The Radiological and Histological Phenotype of Skeletal Abnormalities in Fetal ARCN1-Related Syndrome

Mutations in ARCN1 give rise to a syndromic disorder with rhizomelic short stature with microretrognathia and developmental delay. ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking of collagen 1 and which may also be involved in the endoplasmic reticulum (ER) stress response. In this paper we describe for the first time the skeletal histological abnormalities in an 18-week-old fetus with an ARCN1 mutation, and we suggest that the skeletal phenotype in ARCN1-related syndrome has more resemblance with ER stress than with a defect in collagen 1 metabolism

Context server on a mobile device

Da bi mobilne aplikacije lahko učinkovito nudile vse svoje storitev in jih prilagodile uporabniku, bi morale pri tem uporabiti ves kontekst uporabnika in njegove okolice. V obstoječih raziskavah to nalogo prevzema poseben kontekstni strežnik, ki skrbi za zbiranje podatkov ter posredovanje informacij aplikaciji. V primeru, da bi tak kontekstni strežnik deloval na mobilni napravi, bi bila postopoma odpravljena potreba po omenjenem sistemu. V sklopu naloge smo predlagani model kontekstnega strežnika uspešno implementirali in njegovo delovanje preizkusili s pomočjo kontekstno odvisne aplikacije, ki deluje na principu tekstovne klasifikacije uporabnikovih vnosov v spletnih iskalnikih in njegovi trenutni lokaciji. Aplikaciji omenjenih podatkov ni potrebno zajeti ročno, saj so ti ob pojavitvi novega podatka avtomatično posredovani preko kontekstnega strežnika.In order for mobile applications to efficiently offer all of their services and adjust them according to the end user, they would need to monitor all of his context and surroundings. In the existing researches this is done by a special context server which is responsible for data retrieval and transmission of information application. In the event, when the context server would work on a mobile device, the before mentioned system would gradually not be needed anymore. In the context of the thesis we have successfully implemented the proposed model of context server and tested it with a context application, which operates in the principle of text classification of user entries in the search engines and its current location. The application of this data does not need to be captured manually, since they are automatically transmitted to the server when the new data appears

Ustekinumab for the treatment of moderate‐to‐severe plaque psoriasis in paediatric patients (≥ 6 to < 12 years of age): efficacy, safety, pharmacokinetic and biomarker results from the open‐label CADMUS Jr study

Background Limited options are available for treatment of paediatric psoriasis. Objectives To evaluate the efficacy and safety of ustekinumab in paediatric patients with psoriasis (>= 6 to = 60 to 100 kg: 90 mg) administered by subcutaneous injection at weeks 0 and 4, then every 12 weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) and >= 75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90), and change in Children's Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, antidrug antibodies and cytokine levels were measured through week 52. Safety was evaluated through week 56. Results In total, 44 patients (median age 9 center dot 5 years) received at least one dose of ustekinumab. Three patients discontinued the study agent through week 40. At week 12, 77% of patients achieved PGA 0/1, 84% achieved PASI 75 and 64% achieved PASI 90 response. The mean change in CDLQI was -6 center dot 3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of antidrug antibodies was 10% (n = 4). Mean serum concentrations of interleukin-17A/F and interleukin-22 were significantly reduced at weeks 12 and 52. Overall, 34 patients (77%) had at least one adverse event and three (7%) had a serious adverse event. Conclusions Ustekinumab effectively treated moderate-to-severe psoriasis in paediatric patients, and no new safety concerns were identified. What is already known about this topic? Ustekinumab is approved for use in adolescents (>= 12 to = 18 years) with moderate-to-severe psoriasis. What does this study add? Ustekinumab effectively treats moderate-to-severe psoriasis in paediatric patients (>= 6 to < 12 years of age), with no new safety concerns

Effects of Antenatal Glucocorticoid Therapy on Hippocampal Histology of Preterm Infants

Objective: To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. Patients and Methods: Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. Results: The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. Conclusion: We found a significantly lower density of neurons in the hippocampus of neonates after antenata

Design of an RCT on cost-efectiveness of group schema therapy versus individual schema therapy for patients with Cluster-C personality disorder: the QUEST-CLC study protocol

