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We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome. [ABSTRACT FROM AUTHOR]

Background: Depression is common among older adults and is typically treated with antidepressants.Objective: To determine the non-adherence rates to antidepressants among older adults in primary care, based on non-initiation, suboptimal implementation or non-persistence.Methods: We selected all patients aged ≥60 years and diagnosed with depression in 2012, from the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Non-initiation was defined as no dispensing within 14 days of the first prescription; suboptimal implementation, as fewer than 80% of the days covered by dispensed dosages; and non-persistence, as discontinuation within 294 days after first dispense. First, we determined the antidepressant non-initiation, suboptimal implementation and non-persistence rates. Second, we examined whether comorbidity and chronic drug use were associated with non-adherence by mixed-effects logistic regression (non-initiation or suboptimal implementation as dependent variables) and a clustered Cox regression (time to non-persistence).Results: Non-initiation, suboptimal implementation and non-persistence rates were 13.5%, 15.2% and 37.1%, respectively. As the number of chronically used drugs increased, the odds of suboptimal implementation (odds ratio, 0.89; 95% confidence interval, 0.83-0.95) and of non-persistence (hazard ratio, 0.87; 95% confidence interval, 0.82-0.92) reduced.Conclusions: Non-adherence to antidepressants is high among older patients with depression in primary care settings. Adherence is better when patients are accustomed to taking larger numbers of prescribed drugs, but this only provides partial explanation of the variance. GPs should be aware of the high rates of non-adherence. Emphasizing the importance of adhering to the optimal length of antidepressant therapy might be prudent first steps to improving adherence. [ABSTRACT FROM AUTHOR]

Abstract: Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo‐ to ganglio‐series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self‐contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo‐series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate‐limiting ganglioside‐producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo–AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology. [ABSTRACT FROM AUTHOR]

Background: Late-life depression often coincides with chronic somatic diseases and, consequently, with polypharmacy, which may complicate medical treatment.Objective: To determine the associations between patients diagnosed with late-life depression in primary care and multimorbidity and polypharmacy.Methods: This cross-sectional observational study was performed using 2012 primary care data. Depressed patients aged ≥60 years were compared to age and gender matched patients diagnosed with other psychological diagnoses and mentally healthy controls. Morbidity and prescription data were combined, and regression analyses were performed for the associations between depression and chronic disease and chronic drug use.Results: We included 4477 patients; 1512 had a record of depression, 1457 of other mental health or psychological diagnoses and 1508 were controls. Depressed patients had a 16% [Prevalence Ratio (PR) 1.16; 95% confidence interval (95% CI) 10%-24%] higher rate of chronic somatic disease and higher odds for multimorbidity (OR 1.55; 95% CI 1.33-1.81) compared with controls. No differences existed between depressed patients and patients with other psychological diagnoses. Compared with controls, depressed patients had a 46% (95% CI 39-53%) higher rate of chronic drug use and higher odds for polypharmacy (OR 2.89; 95% CI 2.41-3.47). Depressed patients also had higher rates of chronic drug use and higher odds for polypharmacy compared with patients with other psychological diagnoses (PR 1.26; OR 1.75; both P < 0.001).Conclusions: Late-life depression in primary care patients is associated with more chronic drug use, even beyond the increased rates of comorbid somatic diseases. General practitioners should consider medication reviews to prevent unnecessary drug-related problems in these patients. [ABSTRACT FROM AUTHOR]

Compiling syllable type inventories from children's spontaneous speech is all but straightforward: so far studies vary considerably in their methodologies and consequently the selection of the speech samples differs. This paper shows that different methodologies for selecting a speech sample lead to substantial differences in syllable inventories. Two main sources for this variation are explored: differences in size and content of the speech samples. Both factors influence the results significantly and this questions the comparability of previous study results. An empirical procedure to investigate syllable type development is proposed to overcome such methodological problems, and this procedure is implemented to provide an initial empirically sound assessment of the acquisition of syllable types in Dutch speaking toddlers. [ABSTRACT FROM AUTHOR]

In this study, we examine students' educational attitudes upon the transition to Dutch senior vocational education (SVE), a transition associated with high dropout rates in the first year. Prior studies have identified differences in educational attitudes between sociodemographic groups. However, the mechanisms underlying those differences remain topic of debate: some studies point at differences in the school orientation and support in students' social communities outside school, others focus on differences in educational experiences between sociodemographic groups. Multilevel sequential regression analyses on a diverse sample of 1438 students in urban SVE schools reveal that students have very positive educational attitudes upon their transition to SVE. Ethnic minority students express particularly positive attitudes. School-related encouragement and support at home plays an important role in students' attitudes, but the attitudes of students from lower educated or ethnic minority communities are less related to this support. Prior school experiences play an essential, but occasionally counterproductive, role in students' attitudes upon transition, depicting the transition as a fresh new start for some, and an unwelcome threshold for others. [ABSTRACT FROM AUTHOR]