, 804 Ghanaian, 817 Turkish and 778 Moroccan origin participants of the HELIUS study (Amsterdam, the Netherlands). We used multiple linear regression to assess ethnic differences in CRP levels. We determined the association of CRP with T2D and the modifying effect of ethnicity by cox regression, and compared hazard ratios for the association between ethnicity and T2D before and after adjustment for CRP. CRP levels were higher in ethnic minority groups than in Dutch origin participants. CRP was associated with a higher T2D incidence, similarly across ethnic groups (overall HR per SD 1.38 [95% CI 1.14; 1.68]). However, the association was attenuated and no longer statistically significant after adjustment for adiposity measures (HR 1.11 [95% CI 0.90; 1.37]). CRP accounted for a very small part of the ethnic differences in T2D, but only in models unadjusted for adiposity. Low-grade inflammation does not substantially contribute to the higher risk of T2D among ethnic minority populations compared to the Dutch.

BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite.OBJECTIVE: To provide health care professionals with contemporary age- and gender-based pediatric reference values for lipid and lipoprotein levels to help the identification of children with dyslipidemia, especially FH.METHODS: Lifelines is a large prospective population-based Dutch cohort study. Children from 8 till 18 years of age were included and fasting lipid levels were measured. Smoothed reference curves and percentiles (5th, 10th, 25th, 50th, 7th, 90th, and 95th) were generated using the Generalized Additive Models for Location, Scale and Shape package in the statistical software R.RESULTS: A total of 8071 children (3823 boys and 4248 girls) were included. In the total cohort we noted marked dynamic changes in lipid and lipoprotein levels over age, which were in part gender specific. Our data highlight a high and unexpected prevalence of severely elevated LDL-c (>190 mg/dL) in both boys and girls.CONCLUSION: Our cross-sectional data provide contemporary reference ranges for plasma lipids that can assist physicians in identifying children at increased risk of premature atherosclerosis, especially FH. (C) 2018 National Lipid Association. Published by Elsevier Inc.

Background Maternal pre-pregnancy overweight is known to program offspring for adverse health outcomes later in life. Aims To investigate how growth patterns of weight, height and BMI from birth to 7 years differ according to maternal pre-pregnancy weight (normal weight, overweight and obesity), with specific attention for sex differences. Study design Prospective multi-ethnic ABCD-study. Subjects 3805 mother-child pairs were included. Self-reported maternal pre-pregnancy body mass index was categorized into: normal weight (18.5–25 kg/m 2 ; n = 3354), overweight (25–30 kg/m 2 ; n = 711) and obesity (≥ 30 kg/m 2 ; n = 241). Outcome measures Population-specific growth patterns were used to compute SD-scores for weight, height and BMI (on average 12.7 (SD = 2.6) measurements for each child) for term born boys and girls separately. Mixed effect models were fitted to these SD-scores to determine the effect of pre-pregnancy BMI category on postnatal growth, corrected for maternal characteristics. Results Compared to children of mothers with normal weight before pregnancy, children of overweight mothers grew faster in weight and BMI (boys and girls) and children of obese mothers grew faster in height (only girls), weight and BMI (boys and girls) during the first years of life. The differences seemed to increase with age and were in general larger in girls. Conclusion Maternal overweight and obesity impact on offspring's weight, height and BMI growth pattern with increasing differences when children age. Effects were in general stronger for girls. These results suggest that a healthy weight before pregnancy may be beneficial for optimal weight, height and BMI growth in the offspring.