Background Given the high prevalence of Cluster-C Personality Disorders (PDs) in clinical populations, disease burden, high societal costs and poor prognosis of comorbid disorders, a major gain in health care can be achieved if Cluster-C PDs are adequately treated. The only controlled cost-effectiveness study published so far found Individual Schema Therapy (IST) to be superior to Treatment as Usual (TAU). Group ST (GST) might improve cost-effectiveness as larger numbers can be treated in (>50%) less time compared to IST. However, to date there is no RCT supporting its (cost-) effectiveness. The overall aim of this study is to assess the evidence for GST for Cluster-C PDs and to improve treatment allocation for individual patients. Three main questions are addressed: 1) Is GST for Cluster-C PDs (cost-) effective compared to TAU? 2) Is GST for Cluster-C PDs (cost-) effective compared to IST? 3) Which patient-characteristics predict better response to GST, IST, or TAU? Methods In a multicenter RCT, the treatment conditions GST, IST, and TAU are compared in 378 Cluster-C PD patients within 10 sites. GST and IST follow treatment protocols and are completed within 1 year. TAU is the optimal alternative treatment available at the site according to regular procedures. Severity of the Cluster-C PD is the primary outcome, assessed with clinical interviews by independent raters blind for treatment. Functioning and wellbeing are important secondary outcomes. Assessments take place at week 0 (baseline), 17 (mid-GST), 34 (post-GST), 51 (postbooster sessions of GST), and 2 years (FU). Patient characteristics predicting better response to a specifc treatment are studied, e.g., childhood trauma, autistic features, and introversion. A tool supporting patients and clinicians in matching treatment to patient will be developed. An economic evaluation investigates the cost-effectiveness and costutility from a societal perspective. A process evaluation by qualitative methods explores experiences of participants, loved ones and therapists regarding recovery, quality of life, and improving treatment. Discussion This study will determine the (cost-)effectiveness of treatments for Cluster-C PDs regarding treatment type as well as optimal matching of patient to treatment and deliver insight into which aspects help Cluster-C-PD patients recover and create a fulfilling life. Trial registration Dutch Trial Register: NL9209. Registered on 28-01-2021

A continuous-discontinuous model for crack branching

This is the peer reviewed version of the following article: Tamayo, E. [et al.]. A continuous-discontinuous model for crack branching. "International journal for numerical methods in engineering", 5 Octubre 2019, vol. 120, núm. 1, p. 86-104, which has been published in final form at https://doi.org/10.1002/nme.6125. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.A new continuous-discontinuous model for fracture that accounts for crack branching in a natural manner is presented. It combines a gradient-enhanced damage model based on nonlocal displacements to describe diffuse cracks and the extended finite element method (X-FEM) for sharp cracks. Its most distinct feature is a global crack tracking strategy based on the geometrical notion of medial axis: the sharp crack propagates following the direction dictated by the medial axis of a damage isoline. This means that, if the damage field branches, the medial axis automatically detects this bifurcation, and a branching sharp crack is thus easily obtained. In contrast to other existing models, no special crack-tip criteria are required to trigger branching. Complex crack patterns may also be described with this approach, since the X-FEM enrichment of the displacement field can be recursively applied by adding one extra term at each branching event. The proposed approach is also equipped with a crack-fluid pressure, a relevant feature in applications such as hydraulic fracturing or leakage-related events. The capabilities of the model to handle propagation and branching of cracks are illustrated by means of different two-dimensional numerical examples.Peer ReviewedPostprint (author's final draft

Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial.

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The presence of extracellular matrix degrading metalloproteinases during fetal development of the intervertebral disc

Matrix metalloproteinases (MMPs) regulate connective tissue architecture and cell migration through extracellular matrix (ECM) degradation and are associated with both physiological and pathological processes. Although they are known to play a role in skeletal development, little is known about the role of MMPs in intervertebral disc (IVD) development. Sixteen fetal human lumbar spine segments, obtained at autopsy, were compared with five normal, non-fetal L4–L5 IVDs. Intensity and/or localization of immunohistochemical staining for MMP-1, -2, -3 and -14 were evaluated by three independent observers. MMP-2 production and activation was quantified by gelatin zymography. MMP-1 and -14 were abundantly present in the nucleus pulposus (NP) and notochordal (NC) cells of the fetal IVDs. In non-fetal IVDs, MMP-1 and -14 staining was significantly less intense (p = 0.001 and p < 0.001, respectively). MMP-3 was found in almost the entire IVD with no significant difference from non-fetal IVDs. MMP-2 staining in the NC and NP cells of the fetal IVD was moderate, but weak in the non-fetal IVD. Gelatin zymography showed a negative correlation of age with MMP-2 activity (p < 0.001). MMP-14 immunostaining correlated positively with MMP-2 activity (p = 0.001). For the first time, the presence of MMP-1, -2, -3 and -14 in the fetal human IVD is shown and the high levels of MMP-1, -2 and -14 suggest a role in the development of the IVD. In particular, the gradual decrease in MMP-2 activation during gestation pinpoints this enzyme as key player in fetal development, possibly through activation by MMP-1 and -14

Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities

BACKGROUND: Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. METHODOLOGY/PRINCIPAL FINDINGS: In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. CONCLUSIONS: These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner