Cerebellar volumes and language functions in school-aged children born very preterm.

BACKGROUND: Volumes of cerebellar posterior lobes have been associated with cognitive skills, such as language functioning. Children born very preterm (VPT) often have language problems. However, only total cerebellar volume has been associated with language functioning, with contradicting results. The objective of this study was to ascertain whether total cerebellar structures or specific posterior lobular structures are associated with language ability of school-aged VPT children. METHODS: This is a prospective cohort study of 42 school-aged VPT children without major handicaps. Structural MRI was performed and the cerebellum segmentation pipeline was used for segmentation of separate lobules. Narrative retelling assessment was performed and language content and language structure scores were extracted. Linear regression analyses were used to associate language scores with whole gray matter (GM) cerebellar volume and right Crus I+II GM volume. RESULTS: Whole cerebellar GM volume was not significantly associated with language content nor with language structure; however, right Crus I+II GM volume was significantly associated with language content (ß = 0.192 (CI = 0.033, 0.351), p = 0.020). CONCLUSIONS: GM volume of Crus I+II appears to be associated with language functions in school-aged VPT children without major handicaps, while whole cerebellar volume is not. This study showed the importance of studying cerebellar lobules separately, rather than whole cerebellar volume only, in relation to VPT children's language functions. IMPACT: GM volume of Crus I+II is associated with semantic language functions in school-aged very preterm children without overt brain injury, whereas whole cerebellar volume is not. This study showed the importance of studying cerebellar lobules separately, rather than whole cerebellar volume only, in relation to very preterm children's language functions. This study might impact future research in very preterm children. Lobular structures rather than whole cerebellar structures should be the region of interest in relation to language functions.

The Prognostic Role of ß-Catenin Mutations in Desmoid-type Fibromatosis Undergoing Resection Only: A Meta-analysis of Individual Patient Data.

OBJECTIVE: This meta-analysis (PROSPERO CRD42018100653) uses individual patient data (IPD) to assess the association between recurrence and CTNNB1 mutation status in surgically treated adult desmoid-type fibromatosis (DTF) patients. SUMMARY OF BACKGROUND DATA: The majority of sporadic DTF tumors harbor a CTNNB1 (ß-catenin) mutation: T41A, S45F, and S45P or are wild-type (WT). Results are conflicting regarding the recurrence risk after surgery for these mutation types. METHODS: A systematic literature search was performed on June 6th, 2018. IPD from eligible studies was used to analyze differences in recurrence according to CTNNB1 mutation status using Cox proportional hazards analysis. Predictive factors included: sex, age, mutation type, tumor site, tumor size, resection margin status, and cohort. The PRISMA-IPD guideline was used. RESULTS: Seven studies, describing retrospective cohorts were included and the IPD of 329 patients were used of whom 154 (46.8%) had a T41A mutation, 66 (20.1%) a S45F mutation, and 24 (7.3%) a S45P mutation, whereas 85 (25.8%) patients had a WT CTNNB1. Eighty-three patients (25.2%) experienced recurrence. Multivariable analysis, adjusting for sex, age, and tumor site yielded a P-value of 0.011 for CTNNB1 mutation. Additional adjustment for tumor size yielded a P-value of 0.082 with hazard ratio's of 0.83 [95% confidence interval (CI) 0.48-1.42), 0.37 (95% CI 0.12-1.14), and 0.44 (95% CI 0.21-0.92) for T41A, S45P and WT DTF tumors compared to S45F DTF tumors. The effect modification between tumor size and mutation type suggests that tumor size is an important mediator for recurrence. CONCLUSIONS: Primary sporadic DTFs harboring a CTNNB1 S45F mutation have a higher risk of recurrence after surgery compared to T41A, S45P, and WT DTF, but this association seems to be mediated by tumor size.

Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy.

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.

Prenatal markers and longitudinal follow-up in simple and complex gastroschisis.