Introduction Children from minority groups are at increased risk of overweight. This study compared BMI growth patterns from birth onwards of boys and girls with overweight at 5-6 years, according to socioeconomic status (SES) and country of origin, in order to gain more insight into the critical periods of growth to overweight. Methods A total of 3714 singletons of the multi-ethnic ABCD study were included. Within children with overweight at age 5-6 years (N = 487, prevalence boys: 11.6%, girls: 14.6%), BMI growth patterns from birth onwards (12.8 serial measurements; SD = 3.1) were compared between children from European (69.4%) and non-European mothers (30.6%), and between children from low (20.8%), mid (37.0%) or high SES (42.2%), based on maternal educational level. Results BMI growth to overweight did not differ between children of European or non-European mothers, but it did differ according to maternal SES. Children with overweight in the low and mid SES group had a lower BMI in the first 2 years of life, an earlier adiposity rebound and increased in BMI more rapidly after age 2, resulting in a higher BMI at age 7 years compared to children with overweight in the high SES group [∆BMI (kg/m2 ) between high and low SES: boys 1.43(95%CI:0.16;3.01) and girls 1.91(0.55;3.27)]. Conclusion Children with overweight from low SES have an early adiposity rebound and accelerated growth to a higher BMI at age 5-6 years compared to children with overweight from the high SES group. These results imply that timing of critical periods for overweight development is earlier in children with a low socioeconomic background as compared to other children.

BACKGROUND Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce. METHODS We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. RESULTS Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter)-a decrease of 32% from the baseline level; treatment goals (LDL cholesterol

Background Antenatal detection of intrauterine growth restriction remains a major obstetrical challenge, with the majority of cases not detected before birth. In these infants with undetected intrauterine growth restriction, the diagnosis must be made after birth. Clinicians use birthweight charts to identify infants as small-for-gestational-age if their birthweights are below a predefined threshold for gestational age. The choice of birthweight chart strongly affects the classification of small-for-gestational-age infants and has an impact on both research findings and clinical practice. Despite extensive literature on pathological risk factors associated with small-for-gestational-age, controversy exists regarding the exclusion of affected infants from a reference population. Objective This study aims to identify pathological risk factors for abnormal fetal growth, to quantify their effects, and to use these findings to calculate prescriptive birthweight charts for the Dutch population. Materials and Methods We performed a retrospective cross-sectional study, using routinely collected data of 2,712,301 infants born in The Netherlands between 2000 and 2014. Risk factors for abnormal fetal growth were identified and categorized in 7 groups: multiple gestation, hypertensive disorders, diabetes, other pre-existing maternal medical conditions, maternal substance (ab)use, medical conditions related to the pregnancy, and congenital malformations. The effects of these risk factors on mean birthweight were assessed using linear regression. Prescriptive birthweight charts were derived from live-born singleton infants, born to ostensibly healthy mothers after uncomplicated pregnancies and spontaneous onset of labor. The Box-Cox-t distribution was used to model birthweight and to calculate sex-specific percentiles. The new charts were compared to various existing birthweight and fetal-weight charts. Results We excluded 111,621 infants because of missing data on birthweight, gestational age or sex, stillbirth, or a gestational age not between 23 and 42 weeks. Of the 2,599,640 potentially eligible infants, 969,552 (37.3%) had 1 or more risk factors for abnormal fetal growth and were subsequently excluded. Large absolute differences were observed between the mean birthweights of infants with and without these risk factors, with different patterns for term and preterm infants. The final low-risk population consisted of 1,629,776 live-born singleton infants (50.9% male), from which sex-specific percentiles were calculated. Median and 10th percentiles closely approximated fetal-weight charts but consistently exceeded existing birthweight charts. Conclusion Excluding risk factors that cause lower birthweights results in prescriptive birthweight charts that are more akin to fetal-weight charts, enabling proper discrimination between normal and abnormal birthweight. This proof of concept can be applied to other populations.

Hintergrund Die Resistenz von uropathogenen Bakterien gegenuber den ublichen Antibiotika ist erheblich – v. a. im Alter.

Lebende Mikroorganismen, darunter das Hepatitis-E-Virus, Listerien, Toxoplasmen und eine Reihe anderer Erreger, in diversen Nahrungsmitteln sind in der Lage, eine Schwangere zu infizieren. Konnen diese Erreger die Plazentabarriere uberwinden, kann auch der Fetus direkt betroffen sein. Daruber hinaus besteht ein Risiko fur die Gesundheit der Mutter und des Kindes durch diverse Mykotoxine, wie etwa Ochratoxin, Fumonisin, Aflatoxin und Zearalenon, in Lebensmitteln pflanzlichen sowie tierischen Ursprungs.

Background: Socioeconomically disadvantaged children often have psychosocial problems. This study examined the mediating role of maternal depressive symptoms during pregnancy, infancy and early childhood in the association between maternal education, as indicator of socioeconomic status (SES), and child's psychosocial problems. Methods: Included were 3410 children from the Amsterdam Born Children and their Development (ABCD) study. To assess the child's psychosocial problems at age 5-6 years, mothers and teachers completed the Strengths and Difficulties Questionnaire (SDQ). Maternal depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and the Depressive Anxiety and Stress Scale 21. Mediation analysis was performed to calculate the direct effect of maternal education on SDQ score and indirect effects through maternal depressive symptoms. Results: The mean mother-reported SDQ total score was significantly higher (P < 0.001) for children of low-educated mothers (6.74 ± 4.41) compared with children of highly educated mothers (4.47 ± 3.73). Levels of maternal depressive symptoms were also higher in low-educated mothers during pregnancy, infancy and early childhood. Maternal depressive symptoms explained 27.5% of the association between maternal education and mother-reported SDQ scores and 22.9% for combined mother/teacher SDQ scores. Maternal depressive symptoms during pregnancy had the strongest indirect effect. Conclusion: Maternal depressive symptoms during pregnancy mediate the association between low maternal education and child's psychosocial problems. Early recognition and treatment of maternal depressive symptoms is important to prevent psychosocial problems in children, especially in those with low education.

Introduction Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen). Materials and methods We assessed the accuracy of the models’ predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1 h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated. Results With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52–4.19 mg/L with the Bos model, 1.42–4.04 mg/L with the Mumtaz model, and 1.81–4.31 mg/L with the Jongeneelen model compared to 0.27–5.44 mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4–2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels. Conclusions The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.

Redundancy Analysis (RDA) is a well‐known method used to describe the directional relationship between related data sets. Recently, we proposed sparse Redundancy Analysis (sRDA) for high‐dimensional genomic data analysis to find explanatory variables that explain the most variance of the response variables. As more and more biomolecular data become available from different biological levels, such as genotypic and phenotypic data from different omics domains, a natural research direction is to apply an integrated analysis approach in order to explore the underlying biological mechanism of certain phenotypes of the given organism. We show that the multiset sparse Redundancy Analysis (multi‐sRDA) framework is a prominent candidate for high‐dimensional omics data analysis since it accounts for the directional information transfer between omics sets, and, through its sparse solutions, the interpretability of the result is improved. In this paper, we also describe a software implementation for multi‐sRDA, based on the Partial Least Squares Path Modeling algorithm. We test our method through simulation and real omics data analysis with data sets of 364,134 methylation markers, 18,424 gene expression markers, and 47 cytokine markers measured on 37 patients with Marfan syndrome.

The ascomycetous yeast Cyberlindera fabianii is not only present in the environment, but is also occasionally pathogenic. Especially, neonates seem to be prone to infection. Here, we describe a case of peritoneal infection of a neonate after congenital heart surgery. The correct identification of this peculiar species is made by MALDI-TOF and especially by molecular biology methods, whereas the standard biochemical identification methods fail.The neonate with a hypoplastic left heart syndrome had a Norwood palliation followed by transient ECMO therapy for 3 days. The patient developed a renal insufficiency, so that peritoneal dialysis was initiated. After a few days, a peritoneal infection due to C. fabianii emerged. The proper source of this rare and particular yeast remains obscure. In spite of a reasonable antimycotic therapy, the patient developed a capillary leak syndrome and died finally in septic shock with multiorgan failure. One reason is probably that the yeast population, which was highly susceptible to all common antimycotic drugs at the beginning of therapy with fluconazole (and for a short period with caspofungin and liposomal amphotericin B), became rapidly resistant.

Motivation Recent technological developments have enabled the possibility of genetic and genomic integrated data analysis approaches, where multiple omics datasets from various biological levels are combined and used to describe (disease) phenotypic variations. The main goal is to explain and ultimately predict phenotypic variations by understanding their genetic basis and the interaction of the associated genetic factors. Therefore, understanding the underlying genetic mechanisms of phenotypic variations is an ever increasing research interest in biomedical sciences. In many situations, we have a set of variables that can be considered to be the outcome variables and a set that can be considered to be explanatory variables. Redundancy analysis (RDA) is an analytic method to deal with this type of directionality. Unfortunately, current implementations of RDA cannot deal optimally with the high dimensionality of omics data (p≫n). The existing theoretical framework, based on Ridge penalization, is suboptimal, since it includes all variables in the analysis. As a solution, we propose to use Elastic Net penalization in an iterative RDA framework to obtain a sparse solution. Results We proposed sparse redundancy analysis (sRDA) for high dimensional omics data analysis. We conducted simulation studies with our software implementation of sRDA to assess the reliability of sRDA. Both the analysis of simulated data, and the analysis of 485 512 methylation markers and 18,424 gene-expression values measured in a set of 55 patients with Marfan syndrome show that sRDA is able to deal with the usual high dimensionality of omics data. Availability and implementation http://uva.csala.me/rda. Supplementary information Supplementary data are available at Bioinformatics online.

In the absence of a unique identifier, combining information from multiple files relies on partially identifying variables (e.g., gender, initials). With a record linkage procedure, these variables are used to distinguish record pairs that belong together (matches) from record pairs that do not belong together (nonmatches). Generally, the combined strength of the partially identifying variables is too low causing imperfect linkage; some true nonmatches are identified as match and, on the other hand, some true matches as nonmatch. To avoid bias in further analyses, it is necessary to correct for imperfect linkage. In this article, pregnancy data from the Perinatal Registry of the Netherlands were used to estimate the associations between the (baseline) characteristics from the first delivery and the time to a second delivery. Because of privacy regulations, no unique identifier was available to determine which pregnancies belonged to the same woman. To deal with imperfect linkage in a time-to-event setting, where we have a file with baseline characteristics and a file with event times, we developed a joint model in which the record linkage procedure and the time-to-event analysis are performed simultaneously. R code and example data are available as online supplemental material

Objective We assessed, in women with a previous spontaneous preterm birth, the effect of interpregnancy interval on the subsequent preterm birth rate. Design Retrospective cohort study. Setting A nationwide longitudinal dataset of the the Netherlands Perinatal Registry. Population Women with three sequential singleton pregnancies between 1999 and 2009 and a spontaneous preterm birth

Combining information from two data sources depends on finding records that belong to the same individual (matches). Sometimes, unique identifiers per individual are not available, and we have to rely on partially identifying variables that are registered in both data sources. A risk of relying on these variables is that some records from both datasets are wrongly linked to each other, which introduces bias in further regression analyses. In this paper, we propose a mixture model where we treat the indicator whether records belong to the same individual as missing. Each pair of records from both datasets contributes independently to a pairwise pseudo-likelihood, which we maximize with an expectation-maximization algorithm. Each part of the pseudo-likelihood is parameterized by the appropriate (parametric) density function. Moreover, some structures of the data allow for simplifying assumptions, which makes the pseudo-likelihood considerably easier to parameterize. Because the optimization requires a product over all combinations of records from both datasets, we suggest a procedure that summarizes information from highly unlikely matches. With simulations, we showed that the new approach produces accurate estimates in different linkage scenarios. Moreover, the estimator remained accurate in scenarios where previously proposed analysis approaches give biased results. We applied the method to estimation of the association between pregnancy duration of the first and second born children from the same mother from a register without mother identifier.

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.

Gerade bei Frauen uber 60 Jahre treten Harnwegsinfektionen sehr oft auf. E. coli ist der haufigste Erreger, seine Resistenz gegenuber Chinolonen wachst standig und erreicht bei Frauen >80 Jahren bereits eine Rate von ca. 30%. Die Nebenwirkungen der Chinolone, wie QT-Zeit-Verlangerung, Tendopathien und ZNS-Storungen, sind im Alter besonders haufig. Ferner verursachen Chinolone Kollateralschaden mit erheblichen Folgen. In Schweis und in Schleimhautsekreten treten sie hoch konzentriert auf, konnen die empfindliche autochthone Flora storen und den Weg fur multiresistente Staphylokokken (MRSA) bahnen. Insgesamt sind Chinolone also wenig fur die Therapie von Harnwegsinfektionen der alteren Frau geeignet. Alternative Medikamente sind Cephalosporine und vor allem Fosfomycin; gerade fur letzteres wurden kurzlich Einschrankungen, namlich Alter >65 Jahre und Kreatininclearance

Als typische Opportunisten infizieren Pilze, z. B. Pneumocystis jirovecii, hauptsachlich abwehrgeschwachte Personen. Aber einige Pilze, wie z. B. Coccidioides immitis und Cryptococcus neoformans, bedrohen auch Abwehrtuchtige. Pilze werden in der deutschen Leitlinie zur ambulant erworbenen Pneumonie als mogliche Erreger gar nicht erwahnt. In der deutschen Leitlinie fur nosokomiale Infektionen werden Pilze – aber auch nur wenige, namlich Aspergillus und Candida – kurz gestreift. Zumindest aber bei schweren Verlaufen von Pneumonien und besonders bei Patienten mit Komorbiditaten, die auf die ubliche antibakterielle Therapie nicht ansprechen, muss man als Differenzialdiagnose an Pilze denken.

Alte Menschen haben eine hohe Anfalligkeit gegen Pneumokokken. Eine Datensammlung von Laborergebnisse aus Deutschland in den Jahren 2005–2010 belegt, dass eine Infektion mit diesen Bakterien gerade bei Senioren haufig noch durch eine bedrohliche Sepsis erschwert wird. Frauen sind offensichtlich weniger betroffen. Die Mehrzahl der Infektionen trat wahrend der Wintermonate auf. Ein Grosteil, namlich ca. 80% aller Isolate, gehoren zu denjenigen Serovarietaten, die im 23-valenten Polysaccharidimpfstoff enthalten sind, ca. 70% aller Isolate sind im 13-valenten Konjugatimpfstoff enthalten. Folglich hatten solche schwerwiegende Komplikationen, die mit langen Aufenthaltsdauern auf Intensivstationen und mit einer hohen Mortalitat einhergehen, vermieden werden konnen, wenn die alten Menschen vorher geimpft worden waren, was aber nur fur einen kleinen Teil (28%) zutrifft. Vor Kurzem wurde ein neuer konjugierter Impfstoff zugelassen. Fur eine antibiotische Therapie stehen im Grunde viele Medikamente zur Verfugung: Cefotaxim und Ceftriaxon sind in Deutschland eigentlich immer, zumindest in vitro, wirksam. Resistenzen gegen Penicillin und Ampicillin sind ganz selten. Auch gegen Chinolone, wie Levofloxacin und Moxifloxacin, sind die Isolate fast ausnahmslos empfindlich. Gegen Makrolide, wie Erythromycin, sind einige Isolate resistent; aber in den letzten Jahren nimmt die Haufigkeit stetig ab. Dennoch kommt in vielen Fallen diese Therapie zu spat. Deshalb ware Pravention sehr wichtig.

Resistance of uropathogenic bacteria against the common antibiotics is considerable-especially in the elderly.In Germany nitroxoline is licensed for the treatment of acute urinary tract infections and for prophylaxis of recurrent infections. What is the actual resistance pattern of uropathogenic bacteria?The in vitro susceptibility of 477 uropathogenic bacteria from patients in 2015 was determined by means of the agar diffusion method.Obviously, this agent is still active against the vast majority of uropathogenic bacteria and in particular against strains of Escherichia coli (E. coli). Pseudomonas aeruginosa and enterococci are not really within the spectrum of nitroxoline. One has to keep in mind, however, that even among E. coli and other enterobacteriaceae there are single resistant isolates. This applies in particular to problem strains resistant to many other antibiotics.Nitroxoline is a reasonable alternative and a promising option for calculated treatment of urinary tract infections-especially of the elderly, although this drug is not recommended in the current guideline. Laboratory testing of clinical isolates should be requested-at least when treatment fails.

