Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: linking blood levels to weight gain and effectiveness

Aims: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. Methods: Twenty-four children and adolescents (15 males, 9 females) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM (R)) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. Results: For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P New methods for child psychiatric diagnosis and treatment outcome evaluatio

Exploring imaging features of molecular subtypes of large cell neuroendocrine carcinoma (LCNEC)

Objectives: Radiological characteristics and radiomics signatures can aid in differentiation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). We investigated whether molecular subtypes of large cell neuroendocrine carcinoma (LCNEC), i.e. SCLC-like (with pRb loss) vs. NSCLC-like (with pRb expression), can be distinguished by imaging based on (1) imaging interpretation, (2) semantic features, and/or (3) a radiomics signature, designed to differentiate between SCLC and NSCLC. Materials and Methods: Pulmonary oncologists and chest radiologists assessed chest CT-scans of 44 LCNEC patients for ‘small cell-like’ or ‘non-small cell-like’ appearance. The radiologists also scored semantic features of 50 LCNEC scans. Finally, a radiomics signature was trained on a dataset containing 48 SCLC and 76 NSCLC scans and validated on an external set of 58 SCLC and 40 NSCLC scans. This signature was applied on scans of 28 SCLC-like and 8 NSCLC-like LCNEC patients. Results: Pulmonary oncologists and radiologists were unable to differentiate between molecular subtypes of LCNEC and no significant differences in semantic features were found. The area under the receiver operating characteristics curve of the radiomics signature in the validation set (SCLC vs. NSCLC) was 0.84 (95% confidence interval (CI) 0.77-0.92) and 0.58 (95% CI 0.29-0.86) in the LCNEC dataset (SCLC-like vs. NSCLC-like). Conclusion: LCNEC appears to have radiological characteristics of both SCLC and NSCLC, irrespective of pRb loss, compatible with the SCLC-like subtype. Imaging interpretation, semantic features and our radiomics signature designed to differentiate between SCLC and NSCLC were unable to separate molecular LCNEC subtypes, which underscores that LCNEC is a unique disease

Netwerkrichtlijn kindermishandeling en huiselijk geweld in Limburg

In the netherlands partners of the network acute care of the province of limburg, the advice and reporting centre for child abuse and neglect, and the regional centre for domestic violence have launched a network guideline in august 2012. The network guideline aims for strengthening collaboration and information transfer between organisations in the network, to improve the care for the child and the parents. The interconnections between the different partners were defined and minimal criteria for information transfer were formulated. Individual partners remained responsible for their own protocol on child abuse and domestic violence. Evaluation of the network guideline in 2013 showed a more active participation of the partners in the management of child abuse. Information transfer between partners showed great improvements. However, further optimization of the information transfers are needed together with agreements about the approach to domestic violence

Unique Metastatic Patterns in Neuroendocrine Neoplasms of Different Primary Origin

Introduction: Neuroendocrine neoplasms (NEN) can originate in different organs, for example, the gastroenteral tract (GE), pancreas (Pan), or lungs (L). Our aim was to examine metastatic patterns for patients with NEN of various primary origins with a special focus on brain metastases to indicate utility for screening. Methods: All NEN patients except for small cell lung cancer registered in the Netherlands Cancer Registry from 2008 to 2018 were selected. Metastatic patterns at initial diagnosis for NEN with different primary origins were compared. In a subcohort of patients from 2 referral hospitals (2014-2019), additional information on, for example, development of metastases after initial presentation was available. Results: In the nationwide cohort, 4,768/11,120 (43%) patients had metastatic disease at diagnosis (GE: 1,504/4,710 [32%]; Pan: 489/1,150 [43%]; and L: 1,230/2,978 [41%]). For GE- and Pan-NEN, the most prevalent metastatic site was the liver (25 and 39%), followed by distant lymph nodes (8 and 8%), whereas only few patients with brain metastases were identified (0% in both). In contrast, for L-NEN, prevalence of metastases in the liver (19%), brain (9%), lung (7%), and bone (14%) was more equal. In the reference network cohort, slightly more NEN patients had metastatic disease (260/539, 48%) and similar metastatic patterns were observed. Conclusion: Almost half of NEN patients were diagnosed with synchronous metastatic disease. L-NEN have a unique metastatic pattern compared to GE- and Pan-NEN. Remarkably, an important part of L-NEN metastases was in the brain, whereas brain metastases were almost absent in GE- and Pan-NEN, indicating utility of screening in L-NEN