CYRI controls epidermal wound closure and cohesion of invasive border cell cluster in Drosophila.

Cell motility is crucial for many biological processes including morphogenesis, wound healing, and cancer invasion. The WAVE regulatory complex (WRC) is a central Arp2/3 regulator driving cell motility downstream of activation by Rac GTPase. CYFIP-related Rac1 interactor (CYRI) proteins are thought to compete with WRC for interaction with Rac1 in a feedback loop regulating lamellipodia dynamics.

Methotrexate Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study.

Introduction: Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG resulting in enhanced cellular retention.

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate.

Methotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low-dose MTX therapy. We investigated the association and interpatient variability between RBC-MTX-PG -exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown.

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

Objective: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline.

Methods: 81 HV and 80 SZ were tested at one of four study sites.

A proteogenomic view of Parkinson's disease causality and heterogeneity.

The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed.

Diagnostic work-up of urinary tract infections in pregnancy: study protocol of a prospective cohort study.

Introduction: Symptoms of urinary tract infections in pregnant women are often less specific, in contrast to non-pregnant women where typical clinical symptoms of a urinary tract infection are sufficient to diagnose urinary tract infections. Moreover, symptoms of a urinary tract infection can mimic pregnancy-related symptoms, or symptoms of a threatened preterm birth, such as contractions. In order to diagnose or rule out a urinary tract infection, additional diagnostic testing is required.

Complex Machine-Learning Algorithms and Multivariable Logistic Regression on Par in the Prediction of Insufficient Clinical Response to Methotrexate in Rheumatoid Arthritis.

The goals of this study were to examine whether machine-learning algorithms outperform multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX); secondly, to examine which features are essential for correct prediction; and finally, to investigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) > 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost).

Validation of a Prognostic Multivariable Prediction Model for Insufficient Clinical Response to Methotrexate in Early Rheumatoid Arthritis and Its Clinical Application in Evidencio.

Introduction: Methotrexate (MTX) constitutes the first-line therapy in rheumatoid arthritis (RA), yet approximately 30% of the patients do not benefit from MTX. Recently, we reported a prognostic multivariable prediction model for insufficient clinical response to MTX at 3 months of treatment in the treatment in the Rotterdam Early Arthritis Cohort (tREACH), including baseline predictors: Disease activity score 28 (DAS28), Health Assessment Questionnaire (HAQ), erythrocyte folate, single-nucleotide polymorphisms (SNPs; ABCB1, ABCC3), smoking, and BMI. The purpose of the current study was (1) to externally validate the model and (2) to enhance the model's clinical applicability.

Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study.

Background: Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury.

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.

Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients.

Background: Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups.

Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis.

Objective: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients.

Methods: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic.

Compliance with the guidelines for laboratory monitoring of patients treated with lithium: A retrospective follow-up study among ambulatory patients in the Netherlands.

Objectives: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups.

Methods: Patients having at least one lithium dispensing for 6 months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network.

Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats.

Rationale: Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission.

Objectives: The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake.

Methods: The effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist sumanirole and the dopamine D2 receptor antagonist L741,626 on alcohol consumption and preference were assessed at different time points after treatment in subgroups of low and high alcohol drinking rats (LD and HD) using an intermittent alcohol access paradigm.

Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats.

Background: Alcohol is one of the most commonly used psychoactive substances. Prolonged alcohol use can result in alcohol use disorder (AUD), characterized by excessive and compulsive alcohol consumption. Importantly, however, the development of AUD only happens in a minority of individuals who consume alcohol.

Dirty deeds and dirty bodies: Embodiment of the Macbeth effect is mapped topographically onto the somatosensory cortex.

The theory of embodied cognition claims that knowledge is represented in modal systems derived from perception. Recent behavioral studies found evidence for this hypothesis, for example, by linking moral purity with physical cleansing (the Macbeth effect). Neurophysiological approaches provided further support by showing an involvement of sensorimotor cortices for embodied metaphors.

Early social isolation augments alcohol consumption in rats.

There is a considerable degree of individual vulnerability for alcohol use disorder (AUD) as only a subpopulation of individuals who regularly consume alcohol develop AUD. It is therefore very important to understand the factors and mechanisms that contribute towards the individual risk for AUD. In this respect, social influences, in particular during development, may be relevant for AUD as disruptions in early social experiences are associated with an increased risk for AUD.

The neural bases of the pseudohomophone effect: Phonological constraints on lexico-semantic access in reading.

We investigated phonological processing in normal readers to answer the question to what extent phonological recoding is active during silent reading and if or how it guides lexico-semantic access. We addressed this issue by looking at pseudohomophone and baseword frequency effects in lexical decisions with event-related functional magnetic resonance imaging (fMRI). The results revealed greater activation in response to pseudohomophones than for well-controlled pseudowords in the left inferior/superior frontal and middle temporal cortex, left insula, and left superior parietal lobule.

Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study.

Background: Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance.

Determinants of erythrocyte methotrexate polyglutamate levels in rheumatoid arthritis.

Objective: Low-dose methotrexate (MTX) is the anchor drug in the treatment for rheumatoid arthritis (RA). Response to MTX is related to the intracellular MTX-polyglutamate (MTX-PG) levels and little is known about its determinants. We aimed to define the determinants of erythrocyte MTX-PG concentrations in 2 prospective cohorts of patients with RA.

Lying and the Subsequent Desire for Toothpaste: Activity in the Somatosensory Cortex Predicts Embodiment of the Moral-Purity Metaphor.

It is well known from literature and religious ceremonies that there is a link between physical cleansing and moral transgressions. Only recently, psychological experiments explored this association and demonstrated that a threat to moral purity increases the demand of physical cleansing. Moreover, it has been shown that physical cleansing is actually efficacious to cope with threatened morality.

Use of ultrasound to diagnose and manage a five-liter empyema in a rural clinic in sierra leone.

We report the case of a dyspneic patient with a five-liter pleural empyema that was diagnosed and managed in a resource-limited clinic in a rural part of Sierra Leone. The diagnosis and management of this condition are usually guided by imaging modalities such as X-rays or CT scans. However, these resources may not be available in austere settings in developing countries.

Belief in a just world is associated with activity in insula and somatosensory cortices as a response to the perception of norm violations.

Previous studies identified a network of brain regions involved in the perception of norm violations, including insula, anterior cingulate cortex (ACC), and right temporoparietal junction area (RTPJ). Activations in these regions are suggested to reflect the perception of norm violations and unfairness. The current study aimed to test this hypothesis by exploring whether a personal disposition to perceive the world as being just is related to neural responses to moral evaluations.