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Land subsidence in areas with weak soils affects a large part of the Netherlands and causes many problems. To solve them diverse and specialized knowledge of possible measures to prevent, mitigate or reverse land subsidence is needed. This knowledge is fragmented over many agencies, companies and individuals. Here we show how data and knowledge are related and we stress the importance of implicit knowledge for knowledge transfer on land subsidence. It is demonstrated that land subsidence in the Netherlands is a “wicked problem”. This makes its solution cumbersome. However, we show that self-learning digital environments can help considerably in knowledge acquisition, storage and retrieval. We give an inventory of research questions that have still to be answered to make an digital environment really effective for a wicked problem like land subsidence.

FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The assessment of risk factors, including mediolateral episiotomy (MLE), for the recurrence of obstetric anal sphincter injury (rOASI)., Design: Population-based cohort study., Setting: Data from the nationwide database of the Dutch Perinatal Registry (Perined)., Population: A cohort of 391 026 women at term, of whom 9943 had an OASI in their first delivery and had a second vaginal delivery of a liveborn infant in cephalic position., Methods: Possible risk factors were tested for statistical significance using univariate and multivariate logistic regression analysis., Main Outcome Measures: Rate of rOASI., Results: The rate of rOASI was 5.8%. Multivariate analysis identified a birthweight of ≥4000 g (adjusted OR, aOR, 2.1, 95% CI 1.6-2.6) and a duration of second stage of ≥30 minutes (aOR 1.8, 95% CI 1.4-2.3) as statistically significant risk factors for rOASI. Mediolateral episiotomy was associated with a statistically significant lower rate of rOASI in spontaneous vaginal delivery (SVD) (aOR 0.4, 95% CI 0.3-0.5) and in operative vaginal delivery (OVD) (aOR 0.2, 95% CI 0.1-0.5)., Conclusions: Women with a history of OASI have a higher rate of OASI in their next delivery. Duration of the second stage of ≥30 minutes and a birthweight of ≥4000 g are significantly associated with an increased rate of rOASI. Mediolateral episiotomy is associated with a significantly lower rate of rOASI in both SVD and OVD., Tweetable Abstract: Mediolateral episiotomy is associated with a significant lower recurrence rate of OASI in women with an OASI in their first delivery., (© 2020 Royal College of Obstetricians and Gynaecologists.)

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders., Competing Interests: Competing interestsC.A.S., A.S.R. and N.J.L. are employed by Congenica Ltd. P.F. is a member of the scientific advisory boards for Fabric Genomics, Inc., and Eagle Genomics, Ltd. S.P. is an employee and D.V. is a postdoc of AstraZeneca. The remaining authors declare they have no competing interests., (© The Author(s) 2019.)

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. 1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons, 4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly. 6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Gene regulation is the term used to describe the mechanisms by which a cell increases or decreases the amount of a gene product (RNA or protein). In complex organs such as the brain, gene regulation is of the utmost importance; aberrations in the regulation of specific genes can lead to neurological disorders. Understanding these mechanisms can create new strategies for targeting these disorders and progress is being made. Two drugs that function at the RNA level (nusinersen and eteplirsen) have now been approved by the FDA for the treatment of Spinomuscular atrophy and Duchenne muscular dystrophy, respectively; several other compounds for neurological disease are currently being investigated in preclinical studies and clinical trials. Areas covered: We highlight how gene regulation at the level of RNA molecules can be used as a therapeutic strategy to treat neurological disorders. We provide examples of how such an approach is being studied or used and discuss the current hurdles. Expert opinion: Targeting gene expression at the RNA level is a promising strategy to treat genetic neurological disorders. Safe administration, long-term efficacy, and potential side effects, however, still need careful evaluation before RNA therapeutics can be applied on a larger scale.

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1 +/- mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1 +/- mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1 +/- mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1 +/- mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology.

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803., (© 2018 American Neurological Association.)

