Sanne Roels

Sleep fragmentation and periodic limb movements in children with monosymptomatic nocturnal enuresis and polyuria

BackgroundChildren with nocturnal enuresis (NE) have been found to have sleep fragmentation and a high incidence of periodic limb movements in sleep (PLMS). This study explored the association of monosymptomatic NE and polyuria in relation to fluid intake, bladder volume, number of wet nights, and number of nights with polyuria to the frequency of PLMS and cortical arousals during sleep.Materials and methodsThirty children with monosymptomatic NE and polyuria were enrolled in the study. Enuretic parameters were determined by diaries, forced drinking, uroflow, and ultrasound examination. All subjects participated in one polysomnographic study. The number of cortical arousals and PLMS were compared with those recorded in a former pilot study which included only children with refractory NE.ResultsOf the 30 children who participated in the study, the mean age was 10.43 ± 3.08 (range 6–16) years, and 23 were boys. The PLMS index was positively associated with the arousal index and the awakening index (p < 0.001). No significant association between the sleep and the enuretic parameters was found. Children with refractory NE showed a significantly higher PLMS index (p < 0.001).ConclusionsWe found that PLMS and cortical arousals in sleep were increased in children with monosymptomatic NE and polyuria, without a significant association with the enuretic parameters. These observations suggest the presence of a comorbid mechanism driven by a common, independent pacemaker. We hypothesize the autonomic system, its sympathetic branch, and the dopaminergic system as candidates for this pacemaker.

Neuropsychological functioning related to specific characteristics of nocturnal enuresis

INTRODUCTION/BACKGROUND There is a high comorbidity demonstrated in the literature between nocturnal enuresis and several neuropsychological dysfunctions, with special emphasis on attention deficit hyperactivity disorder (ADHD). However, the majority of the psychological studies did not include full non-invasive screening and failed to differentiate between monosymptomatic nocturnal enuresis (MNE) and non-MNE patients. OBJECTIVE The present study primarily aimed to investigate the association between nocturnal enuresis and (neuro)psychological functioning in a selective homogeneous patient group, namely: children with MNE and associated nocturnal polyuria (NP). Secondly, the study investigated the association between specific characteristics of nocturnal enuresis (maximum voided volume, number of wet nights and number of nights with NP) and ADHD-inattentive symptoms, executive functioning and quality of life. STUDY DESIGN The psychological measurements were multi-informant (parents, children and teachers) and multi-method (questionnaires, clinical interviews and neuropsychological testing). RESULTS Thirty children aged 6-16 years (mean 10.43 years, SD 3.08) were included. Of them, 80% had at least one psychological, motor or neurological difficulty. The comorbid diagnosis of ADHD, especially the predominantly inattentive presentation, was most common. According to the teachers, a low maximum voided volume (corrected for age) was associated with more attention problems, and a high number of nights with NP was associated with more behaviour-regulation problems. No significant correlations were found between specific characteristics of enuresis and quality of life. Details are demonstrated in Table. DISCUSSION The children were recruited from a tertiary referral centre, which resulted in selection bias. Moreover, NP was defined as a urine output exceeding 100% of the expected bladder capacity for age (EBC), and not according to the expert-opinion-based International Childrens Continence Society norm of 130% of EBC. The definition for NP of a urine output exceeding 100% of the EBC is more in line with the recent findings of the Aarhus group. CONCLUSIONS For children with MNE and associated NP, a high comorbidity with the predominantly inattentive presentation of ADHD was demonstrated. Children experienced problems with daytime functioning in relation to their wetting problem at night. According to the teachers, a low maximum voided volume was associated with more attention problems, and a high number of nights with NP was associated with more behaviour-regulation problems. Although comorbidity is still the appropriate word to use, the observation favours a more complex pathogenesis of enuresis with a common pathway in the central nervous system, including: neurotransmitters, influencing neuropsychological functioning as well as sleep, circadian rhythm of diuresis and bladder function control.

Desmopressin (melt) therapy in children with monosymptomatic nocturnal enuresis and nocturnal polyuria results in improved neuropsychological functioning and sleep

BackgroundThere is a high comorbidity between nocturnal enuresis, sleep disorders and psychological problems. The aim of this study was to investigate whether a decrease in nocturnal diuresis volume not only improves enuresis but also ameliorates disrupted sleep and (neuro)psychological dysfunction, the major comorbidities of this disorder.MethodsIn this open-label, prospective phase IV study, 30 children with monosymptomatic nocturnal enuresis (MNE) underwent standardized video-polysomnographic testing and multi-informant (neuro)psychological testing at baseline and 6 months after the start of desmopressin treatment in the University Hospital Ghent, Belgium. Primary endpoints were the effect on sleep and (neuro)psychological functioning. The secondary endpoint was the change in the first undisturbed sleep period or the time to the first void.ResultsThirty children aged between 6 and 16 (mean 10.43, standard deviation 3.08) years completed the study. The results demonstrated a significant decrease in periodic limb movements during sleep (PLMS) and a prolonged first undisturbed sleep period. Additionally, (neuro)psychological functioning was improved on several domains.ConclusionsThe study demonstrates that the degree of comorbidity symptoms is at least aggravated by enuresis (and/or high nocturnal diuresis rate) since sleep and (neuro)psychological functioning were significantly ameliorated by treatment of enuresis. These results indicate that enuresis is not such a benign condition as has previously been assumed.