OBJECTIVE: We aimed to identify gestational-age corrected prenatal ultrasound markers of complex gastroschisis, and to compare physical growth and neurodevelopment between children with simple and complex gastroschisis. DESIGN: We included prenatally diagnosed gastroschisis patients from 2000 to 2012 who joined our longitudinal follow-up programme. Associations between complex gastroschisis and prenatal ultrasound markers collected at 30 weeks' gestation and prior to delivery were tested using logistic regression. Physical growth (SD scores (SDS)), mental and psychomotor developmental index (MDI, PDI; Bayley Scales of Infant Development) were recorded at 12 and 24 months. Data were analysed using general linear models and compared with population norms. RESULTS: Data of 61 children were analysed (82% of eligible cases). Extra-abdominal bowel dilatation at 30 weeks' gestation was significantly associated with complex gastroschisis (OR (95% CI): 5.00 (1.09 to 22.98)), with a high negative (88%) but low positive (40%) predictive value. The mean (95% CI) height SDS at 12 months (-0.46 (-0.82 to -0.11)), and weight SDS at 12 and 24 months (-0.45 (-0.85 to -0.05), and -0.44 (-0.87 to -0.01), respectively) fell significantly below 0 SDS. MDI and PDI were significantly below 100 at 24 months; 93 (88 to 99) and 83 (78 to 87), respectively). Children with complex gastroschisis had a significantly lower PDI (76 (68 to 84)) than those with simple gastroschisis (94 (90 to 97), p<0.001). CONCLUSIONS: Prenatal ultrasound markers could not reliably distinguish between simple and complex gastroschisis. Children with complex gastroschisis may be at increased risk for delayed psychomotor development; they should be monitored more closely, and offered timely intervention.

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. METHODS AND ANALYSIS: The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. ETHICS: Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.

Bayesian hierarchical modeling of longitudinal glaucomatous visual fields using a two-stage approach.

The Bayesian approach has become increasingly popular because it allows to fit quite complex models to data via Markov chain Monte Carlo sampling. However, it is also recognized nowadays that Markov chain Monte Carlo sampling can become computationally prohibitive when applied to a large data set. We encountered serious computational difficulties when fitting an hierarchical model to longitudinal glaucoma data of patients who participate in an ongoing Dutch study. To overcome this problem, we applied and extended a recently proposed two-stage approach to model these data. Glaucoma is one of the leading causes of blindness in the world. In order to detect deterioration at an early stage, a model for predicting visual fields (VFs) in time is needed. Hence, the true underlying VF progression can be determined, and treatment strategies can then be optimized to prevent further VF loss. Because we were unable to fit these data with the classical one-stage approach upon which the current popular Bayesian software is based, we made use of the two-stage Bayesian approach. The considered hierarchical longitudinal model involves estimating a large number of random effects and deals with censoring and high measurement variability. In addition, we extended the approach with tools for model evaluation. Copyright © 2017 John Wiley & Sons, Ltd.

Dealing with missing covariates in epidemiologic studies: a comparison between multiple imputation and a full Bayesian approach.

Incomplete data are generally a challenge to the analysis of most large studies. The current gold standard to account for missing data is multiple imputation, and more specifically multiple imputation with chained equations (MICE). Numerous studies have been conducted to illustrate the performance of MICE for missing covariate data. The results show that the method works well in various situations. However, less is known about its performance in more complex models, specifically when the outcome is multivariate as in longitudinal studies. In current practice, the multivariate nature of the longitudinal outcome is often neglected in the imputation procedure, or only the baseline outcome is used to impute missing covariates. In this work, we evaluate the performance of MICE using different strategies to include a longitudinal outcome into the imputation models and compare it with a fully Bayesian approach that jointly imputes missing values and estimates the parameters of the longitudinal model. Results from simulation and a real data example show that MICE requires the analyst to correctly specify which components of the longitudinal process need to be included in the imputation models in order to obtain unbiased results. The full Bayesian approach, on the other hand, does not require the analyst to explicitly specify how the longitudinal outcome enters the imputation models. It performed well under different scenarios. Copyright © 2016 John Wiley & Sons, Ltd.