Background: To reduce the risk of postoperative stress urinary incontinence (POSUI) prolapse repair might be combined with incontinence surgery., Objectives: Compare efficacy and safety of prolapse surgery with and without incontinence surgery., Search Strategy: Including our earlier review a systematic search in PubMed, EMBASE, the Cochrane Library and the Register of Current Controlled Trials was performed from 1995 to 2017., Selection Criteria: Randomised trials comparing prolapse surgery with a midurethral sling (MUS) or Burch colposuspension., Data Collection and Analysis: Two reviewers selected eligible articles and extracted data. Stress urinary outcomes were pooled for preoperative SUI. Urgency incontinence and adverse events were pooled for incontinence procedure., Main Results: Ten trials were included. Women with preoperative SUI symptoms or occult SUI had a lower risk to undergo subsequent incontinence surgery for POSUI after vaginal prolapse surgery with a MUS than after prolapse surgery only: 0 versus 40% [relative risk (RR) 0.0; 95% CI 0.0-0.2] and 1 versus 15% (RR 0.1; 95% CI 0.0-0.6), respectively. These differences were not significant in continent women not tested for occult SUI or without occult SUI. Serious adverse events were more frequent after vaginal prolapse repair with MUS (14 versus 8%; RR 1.7; 95% CI 1.1-2.7), but not after sacrocolpopexy with Burch colposuspension. Combination surgery did not increase the risk of overactive bladder symptoms, urgency incontinence and surgery for voiding dysfunction., Conclusions: Vaginal prolapse repair with MUS reduced the risk of postoperative SUI in women with preoperative SUI symptoms or occult SUI, but serious adverse events were more frequent., Tweetable Abstract: Less stress incontinence after vaginal prolapse repair with sling, but more adverse events., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Objective: To compare recurrence of a cyst or abscess of the Bartholin gland after surgical treatment using a Word catheter or marsupialisation., Design: Multicentre, open-label, randomised controlled trial., Setting: Eighteen hospitals in the Netherlands and one hospital in England., Population: Women with a symptomatic cyst or abscess of the Bartholin gland., Methods: Women were randomised to treatment with Word catheter or marsupialisation., Main Outcome Measures: The primary outcome was recurrence of the cyst or abscess within 1 year of treatment. The secondary outcomes included pain during and after treatment (measured on a 10-point scale), use of analgesics, and time from diagnosis to treatment. Analysis was by intention-to-treat. To assess whether marsupialisation would reduce the recurrence rate by 5% (from 20 to 15%) we needed to include 160 women (alpha error 0.05, beta error 0.2)., Results: One hundred and sixty-one women were randomly allocated to treatment by Word catheter (n = 82) or marsupialisation (n = 79) between August 2010 and May 2014. Baseline characteristics were comparable. Recurrence occurred in 10 women (12%) allocated to Word catheter versus eight women (10%) allocated to marsupialisation: relative risk (RR) 1.1, 95% confidence interval (CI) 0.64-1.91; P = 0.70. Pain scores after treatment were also comparable. In the first 24 hours after treatment, 33% used analgesics in the Word catheter group versus 74% in the marsupialisation group (P < 0.001). Time from diagnosis to treatment was 1 hour for placement of Word catheter versus 4 hours for marsupialisation (P = 0.001)., Conclusions: In women with an abscess or cyst of the Bartholin gland, treatment with Word catheter and marsupialisation results in comparable recurrence rates., Tweetable Abstract: Comparable recurrence rates for treatment of Bartholinic abscess/cyst with Word catheter and marsupialisation., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Objective: We investigated patients' preferences for anterior colporrhaphy or mesh surgery as surgical correction of anterior vaginal wall prolapse., Design: Labelled discrete choice experiment., Setting: Three Dutch teaching hospitals., Population: Women with anterior vaginal wall prolapse Pelvic Organ Prolapse Quantification stage 2 or more, indicated for anterior colporrhaphy (n = 100)., Methods: Discrete choice experiments are an attribute-based survey method for measuring preferences. In this experiment, women were asked to choose between two treatment scenarios, mesh surgery or anterior colporrhaphy. These surgical treatments differed in four treatment attributes: (i) recurrence rate, (ii) exposure rate, (iii) infection rate, (iv) dyspareunia. Data were analysed using a multinomial logit model., Main Outcome Measures: Women's preferences for anterior colporrhaphy or mesh surgery for the repair of vaginal wall prolapse., Results: All treatment attributes, i.e. recurrence, exposure, infection and dyspareunia, proved to be significant in the woman's decision to choose mesh surgery (P < 0.001), while only two attributes out of three, recurrence and infection, were significant for anterior colporrhaphy (P < 0.001). The relative importance data showed that with regards to the four statistically significant attributes for mesh, dyspareunia was the most important attribute, and of the two significant attributes for anterior colporrhaphy, the risk of infection. Based on the attributes and levels in our discrete choice experiment, anterior colporrhaphy was preferred in 74% as a primary correction of anterior vaginal wall prolapse, followed by a preference for mesh in 26% of all choices., Conclusion: This study showed that next to the risk of recurrence, other aspects like risk of infection, dyspareunia and exposure play a role in the woman's preference for a surgical treatment. In addition, our results indicate that anterior colporrhaphy is preferred in the majority of the choices, followed by a preference for mesh surgery in a quarter of all choice sets. However, these results represent the average preference of a sample of women and cannot be taken as the preference of each individual. In the medical decision-making context, information from the current study should be personalised to fit patient's unique circumstances. For patients to construct their own, individual preferences, they should be well informed about the existence and magnitude of the potential benefits and risks related to either anterior colporrhaphy or mesh surgery., (© 2014 Royal College of Obstetricians and Gynaecologists.)

