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IntroductionKawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.Materials and methodsWe investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.ResultsFCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.DiscussionFCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P

This study focuses on the systematic collective reflections of four teacher educators as they interrogate their own practice engaging in community-based settings, specifically considering how these settings can serve as an additional teacher. It is informed by a theory that centers educational experiences within the community and is guided by Gutiérrez's use of the concept of third space. Connected to third spaces, the results of this study reveal that traditional PK-12 settings serve as the first spaces, the university teacher education programs as the second spaces, and the community-based settings as third spaces. Results showcase how these third spaces can be transformative for teacher educators as they consider preservice teachers' learning. Findings are drawn from a 2-year collective self-study of four teacher educators facilitating community-based field experiences in the United States and Canada. Analysis of the teacher educator reflections of their observations revealed the transformative ways in which these community-based places, as separate and unique constructs, acted as a teacher for preservice teachers when working in community-based settings. This study presents arguments for integrating community-based field experiences within teacher education, particularly as such places can support and facilitate preservice teachers' learning.

IntroductionKawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.Materials and methodsWe investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case–control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.ResultsFCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case–control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15–4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.DiscussionFCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

Objectives Diagnostic prediction models exist to assess the probability of bacterial meningitis (BM) in paediatric patients with suspected meningitis. To evaluate the diagnostic accuracy of these models in a broad population of children suspected of a central nervous system (CNS) infection, we performed external validation.Methods We performed a systematic literature review in Medline to identify articles on the development, refinement or validation of a prediction model for BM, and validated these models in a prospective cohort of children aged 0–18 years old suspected of a CNS infection.Primary and secondary outcome measures We calculated sensitivity, specificity, predictive values, the area under the receiver operating characteristic curve (AUC) and evaluated calibration of the models for diagnosis of BM.Results In total, 23 prediction models were validated in a cohort of 450 patients suspected of a CNS infection included between 2012 and 2015. In 75 patients (17%), the final diagnosis was a CNS infection including 30 with BM (7%). AUCs ranged from 0.69 to 0.94 (median 0.83, interquartile range [IQR] 0.79–0.87) overall, from 0.74 to 0.96 (median 0.89, IQR 0.82–0.92) in children aged ≥28 days and from 0.58 to 0.91 (median 0.79, IQR 0.75–0.82) in neonates.Conclusions Prediction models show good to excellent test characteristics for excluding BM in children and can be of help in the diagnostic workup of paediatric patients with a suspected CNS infection, but cannot replace a thorough history, physical examination and ancillary testing.

Este libro, de brillante factura, es altamente recomendable para cualquier persona, en la academia y en la praxis, con interés y vocación por los estudios sobre el federalismo, el constitucionalismo, y el marco normativo relativo a las personas con discapacidad, particularmente a la luz del Derecho internacional de los derechos humanos. Recibido: 20.01.2024 Aceptado: 10.05.2024

Introduction Endobronchial polarisation sensitive optical coherence tomography (EB-PS-OCT) is a bronchoscopic imaging technique exceeding resolution of high-resolution CT (HRCT) by 50-fold. It detects collagen birefringence, enabling identification and quantification of fibrosis.Study aim To assess pulmonary fibrosis in interstitial lung diseases (ILD) patients with in vivo EB-PS-OCT using histology as reference standard.Primary objective Visualisation and quantification of pulmonary fibrosis by EB-PS-OCT.Secondary objectives Comparison of EB-PS-OCT and HRCT detected fibrosis with histology, identification of ILD histological features in EB-PS-OCT images and comparison of ex vivo PS-OCT results with histology.Methods Observational prospective exploratory study. Patients with ILD scheduled for transbronchial cryobiopsy or surgical lung biopsy underwent in vivo EB-PS-OCT imaging prior to tissue acquisition. Asthma patients were included as non-fibrotic controls. Per imaged lung segment, fibrosis was automatically quantified assessing the birefringent area in EB-PS-OCT images. Fibrotic extent in corresponding HRCT areas and biopsies were compared with EB-PS-OCT detected fibrosis. Microscopic ILD features were identified on EB-PS-OCT images and matched with biopsies from the same segment.Results 19 patients were included (16 ILD; 3 asthma). In 49 in vivo imaged airway segments the parenchymal birefringent area was successfully quantified and ranged from 2.54% (no to minimal fibrosis) to 21.01% (extensive fibrosis). Increased EB-PS-OCT detected birefringent area corresponded to increased histologically confirmed fibrosis, with better predictive value than HRCT. Microscopic ILD features were identified on both in vivo and ex vivo PS-OCT images.Conclusions EB-PS-OCT enables pulmonary fibrosis quantification, thereby has potential to serve as an add-on bronchoscopic imaging technique to diagnose and detect (early) fibrosis in ILD.

Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.

IntroductionVocal analysis of fundamental frequency (f0) represents a suitable index to assess emotional activation. However, although f0 has often been used as an indicator of emotional arousal and different affective states, its psychometric properties are unclear. Specifically, there is uncertainty regarding the validity of the indices of f0mean and f0variabilitymeasures (f0dispersion, f0range, and f0SD) and whether higher or lower f0 indices are associated with higher arousal in stressful situations. The present study therefore aimed to validate f0 as a marker of vocally encoded emotional arousal, valence, and body-related distress during body exposure as a psychological stressor.MethodsN = 73 female participants first underwent a 3-min, non-activating neutral reference condition, followed by a 7-min activating body exposure condition. Participants completed questionnaires on affect (i.e., arousal, valence, body-related distress), and their voice data and heart rate (HR) were recorded continuously. Vocal analyses were performed using Praat, a program for extracting paralinguistic measures from spoken audio.ResultsThe results revealed no effects for f0 and state body dissatisfaction or general affect. F0mean correlated positively with self-reported arousal and negatively with valence, but was not correlated with HRmean/maximum. No correlations with any measure were found for any f0variabililtymeasures.DiscussionGiven the promising findings regarding f0mean for arousal and valence and the inconclusive findings regarding f0 as a marker of general affect and body-related distress, it may be assumed that f0mean represents a valid global marker of emotional arousal and valence rather than of concrete body-related distress. In view of the present findings regarding the validity of f0, it may be suggested that f0mean, but not f0variabilitymeasures, can be used to assess emotional arousal and valence in addition to self-report measures, which is less intrusive than conventional psychophysiological measures.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r 2 = 0.63). LD between these two variants was weaker (r 2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency

Abstract Background Development of neurodegeneration in older people has been associated with microglial cell activation triggered by systemic infection. We hypothesize that α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulation of this process. Methods 8- to 10-week-old male wild-type (WT) and α7nAChR knock-out (α7nAChR −/−) mice were intraperitoneally inoculated with live Escherichia (E.) coli or saline. After inoculation, all mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h and killed at 2 or 3 days. The microglial response was characterized by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry. To quantify inflammatory response, mRNA expression of pro- and anti-inflammatory mediators was measured in brain and spleen. Results We observed no differences in Iba-1 positive cell number or morphology and flow cytometry (CD11b, CD45 and CD14) of microglial cells between WT and α7nAChR −/− mice after systemic infection. Infected α7nAChR −/− mice showed significantly higher mRNA expression in brain for tumor necrosis factor alpha (TNF-α) at day 2 and 3, interleukin 6 (IL-6) at day 2 and monocyte chemotactic protein 1 (MCP-1) and suppressor of cytokine signaling 1 (SOCS1) at day 3, there was significantly lower mRNA expression in brain for mitogen-activated protein kinase 1 (MAPK1) at day 2 and 3, high-mobility group 1 (HMGB-1) and CD11b at day 2, and deubiquitinase protein A20 (A20) at day 3 compared to infected WT mice. Interpretation Loss of function of α7nAChR during systemic infection led to an increased expression of TNF-α and IL-6 in brain after systemic infection with E. coli, but not to distinct differences in microglial cell number or morphological activation of microglia.

Abstract Background Although students are increasingly involved in curriculum design, empirical research on practices of actual student participation is sparse. The purpose of this study is to explore the experiences of students who collaborated in the organizing committee of a large-scale educational event, the Radboud Student Conference (RSC), for fellow students. Methods We conducted three focus group interviews, in which 17 (bio) medical students of three different organizing teams shared their experiences regarding the organization of the large-scale teaching event. The analysis was conducted using thematic content analysis, in which the codes and codebook were constructed on the basis of the data. Results The following four themes were derived from the data. 1) Collaboration, which concentrated on fellow students, teachers who were involved as supervisors, and persons outside the organizing team such as caterers, educational support office members, lecturers, physicians and researchers. 2) Planning and division of labor, with students experiencing a mutual dependence and noticing a gradual improvement of their skills. 3) Freedom implies responsibility, which indicted that students experienced a significant freedom to develop the RSC week, but at the same time felt the responsibility to deliver a successful final week of the academic year. 4) Personal development, where students mentioned the opportunity to practice skills that differed from standard (bio) medical electives. Conclusions We conclude that (bio) medical students are capable of bearing the responsibility to organize a large-scale educational event. Organizing the RSC was an educational experience in the form of cooperative and experiential learning which contributed to students’ personal development. Organizing the event gave students both a sense of freedom and the responsibility to succeed. Supervision of faculty members seemed a prerequisite, and tended to be supportive rather than guiding.

AimsSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and resultsWe carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Medical students consider anatomy, neurology, and traumatology as difficult study topics. A recent study showed that the daily quiz "Two Opportunities to Practice per day (TOPday)" positively supported biomedical students in analyzing and solving biomechanical problems. The main purpose of this study was to investigate the effect of TOPday on self-confidence, enthusiasm, and test results for the topics anatomy, neurology and traumatology. Second-year medical students were enrolled in a four-week course on the human skeletal system at the Radboudumc (n = 799). They were randomized over three topic groups (anatomy, neurology, and traumatology) and received TOPday quizzes on every course day. At the end of the course students filled in a non-anonymous questionnaire. Students highly appreciated TOPday (7.5 ± 0.9) and this did not differ between groups (anatomy: 7.4 ± 0.8; neurology: 7.4 ± 1.1; traumatology: 7.5 ± 0.8; P = 0.68). Many students reported that TOPday increased their self-confidence (65% of the students) and enthusiasm (69% of the students) for their topic. However, test results of the students did not improve. A potential explanation for the latter result may relate to the different cognitive processes that are required to study anatomy, neurology, and traumatology compared to biomechanics. In conclusion, appreciation, self-confidence and enthusiasm were positively associated with TOPday, but test results were not.

El conflicto entre Armenia y Azerbaiyán sobre el Nagorno-Karabaj presenta hondas raíces históricas y se ha visto exacerbado por el conflicto armado de 2020. En este contexto, a menudo la situación de los derechos humanos de las personas afectadas y, en particular, los de las mujeres y niñas, queda invisibilizada. Así, este artículo analiza el conflicto refiriendo la postura general de la ONU y el Derecho Internacional Público y ampliando el lente, en especial, sobre el Derecho internacional de los derechos humanos y los mecanismos de Naciones Unidas articulados para su protección. Se presenta un enfoque específico sobre los derechos humanos de las mujeres y niñas, dando cuenta de las situaciones empíricas que enfrentan, para estudiarlas después bajo la mirada de los derechos humanos con una perspectiva de género, poniendo énfasis en lo que al respecto han manifestado los principales mecanismos de protección internacional dedicados al tema.

While up to 50% of children requiring kidney replacement therapy have congenital anomalies of the kidney and urinary tract (CAKUT), they represent only a fraction of the total patient population with CAKUT. The extreme variability in clinical outcome underlines the fundamental need to devise personalized clinical management strategies for individuals with CAKUT. Better understanding of the pathophysiology of abnormal kidney and urinary tract development provides a framework for precise diagnoses and prognostication of patients, the identification of biomarkers and disease modifiers, and, thus, the development of personalized strategies for treatment. In this review, we provide a state-of-the-art overview of the currently known genetic causes, including rare variants in kidney and urinary tract development genes, genomic disorders, and common variants that have been attributed to CAKUT. Furthermore, we discuss the impact of environmental factors and their interactions with developmental genes in kidney and urinary tract malformations. Finally, we present multi-angle translational modalities to validate candidate genes and environmental factors and shed light on future strategies to better understand the molecular underpinnings of CAKUT. [ABSTRACT FROM AUTHOR]

This study focuses on the systematic collective reflections of four teacher educators as they interrogate their own practice engaging in community-based settings, specifically considering how these settings can serve as an additional teacher. It is informed by a theory that centers educational experiences within the community and is guided by Gutiérrez's use of the concept of third space. Connected to third spaces, the results of this study reveal that traditional PK-12 settings serve as the first spaces, the university teacher education programs as the second spaces, and the community-based settings as third spaces. Results showcase how these third spaces can be transformative for teacher educators as they consider preservice teachers' learning. Findings are drawn from a 2-year collective self-study of four teacher educators facilitating community-based field experiences in the United States and Canada. Analysis of the teacher educator reflections of their observations revealed the transformative ways in which these community-based places, as separate and unique constructs, acted as a teacher for preservice teachers when working in community-based settings. This study presents arguments for integrating community-based field experiences within teacher education, particularly as such places can support and facilitate preservice teachers' learning. [ABSTRACT FROM AUTHOR]