Chest MRI to diagnose early diaphragmatic weakness in Pompe disease

Background: In Pompe disease, an inherited metabolic muscle disorder, severe diaphragmatic weakness often occurs. Enzyme replacement treatment is relatively ineffective for respiratory function, possibly because of irreversible damage to the diaphragm early in the disease course. Mildly impaired diaphragmatic function may not be recognized by spirometry, which is commonly used to study respiratory function. In this cross-sectional study, we aimed to identify early signs of diaphragmatic weakness in Pompe patients using chest MRI. Methods: Pompe patients covering the spectrum of disease severity, and sex and age matched healthy controls were prospectively included and studied using spirometry-controlled sagittal MR images of both mid-hemidiaphragms during forced inspiration. The motions of the diaphragm and thoracic wall were evaluated by measuring thoracic cranial-caudal and anterior–posterior distance ratios between inspiration and expiration. The diaphragm shape was evaluated by measuring the height of the diaphragm curvature. We used multiple linear regression analysis to compare different groups. Results: We included 22 Pompe patients with decreased spirometry results (forced vital capacity in supine position < 80% predicted); 13 Pompe patients with normal spirometry results (forced vital capacity in supine position ≥ 80% predicted) and 18 healthy controls. The mean cranial-caudal ratio was only 1.32 in patients with decreased spirometry results, 1.60 in patients with normal spirometry results and 1.72 in healthy controls (p < 0.001). Anterior–posterior ratios showed no significant differences. The mean height ratios of the diaphragm curvature were 1.41 in patients with decreased spirometry results, 1.08 in patients with normal spirometry results and 0.82 in healthy controls (p = 0.001), indicating an increased curvature of the diaphragm during inspiration in Pompe patients. Conclusions: Even in early-stage Pompe disease, when spirometry results are still within normal range, the motion of the diaphragm is already reduced and the shape is more curved during inspiration. MRI can be used to detect early signs of diaphragmatic weakness in patients with Pompe disease, which might help to select patients for early intervention to prevent possible irreversible damage to the diaphragm

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Linking Mother–Child Discrepancies to Behavioral Observations of Children’s Anxiety

Background Informant discrepancies between mother and child have challenged the assessment, classification, and treatment of childhood anxiety. Despite numerous studies on this matter, the implications and consequences for research and clinical practice remain unclear. Objective The present study aimed to obtain meaningful clinical information about informant discrepancies by examining mother–child agreement for anxiety subtypes, and by exploring mother–child discrepancies in relation to independent observer ratings of behavioral anxiety. Method The screen for child anxiety related emotional disorders was administered to 79 mothers and clinically referred anxious children aged 7–13 years. Mother–child dyads were observed during an anxiety-provoking task and independent observers rated children’s observed anxiety. Results The findings indicated a high level of mother–child disagreement on reports of anxiety. There was variability in levels of agreement between subtypes of anxiety, with significantly stronger mother–child agreement for separation compared to other forms of anxiety. Observed proximity between the mother and child was positively associated with child-reported separation anxiety and children’s observed anxious voice was negatively associated with child-reported panic disorder. Conclusions The results highlight the need to incorporate a multi-informant assessment of childhood anxiety in clinical practice and research, in particular for subtypes of anxiety problems that are characterized by less observable and more internally experienced components

Linking Mother–Child Discrepancies to Behavioral Observations of Children’s Anxiety

Background Informant discrepancies between mother and child have challenged the assessment, classification, and treatment of childhood anxiety. Despite numerous studies on this matter, the implications and consequences for research and clinical practice remain unclear. Objective The present study aimed to obtain meaningful clinical information about informant discrepancies by examining mother–child agreement for anxiety subtypes, and by exploring mother–child discrepancies in relation to independent observer ratings of behavioral anxiety. Method The screen for child anxiety related emotional disorders was administered to 79 mothers and clinically referred anxious children aged 7–13 years. Mother–child dyads were observed during an anxiety-provoking task and independent observers rated children’s observed anxiety. Results The findings indicated a high level of mother–child disagreement on reports of anxiety. There was variability in levels of agreement between subtypes of anxiety, with significantly stronger mother–child agreement for separation compared to other forms of anxiety. Observed proximity between the mother and child was positively associated with child-reported separation anxiety and children’s observed anxious voice was negatively associated with child-reported panic disorder. Conclusions The results highlight the need to incorporate a multi-informant assessment of childhood anxiety in clinical practice and research, in particular for subtypes of anxiety problems that are characterized by less observable and more internally experienced components

Measuring Anxiety in Children : The Importance of Separate Mother and Father Reports