We present a systematic investigation of well-characterized, experimentally pure polystyrene (PS) rings with molar mass of 161 000 g/mol in dilute solutions. We measure the ring form factor at θ - and good-solvent conditions as well as in a polymeric solvent (linear PS of roughly comparable molar mass) by means of small-angle neutron scattering (SANS). Additional dynamic light scattering (DLS) measurements support the SANS data and help elucidate the role of solvent quality and solution preparation. The results indicate the increase of ring dimensions as the solvent quality improves. Furthermore, the experimental form factors in both θ -solvent and linear matrix behave as ideal rings and are fully superimposable. The nearly Gaussian conformations of rings in a melt of linear chains provide evidence of threading of linear chains through rings. The latter result has implications for the dynamics of ring-linear polymer mixtures.

Introduction and Hypothesis: The objective of this study was to compare the Manchester Fothergill (MF) procedure with vaginal hysterectomy (VH) as surgical treatment of uterine descent., Methods: Consecutive patients who underwent MF were matched for prolapse grade, age and parity to consecutive patients treated with VH. Evaluated outcomes included functional outcome, morbidity, recurrence of pelvic organ prolapse (POP) and sexual function. Follow-up was performed using validated questionnaires., Results: We included 196 patients (98 patients per group). The response rate after a follow-up of 4-9 years was 80%. We found no differences in functional outcome and recurrence rates of POP between groups. Blood loss was significantly less and operating time was significantly shorter in the MF group. However, incomplete emptying of the bladder was more common in the MF group., Conclusions: The MF procedure is equally effective to the VH and should be considered as a surgical option that allows preservation of the uterus.

Two types of 32 arm star polymers incorporating amphiphilic block copolymer arms have been synthesized and characterized. The first type, stPCL-PEG 32, is composed of a polyamidoamine (PAMAM) dendrimer as the core with radiating arms having poly(epsilon-caprolactone) (PCL) as an inner lipophilic block in the arm and poly(ethylene glycol) (PEG) as an outer hydrophilic block. The second type, stPLA-PEG 32, is similar but with poly(L-lactide) (PLA) as the inner lipophilic block. Characterization with SEC, (1)H NMR, FTIR, and DSC confirmed the structure of the polymers. Micelle formation by both star copolymers was studied by fluorescence spectroscopy. The stPCL-PEG 32 polymer exhibited unimolecular micelle behavior. It was capable of solubilizing hydrophobic molecules, such as pyrene, in aqueous solution, while not displaying a critical micelle concentration. In contrast, the association behavior of stPLA-PEG 32 in aqueous solution was characterized by an apparent critical micelle concentration of ca. 0.01 mg/mL. The hydrophobic anticancer drug etoposide can be encapsulated in the micelles formed from both polymers. Overall, the stPCL-PEG 32 polymer exhibited a higher etoposide loading capacity (up to 7.8 w/w % versus 4.3 w/w % for stPLA-PEG 32) as well as facile release kinetics and is more suitable as a potential drug delivery carrier.

We examine the vitrification and melting of asymmetric star polymer mixtures by combining rheological measurements with mode coupling theory. We identify two types of glassy states, a single glass, in which the small component is fluid in the glassy matrix of the big one, and a double glass, in which both components are vitrified. Addition of small-star polymers leads to melting of both glasses, and the melting curve has a nonmonotonic dependence on the star-star size ratio. The phenomenon opens new ways for externally steering the rheological behavior of soft matter systems.

Several [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine and its derivatives) complexes were synthesized and compared electrochemically and spectroscopically in the search for better luminophores for electrochemiluminescence (ECL)-based analytical applications. ECL measurement in [Ru(bpy)3]2+/tripropylamine (TPA) aqueous buffer solutions has led to a conclusion that due to the complexity of the ECL generation process, the photoluminescence efficiency cannot be used to predict ECL intensity and there is no obvious relationship between the photoluminescence quantum yield and the ECL intensity. Under the present experimental condition, when compared with the pristine [Ru(bpy)3]2+, the ethoxycarbonyl-substituted derivative, [Ru(bpy-COOEt)3]2+, one of the most efficient luminophores under photoexcitation, did not generate reasonably intense ECL, whereas luminophores with lower photoluminescence quantum yields demonstrated higher ECL. These findings are useful for further efforts in the search for more efficient ECL luminophores.

