Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Structural Model of Biomedical and Contextual Factors Predicting In-Hospital Mortality due to Heart Failure.

Background: Among the clinical predictors of a heart failure (HF) prognosis, different personal factors have been established in previous research, mainly age, gender, anemia, renal insufficiency and diabetes, as well as mediators (pulmonary embolism, hypertension, chronic obstructive pulmonary disease (COPD), arrhythmias and dyslipidemia). We do not know the role played by contextual and individual factors in the prediction of in-hospital mortality. Methods: The present study has added hospital and management factors (year, type of hospital, length of stay, number of diagnoses and procedures, and readmissions) in predicting exitus to establish a structural predictive model. The project was approved by the Ethics Committee of the province of Almeria. Results: A total of 529,606 subjects participated, through databases of the Spanish National Health System. A predictive model was constructed using correlation analysis (SPSS 24.0) and structural equation models (SEM) analysis (AMOS 20.0) that met the appropriate statistical values (chi-square, usually fit indices and the root-mean-square error approximation) which met the criteria of statistical significance. Individual factors, such as age, gender and chronic obstructive pulmonary disease, were found to positively predict mortality risk. Isolated contextual factors (hospitals with a greater number of beds, especially, and also the number of procedures performed, which negatively predicted the risk of death. Conclusions: It was, therefore, possible to introduce contextual variables to explain the behavior of mortality in patients with HF. The size or level of large hospital complexes, as well as procedural effort, are key contextual variables in estimating the risk of mortality in HF.

Medical management of small uterocutaneous fistulae with gonadotrophin releasing hormone analogs: Case report and literature review.

Conventional management of uterocutaneous fistula involves open or laparoscopic excision as well as hysterectomy but there is now increasing recognition of successful medical treatment with gonadotrophin releasing hormone agonists. We describe the fourth case in the literature of successful nonsurgical treatment of uterocutaneous fistula and discuss two important factors affect the success of medical management, namely the size of the fistula and the duration of treatment. We would recommend that a trial of gonadotrophin releasing hormone analogues for at least 6 months particularly in cases of uterocutaneous fistula of 5 mm or less in diameter as this conservative treatment is likely to obviate the need for more hazardous surgical intervention.

Microfluidics for Neuronal Cell and Circuit Engineering.

The widespread adoption of microfluidic devices among the neuroscience and neurobiology communities has enabled addressing a broad range of questions at the molecular, cellular, circuit, and system levels. Here, we review biomedical engineering approaches that harness the power of microfluidics for bottom-up generation of neuronal cell types and for the assembly and analysis of neural circuits. Microfluidics-based approaches are instrumental to generate the knowledge necessary for the derivation of diverse neuronal cell types from human pluripotent stem cells, as they enable the isolation and subsequent examination of individual neurons of interest. Moreover, microfluidic devices allow to engineer neural circuits with specific orientations and directionality by providing control over neuronal cell polarity and permitting the isolation of axons in individual microchannels. Similarly, the use of microfluidic chips enables the construction not only of 2D but also of 3D brain, retinal, and peripheral nervous system model circuits. Such brain-on-a-chip and organoid-on-a-chip technologies are promising platforms for studying these organs as they closely recapitulate some aspects of in vivo biological processes. Microfluidic 3D neuronal models, together with 2D in vitro systems, are widely used in many applications ranging from drug development and toxicology studies to neurological disease modeling and personalized medicine. Altogether, microfluidics provide researchers with powerful systems that complement and partially replace animal models.

A Path Analysis Model of Self- vs. Educational-Context- Regulation as Combined Predictors of Well-Being in Spanish College Students.

Previous literature has established the importance of personal and contextual factors in college students' trajectories. Following the Self- vs. External-Regulation Behavior Theory (2021) and the 3P Biggs Model, the present study aimed at analyzing a structural linear model that validates the joint effect of self-regulation, educational context, age, and gender (as personal and contextual presage variables) with other meta-abilities, such as coping strategies, resilience, and positivity (process variables), and specific well-being outcomes, such as flourishing and health (product variables). A sample of 1310 Spanish college students was analyzed, aged 17 to 25, and a cross-sectional study with an ex post facto design was performed. Association and structural equation modeling (SEM) was performed using SPSS software (v.26) and AMOS (v.23). Results show that individual and contextual factors have an important role in the acquisition of psychological competencies in young adults. Self-regulation was proven to be an important meta-ability that predicts personal well-being and behavioral health outcomes. Complementarily, educational context was shown to be an external predictor of other skills, such as problem-focused strategies, and positive outcomes such as flourishing and behavioral health. Practical implications and limitations are discussed.

Validation of the Child and Youth Resilience Measure-28 (CYRM-28) among Spanish youth.

Objectives: This article presents a validation study of the 28-item Child and Youth Resilience Measure (CYRM-28). The sample contained 365 Spanish youth ages between 15 to 21, from Navarre (Spain), all of them enrolled in Initial Vocational Qualification Programs. Method: The CYRM-28 was administered to students from 27 secondary schools in the province of Navarre. Confirmatory analyses were conducted. Results: The structure of the original scale was confirmed, as well as acceptable psychometric properties. Discussion: Findings add support to the CYRM-28 as a reliable and valid self-report instrument that measures three components of resilience processes in the lives of youth with complex needs. The CYRM-28 shows adequate psychometric properties, the CFA presents indices of goodness and fit (Chi-squared = 60,170, df = 17, p < .001; CFI = .960, TLI = .934, IFI = .961, RFI = .911 and NFI = .946; RMSEA = .084). Conclusion: Advanced statistical modeling yielded evidence that the scale, originally developed for use in several countries, can be used to assess resilience in Spanish youth.

VEGF-Trap Modulates Retinal Inflammation in the Murine Oxygen-Induced Retinopathy (OIR) Model.

Anti-Vascular Endothelial Growth Factor (VEGF) agents are the first-line treatment for retinal neovascular diseases, which represent the most prevalent causes of acquired vision loss world-wide. VEGF-Trap (Aflibercept, AFL), a recombinant decoy receptor recognizing ligands of both VEGFR-1 and -2, was recently reported to be highly efficient in improving visual acuity and preserving retinal anatomy in individuals affected by diabetic macular edema. However, the precise molecular and cell biological mechanisms underlying the beneficial effects of this novel tool have yet to be elucidated. Using the mouse oxygen-induced retinopathy (OIR) model as a surrogate of retinopathies with sterile post-ischemic inflammation, such as late proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and diabetic macular edema (DME), we provide evidence that AFL modulates inflammation in response to hypoxia by regulating the morphology of microglial cells, a parameter commonly used as a proxy for changes in their activation state. We show that AFL administration during the hypoxic period of OIR leads to an increased number of ramified Iba1+ microglial cells/macrophages while subsequently limiting the accumulation of these cells in particular retinal layers. Our results suggest that, beyond its well-documented beneficial effects on microvascular regeneration, AFL might exert important modulatory effects on post-ischemic retinal inflammation.

Gene expression profile of the murine ischemic retina and its response to Aflibercept (VEGF-Trap).

Ischemic retinal dystrophies are leading causes of acquired vision loss. Although the dysregulated expression of the hypoxia-responsive VEGF-A is a major driver of ischemic retinopathies, implication of additional VEGF-family members in their pathogenesis has led to the development of multivalent anti-angiogenic tools. Designed as a decoy receptor for all ligands of VEGFR1 and VEGFR2, Aflibercept is a potent anti-angiogenic agent. Notwithstanding, the molecular mechanisms mediating Aflibercept's efficacy remain only partially understood. Here, we used the oxygen-induced retinopathy (OIR) mouse as a model system of pathological retinal vascularization to investigate the transcriptional response of the murine retina to hypoxia and of the OIR retina to Aflibercept. While OIR severely impaired transcriptional changes normally ensuing during retinal development, analysis of gene expression patterns hinted at alterations in leukocyte recruitment during the recovery phase of the OIR protocol. Moreover, the levels of Angiopoietin-2, a major player in the progression of diabetic retinopathy, were elevated in OIR tissues and consistently downregulated by Aflibercept. Notably, GO term, KEGG pathway enrichment, and expression dynamics analyses revealed that, beyond regulating angiogenic processes, Aflibercept also modulated inflammation and supported synaptic transmission. Altogether, our findings delineate novel mechanisms potentially underlying Aflibercept's efficacy against ischemic retinopathies.

Automated methods for cell type annotation on scRNA-seq data.

The advent of single-cell sequencing started a new era of transcriptomic and genomic research, advancing our knowledge of the cellular heterogeneity and dynamics. Cell type annotation is a crucial step in analyzing single-cell RNA sequencing data, yet manual annotation is time-consuming and partially subjective. As an alternative, tools have been developed for automatic cell type identification. Different strategies have emerged to ultimately associate gene expression profiles of single cells with a cell type either by using curated marker gene databases, correlating reference expression data, or transferring labels by supervised classification. In this review, we present an overview of the available tools and the underlying approaches to perform automated cell type annotations on scRNA-seq data.

A comprehensive library of human transcription factors for cell fate engineering.