Background Previous research suggests that it is important to use parental reports when assessing children’s anxiety, but it remains unclear to what extent there are differences between mothers’ and fathers’ scores and whether these potential differences have any repercussions for the psychometric properties of the scale being used. Objective This study was conducted to investigate parental differences on the Parent version of the Screen for Child Anxiety Related Emotional Disorders-Revised (SCAREDRP), a rating scale for measuring child anxiety symptoms. The second aim was to reexamine the reliability and validity of the SCARED-RP, in light of these possible differences. Methods The SCARED-RP and the Child Behaviour Checklist (CBCL) were administered to parents of clinically anxious children (n = 81), and control children (n = 108). All children (n = 189) completed the SCARED-R. Results Significant correlations between mother and father reports were found within the clinically anxious sample. Mothers showed significantly more correspondence with their children in the control group than fathers. The SCARED-RP internal consistency on total scale was excellent (mothers: .94; fathers: .94) and moderate to good for all subscales (from .66 Situational-Environmental Phobia to .93 Animal Phobia). The SCARED-RP differentiated well between clinically anxious and control children (mother and father data). The concurrent validity was supported by strong correlations with the CBCL anxious-depressed scale. Conclusion Differences between mother and father reports suggest the importance of obtaining information from both parents separately. Furthermore, the SCARED-RP is a useful instrument for assessing children’s anxiety disorder symptoms in clinical and research settings

Measuring Anxiety in Children : The Importance of Separate Mother and Father Reports

Background Previous research suggests that it is important to use parental reports when assessing children’s anxiety, but it remains unclear to what extent there are differences between mothers’ and fathers’ scores and whether these potential differences have any repercussions for the psychometric properties of the scale being used. Objective This study was conducted to investigate parental differences on the Parent version of the Screen for Child Anxiety Related Emotional Disorders-Revised (SCAREDRP), a rating scale for measuring child anxiety symptoms. The second aim was to reexamine the reliability and validity of the SCARED-RP, in light of these possible differences. Methods The SCARED-RP and the Child Behaviour Checklist (CBCL) were administered to parents of clinically anxious children (n = 81), and control children (n = 108). All children (n = 189) completed the SCARED-R. Results Significant correlations between mother and father reports were found within the clinically anxious sample. Mothers showed significantly more correspondence with their children in the control group than fathers. The SCARED-RP internal consistency on total scale was excellent (mothers: .94; fathers: .94) and moderate to good for all subscales (from .66 Situational-Environmental Phobia to .93 Animal Phobia). The SCARED-RP differentiated well between clinically anxious and control children (mother and father data). The concurrent validity was supported by strong correlations with the CBCL anxious-depressed scale. Conclusion Differences between mother and father reports suggest the importance of obtaining information from both parents separately. Furthermore, the SCARED-RP is a useful instrument for assessing children’s anxiety disorder symptoms in clinical and research settings

Multicenter Analytical Validation of Aβ40 Immunoassays

BACKGROUND Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-β peptide 1-42 and 1-40 (Aβ42/Aβ40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aβ40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine. METHODS Aβ40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays. RESULTS Most performance parameters of the different Aβ40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter-laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes. CONCLUSION All validated Aβ40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice

Effectiveness of a cognitive-behavioral therapy (CBT) manualized program for clinically anxious children: Study protocol of a randomized controlled trial.

Background: In the Netherlands, the prevalence of anxiety disorders is 20%; and children with anxiety are at increased risk for psychopathology throughout adulthood. Recently, a revised version of a cognitive behavioral therapy manualized program called ‘Thinking + Doing = Daring’ (TDD) was developed for children between 8 and 12 years old with an anxiety disorder. The main aim of this project is to conduct a Randomized Controlled Trial (RCT) to evaluate the effectiveness of TDD. Methods/Design: The CBT program will be tested with a RCT with 120 clinically anxious children (8-12 years old) referred to one of three mental health care agencies. Children will be randomly assigned to the experimental (N = 60, TDD) or to the control condition (N = 60, treatment as usual). The primary outcome measure will be the child’s anxiety symptoms level. Secondary outcome measures will be externalizing (e.g. aggression) and internalizing problems (e.g. depression). Two potential mediators of change will be examined in the current study: therapeutic alliance and parenting. Mother and child in both the experimental and control condition will be surveyed at baseline, post treatment and after 6 and 12 months (follow-up). It is hypothesized that children in the experimental condition will show a stronger decrease in anxiety symptoms compared to children that receive treatment as usual. Moreover, we expect that a strong therapeutic alliance and decreases in parental control and rejection will contribute to treatment success. Discussion: Early treatment for anxiety problems has the potential to not only result in anxiety reductions, but also to prevent future problems such as substance abuse and psychopathology throughout adulthood. Our results will be immediately relevant to practice, since we are partnering with ‘real world’ community agencies. If the CBT program proves more effective than treatment as usual, it could be implemented in community mental health care agencies across the Netherlands and beyond. Moreover, it has the potential to make treatment in these community settings shorter, more efficient and therefore cost-effective. Trial registration: Nederlands Trial Register NTR2967 (PsycINFO Database Record (c) 2016 APA, all rights reserved