Microbial diversity and metabolite composition of Belgian red-brown acidic ales

Belgian red-brown acidic ales are sour and alcoholic fermented beers, which are produced by mixed-culture fermentation and blending. The brews are aged in oak barrels for about two years, after which mature beer is blended with young, non-aged beer to obtain the end-products. The present study evaluated the microbial community diversity of Belgian red-brown acidic ales at the end of the maturation phase of three subsequent brews of three different breweries. The microbial diversity was compared with the metabolite composition of the brews at the end of the maturation phase. Therefore, mature brew samples were subjected to 454 pyrosequencing of the 16S rRNA gene (bacteria) and the internal transcribed spacer region (yeasts) and a broad range of metabolites was quantified. The most important microbial species present in the Belgian red-brown acidic ales investigated were Pediococcus damnosus, Dekkera bruxellensis, and Acetobacter pasteurianus. In addition, this culture-independent analysis revealed operational taxonomic units that were assigned to an unclassified fungal community member, Candida, and Lactobacillus. The main metabolites present in the brew samples were L-lactic acid, D-lactic acid, and ethanol, whereas acetic acid was produced in lower quantities. The most prevailing aroma compounds were ethyl acetate, isoamyl acetate, ethyl hexanoate, and ethyl octanoate, which might be of impact on the aroma of the end-products.

Bootstrapping fMRI Data: Dealing with Misspecification

The validity of inference based on the General Linear Model (GLM) for the analysis of functional magnetic resonance imaging (fMRI) time series has recently been questioned. Bootstrap procedures that partially avoid modeling assumptions may offer a welcome solution. We empirically compare two voxelwise GLM-based bootstrap approaches: a semi-parametric approach, relying solely on a model for the expected signal; and a fully parametric bootstrap approach, requiring an additional parameterization of the temporal structure. While the fully parametric approach assumes independent whitened residuals, the semi-parametric approach relies on independent blocks of residuals. The evaluation is based on inferential properties and the potential to reproduce important data characteristics. Different noise structures and data-generating mechanisms for the signal are simulated. When the model for the noise and expected signal is correct, we find that the fully parametric approach works well, with respect to both inference and reproduction of data characteristics. However, in the presence of misspecification, the fully parametric approach can be improved with additional blocking. The semi-parametric approach performs worse than the (fully) parametric approach with respect to inference but achieves comparable results as the parametric approach with additional blocking with respect to image reproducibility. We demonstrate that when the expected signal is incorrect GLM-based bootstrapping can overcome the poor performance of classical (non-bootstrap) parametric inference. We illustrate both approaches on a study exploring the neural representation of object representation in the visual pathway.

Data-analytical stability of cluster-wise and peak-wise inference in fMRI data analysis.

BACKGROUND Carp (2012) demonstrated the large variability that is present in the method sections of fMRI studies. This methodological variability between studies limits reproducible research. NEW METHOD Evaluation protocols for methods used in fMRI should include data-analytical stability measures quantifying the variability in results following choices in the methods. Data-analytical stability can be seen as a proxy for reproducibility. To illustrate how one can perform such evaluations, we study two competing approaches for topological feature based inference (random field theory and permutation based testing) and two competing methods for smoothing (Gaussian smoothing and adaptive smoothing). We compare these approaches from the perspective of data-analytical stability in real data, and additionally consider validity and reliability in simulations. RESULTS There is clear evidence that choices in the methods impact the validity, reliability and stability of the results. For the particular comparison studied, we find that permutation based methods render the most valid results. For stability and reliability, the performance of different smoothing and inference types depends on the setting. However, while being more reliable, adaptive smoothing can evoke less stable results when using larger kernel width, especially with cluster size based permutation inference. COMPARISON WITH EXISTING METHODS While existing evaluation methods focus on validity and reliability, we show that data-analytical stability enables to further distinguish between performance of different methods. CONCLUSION Data-analytical stability is an important additional criterion that can easily be incorporated in evaluation protocols.

Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients

Background and aim Numerous outcome studies and interventional trials in hemodialysis (HD) patients are based on uremic toxin concentrations determined at one single or a limited number of time points. The reliability of these studies however entirely depends on how representative these cross-sectional concentrations are. We therefore investigated the variability of predialysis concentrations of uremic toxins over time. Methods Prospectively collected predialysis serum samples of the midweek session of week 0, 1, 2, 3, 4, 8, 12, and 16 were analyzed for a panel of uremic toxins in stable chronic HD patients (N = 18) while maintaining dialyzer type and dialysis mode during the study period. Results Concentrations of the analyzed uremic toxins varied substantially between individuals, but also within stable HD patients (intra-patient variability). For urea, creatinine, beta-2-microglobulin, and some protein-bound uremic toxins, Intra-class Correlation Coefficient (ICC) was higher than 0.7. However, for phosphorus, uric acid, symmetric and asymmetric dimethylarginine, and the protein-bound toxins hippuric acid and indoxyl sulfate, ICC values were below 0.7, implying a concentration variability within the individual patient even exceeding 65% of the observed inter-patient variability. Conclusion Intra-patient variability may affect the interpretation of the association between a single concentration of certain uremic toxins and outcomes. When performing future outcome and interventional studies with uremic toxins other than described here, one should quantify their intra-patient variability and take into account that for solutes with a large intra-patient variability associations could be missed.

Evaluation of second-level inference in fMRI analysis

We investigate the impact of decisions in the second-level (i.e., over subjects) inferential process in functional magnetic resonance imaging on (1) the balance between false positives and false negatives and on (2) the data-analytical stability, both proxies for the reproducibility of results. Second-level analysis based on a mass univariate approach typically consists of 3 phases. First, one proceeds via a general linear model for a test image that consists of pooled information from different subjects. We evaluate models that take into account first-level (within-subjects) variability and models that do not take into account this variability. Second, one proceeds via inference based on parametrical assumptions or via permutation-based inference. Third, we evaluate 3 commonly used procedures to address the multiple testing problem: familywise error rate correction, False Discovery Rate (FDR) correction, and a two-step procedure with minimal cluster size. Based on a simulation study and real data we find that the two-step procedure with minimal cluster size results in most stable results, followed by the familywise error rate correction. The FDR results in most variable results, for both permutation-based inference and parametrical inference. Modeling the subject-specific variability yields a better balance between false positives and false negatives when using parametric inference.

Multiple testing in fMRI: an empirical case study on the balance between sensitivity, specificity, and stability

Functional Magnetic Resonance Imaging is a widespread technique in cognitive psychology that allows visualizing brain activation. The data analysis encompasses an enormous number of simultaneous statistical tests. Procedures that either control the familywise error rate or the false discovery rate have been applied to these data. These methods are mostly validated in terms of average sensitivity and specificity. However, procedures are not comparable if requirements on their error rates differ. Moreover, less attention has been given to the instability or variability of results. In a simulation study in the context of imaging, we first compare the Bonferroni and Benjamini-Hochberg procedures. Considering Bonferroni as a way to control the expected number of type I errors enables more lenient thresholding compared to familywise error rate control and a direct comparison between both procedures. We point out that while the same balance is obtained between average sensitivity and specificity, the Benjamini-Hochberg procedure appears less stable. Secondly, we have implemented the procedure of Gordon et al. () (originally proposed for gene selection) that includes stability, measured through bootstrapping, in the decision criterion. Simulations indicate that the method attains the same balance between sensitivity and specificity. It improves the stability of Benjamini-Hochberg but does not outperform Bonferroni, making this computationally heavy bootstrap procedure less appealing. Third, we show how stability of thresholding procedures can be assessed using real data. In a dataset on face recognition, we again find that Bonferroni renders more stable results.

Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population

Background Chronic kidney disease (CKD) in childhood is poorly explained by routine markers (e.g. urea and creatinine) and is better depicted in adults by other uraemic toxins. This study describes concentrations of representative uraemic toxins in non-dialysis CKD versus healthy children. Methods In 50 healthy children and 57 children with CKD Stages 1-5 [median estimated glomerular filtration rate 48 (25th-75th percentile 24-71) mL/min/1.73 m2; none on dialysis], serum concentrations of small solutes [symmetric and asymmetric dimethyl-arginine (SDMA and ADMA, respectively)], middle molecules [β2-microglobuline (β2M), complement factor D (CfD)] and protein-bound solutes [p-cresylglucuronide (pCG), hippuric acid (HA), indole-acetic acid (IAA), indoxyl sulphate (IxS), p-cresyl sulphate (pCS) and 3-carboxy-4-methyl-5-propyl-furanpropionic acid (CMPF)] were measured. Concentrations in the CKD group were expressed as z-score relative to controls and matched for age and gender. Results SDMA, CfD, β2M, IxS, pCS, IAA, CMPF and HA concentrations were higher in the overall CKD group compared with controls, ranging from 1.7 standard deviations (SD) for IAA and HA to 11.1 SD for SDMA. SDMA, CfD, β2M, IxS and CMPF in CKD Stages 1-2 with concentrations 4.8, 2.8, 4.5, 1.9 and 1.6 SD higher, respectively. In contrast, pCS, pCG and IAA concentrations were only higher than controls from CKD Stages 3-4 onwards, but only in CKD Stage 5 for ADMA and HA (z-score 2.6 and 20.2, respectively). Conclusions This is the first study to establish reference values for a wide range of uraemic toxins in non-dialysis CKD and healthy children. We observed an accumulation of multiple uraemic toxins, each with a particular retention profile according to the different CKD stages.