Yeasts are found in urine specimens relatively often, especially in the elderly and patients under treatment with broad spectrum antibiotics, i. e. especially in intensive care unit (ICU) patients. In some cases, the number of pathogens is very high, i. e.10The antimicrobial agents suitable for therapy of candiduria are limited, namely flucytosine, amphotericin B, which is also used for irrigation and fluconazole.The in vitro effect of nitroxoline on 100 isolates of yeasts from urine was tested by an agar diffusion test.Nitroxoline exerted a good activity against all yeast isolates.The antibiotic nitroxoline has a good antifungal activity. It achieves high concentrations in urine and in addition, it is effective at low pH as well as against pathogens in biofilms, which most antimycotics cannot achieve. Hence, nitroxoline is suitable for termination of candiduria. Foreign bodies in the urinary tract, on which biofilms are formed, should be removed whenever possible.

Die Haufigkeit der Kolonisierung von Patientinnen mit resistenten Bakterien wie MRSA (methicillinresistenter Staphylococus aureus), VRE („vancomycin resistant enterococci“) und 3/4-MRGN(multiresistente Gram-negative)-Enterobakteriazeen (darunter auch die „extended spectrum β-lactamase“, ESBL, bildenden) ist betrachtlich, vor allem in bestimmten Risikopopulationen (etwa Altere, haufig Hospitalisierte und einigen Auslanderinnen). Wahrend die Pravalenz der Kolonisation mit MRSA in den letzten Jahren etwas abnimmt, steigt die Kolonisierung mit VRE bzw. multiresistenten Enterobakteriazeen standig an. Cephalosporine der zweiten Generation, wie Cefazolin und Cefuroxim, die bislang meistens zur perioperativen Prophylaxe eingesetzt werden, sind in solchen Fallen ungeeignet, postoperative Wundinfektionen oder schwerere Komplikationen zu verhindern. Heute ist also ganz dezidiert je nach den potenziellen Erregern eines der zahlreichen Antibiotika auszuwahlen, um das Ergebnis der perioperativen Prophylaxe zu optimieren.

Please cite this paper as: Schaaf J, Hof M, Mol B, Abu-Hanna A, Ravelli A. Recurrence risk of preterm birth in subsequent twin pregnancy after preterm singleton delivery.BJOG 2012;119:1624–1629. Objective To determine the risk of preterm birth in a subsequent twin pregnancy after previous singleton preterm birth. Design Cohort study. Setting Nationwide study in the Netherlands. Population In all, 4071 nulliparous women who had a singleton delivery followed by a subsequent twin delivery between the years 1999 and 2007 were studied. Methods Outcome of subsequent twin pregnancy of women with a history of preterm singleton delivery was compared with pregnancy outcome of women with a history of term singleton delivery. First deliveries were subdivided into iatrogenic and spontaneous preterm deliveries. Furthermore analyses were performed by subgroups for gestational age at the time of singleton delivery. Main outcome measure Spontaneous preterm birth (

In record linkage studies, unique identifiers are often not available, and therefore, the linkage procedure depends on combinations of partially identifying variables with low discriminating power. As a consequence, wrongly linked covariate and outcome pairs will be created and bias further analysis of the linked data. In this article, we investigated two estimators that correct for linkage error in regression analysis. We extended the estimators developed by Lahiri and Larsen and also suggested a weighted least squares approach to deal with linkage error. We considered both linear and logistic regression problems and evaluated the performance of both methods with simulations. Our results show that all wrong covariate and outcome pairs need to be removed from the analysis in order to calculate unbiased regression coefficients in both approaches. This removal requires strong assumptions on the structure of the data. In addition, the bias significantly increases when the assumptions do not hold and wrongly linked records influence the coefficient estimation. Our simulations showed that both methods had similar performance in linear regression problems. With logistic regression problems, the weighted least squares method showed less bias. Because the specific structure of the data in record linkage problems often leads to different assumptions, it?is necessary that the analyst has prior knowledge on the nature of the data. These assumptions are more easily introduced in the weighted least squares approach than in the Lahiri and Larsen estimator. Copyright (c) 2012 John Wiley & Sons, Ltd