A star polymer composed of amphiphilic block copolymer arms has been synthesized and characterized. The core of the star polymer is polyamidoamine (PAMAM) dendrimer, the inner block in the arm is lipophilic poly(epsilon-caprolactone) (PCL), and the outer block in the arm is hydrophilic poly(ethylene glycol) (PEG). The star-PCL polymer was synthesized first by ring-opening polymerization of epsilon-caprolactone with a PAMAM-OH dendrimer as initiator. The PEG polymer was then attached to the PCL terminus by an ester-forming reaction. Characterization with SEC, (1)H NMR, FTIR, TGA, and DSC confirmed the star structure of the polymers. The micelle formation of the star copolymer (star-PCL-PEG) was studied by fluorescence spectroscopy. Hydrophobic dyes and drugs can be encapsulated in the micelles. A loading capacity of up to 22% (w/w) was achieved with etoposide, a hydrophobic anticancer drug. A cytotoxicity assay demonstrated that the star-PCL-PEG copolymer is nontoxic in cell culture. This type of block copolymer can be used as a drug delivery carrier.

Ultrasensitive bioanalytical assays are of great value for early detection of human diseases and pathogens. The sensitivities of immunoassays and DNA probing can be enhanced by multilabeling the biorecognition partner used for affinity-based assays. However, the bioreactivity of biomolecules is affected by a high degree of multilabeling at multiple functional sites. It is proposed that dendritic scaffoldings be used to link multiple signal-generating units to a single site with potentially minimum impact on the bioaffinity. A prototype label, a zeroth-generation dendron, bearing three [Ru(bpy)(3)](2+) units for electrochemiluminescence (ECL) assays was synthesized and characterized preliminarily by spectroscopic, electrochemical, and ECL methods. No evidence of interaction between the neighboring [Ru(bpy)(3)](2+) units in the label molecule was found from these characterizations. Both the photoluminescence and ECL of the prototype label have features very similar to those of mononuclear [Ru(bpy)(3)](2+) compounds. Labeling a model protein with a triad of [Ru(bpy)(3)](2+) at one NH(2) position was demonstrated. The results reported here provide support to applying the proposed multilabeling strategy to affinity-based bioanalytical assays.

Star polymers with a high number of arms, f=263, become kinetically trapped when dispersed in an athermal solvent at concentrations above the overlapping one, forming physical gels. We show that the addition of linear chains at different concentrations and molecular weights reduces the modulus of the gel, eventually melting it. We explain this linear polymer-induced gel-liquid transition in terms of effective interactions and star depletion. In the limit of very high linear-chain molecular weight a "reentrant gelation" is detected and attributed to bridging flocculation, analogous to that observed in colloidal dispersions.

Crowded solutions of multiarm star polymers, representing model colloidal spheres with ultrasoft repulsive interactions, undergo a reversible gelation transition upon heating in solvents of intermediate quality (between good and Theta). This unusual phenomenon is due to the kinetic arrest of the swollen interpenetrating spheres at high temperatures, forming clusters, in analogy to the colloidal glass transition. In this work we demonstrate that the choice of the solvent has a dramatic effect on the gelation transition, because of the different degree of star swelling (at the same temperature) associated with the solvent quality. We construct a generic kinetic phase diagram for the gelation of different stars in different solvents (gelation temperature against effective volume fraction, phi) and propose a critical "soft sphere close packing" volume fraction phi(c) distinguishing the temperature-induced (for phiphi(c)) glass-like gelation. We conclude that appropriate selection of the solvent allows for manipulation of the sol-gel transition in such ultrasoft colloids.

A new example of magnetic nonequivalence of chemically equivalent atoms is identified from the proton and carbon resonance spectra of 9,10-di(9,9-dioctylfluorenyl)anthracene with the aid of its conformation in the crystalline state. Molecular modeling suggests that it has a similar conformation in solution.

Upon heating, concentrated solutions of star polymers and block copolymer micelles in a good solvent, representing soft spheres, undergo a reversible gelation. This phenomenon is attributed to the formation of clusters causing a partial dynamic arrest of the swollen interpenetrating spheres at high temperatures. A phase diagram analogous to that of sterically stabilized colloids is proposed.