Human pluripotent stem cells (hPSCs) offer an unprecedented opportunity to model diverse cell types and tissues. To enable systematic exploration of the programming landscape mediated by transcription factors (TFs), we present the Human TFome, a comprehensive library containing 1,564 TF genes and 1,732 TF splice isoforms. By screening the library in three hPSC lines, we discovered 290 TFs, including 241 that were previously unreported, that induce differentiation in 4 days without alteration of external soluble or biomechanical cues. We used four of the hits to program hPSCs into neurons, fibroblasts, oligodendrocytes and vascular endothelial-like cells that have molecular and functional similarity to primary cells. Our cell-autonomous approach enabled parallel programming of hPSCs into multiple cell types simultaneously. We also demonstrated orthogonal programming by including oligodendrocyte-inducible hPSCs with unmodified hPSCs to generate cerebral organoids, which expedited in situ myelination. Large-scale combinatorial screening of the Human TFome will complement other strategies for cell engineering based on developmental biology and computational systems biology.

VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy.

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper-permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF-A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen-induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho-functional responses of the ischemic retina to anti-angiogenic therapies. Using this model, we investigated the retinal responses to VEGF-Trap (Aflibercept), an anti-angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age-related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light-responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743.

Challenges in microRNAs' targetome prediction and validation.

MicroRNAs (miRNAs) are small RNA molecules with important roles in post-transcriptional regulation of gene expression. In recent years, the predicted number of miRNAs has skyrocketed, largely as a consequence of high-throughput sequencing technologies becoming ubiquitous. This dramatic increase in miRNA candidates poses multiple challenges in terms of data deposition, curation, and validation. Although multiple databases containing miRNA annotations and targets have been developed, ensuring data quality by validating miRNA-target interactions requires the efforts of the research community. In order to generate databases containing biologically active miRNAs, it is imperative to overcome a multitude of hurdles, including restricted miRNA expression patterns, distinct miRNA biogenesis machineries, and divergent miRNA-mRNA interaction dynamics. In the present review, we discuss recent advances and limitations in miRNA prediction, identification, and validation. Lastly, we focus on the most enriched neuronal miRNA, miR-124, and its gene regulatory network in human neurons, which has been revealed using a combined computational and experimental approach.

Retinal miRNA Functions in Health and Disease.

The health and function of our visual system relies on accurate gene expression. While many genetic mutations are associated with visual impairment and blindness, we are just beginning to understand the complex interplay between gene regulation and retinal pathologies. MicroRNAs (miRNAs), a class of non-coding RNAs, are important regulators of gene expression that exert their function through post-transcriptional silencing of complementary mRNA targets. According to recent transcriptomic analyses, certain miRNA species are expressed in all retinal cell types, while others are cell type-specific. As miRNAs play important roles in homeostasis, cellular function, and survival of differentiated retinal cell types, their dysregulation is associated with retinal degenerative diseases. Thus, advancing our understanding of the genetic networks modulated by miRNAs is central to harnessing their potential as therapeutic agents to overcome visual impairment. In this review, we summarize the role of distinct miRNAs in specific retinal cell types, the current knowledge on their implication in inherited retinal disorders, and their potential as therapeutic agents.

Real life outcomes of patients aged ≥75 years old with acute promyelocytic leukemia: experience of the PETHEMA registry.

Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.

Theory of Self- vs. Externally-Regulated LearningTM: Fundamentals, Evidence, and Applicability.

The Theory of Self- vs. Externally-Regulated LearningTM has integrated the variables of SRL theory, the DEDEPRO model, and the 3P model. This new Theory has proposed: (a) in general, the importance of the cyclical model of individual self-regulation (SR) and of external regulation stemming from the context (ER), as two different and complementary variables, both in combination and in interaction; (b) specifically, in the teaching-learning context, the relevance of different types of combinations between levels of self-regulation (SR) and of external regulation (ER) in the prediction of self-regulated learning (SRL), and of cognitive-emotional achievement. This review analyzes the assumptions, conceptual elements, empirical evidence, benefits and limitations of SRL vs. ERL Theory. Finally, professional fields of application and future lines of research are suggested.

Seroprevalence of dengue infection in the municipalities of Armenia, Calarcá, La Tebaida and Montenegro in Quindío, 2014.

INTRODUCTION: Dengue is a serious public health problem in Colombia; it is prevalent in 90% of the municipalities in Quindío. Studies on its seroprevalence are required to address public health interventions. OBJECTIVE: To establish the seroprevalence of dengue infection in neighborhoods with high incidence in the municipalities of Armenia, Calarcá, La Tebaida and Montenegro, Quindío, in 2014. MATERIALS AND METHODS: We conducted a probabilistic, stratified, two-stage prevalence study. We interviewed 658 residents in the urban area of the selected municipalities. After they signed the informed consent, we took a blood sample to determine dengue IgG and IgM antibodies. RESULTS: Seroprevalence of IgG in Quindío was 89,4%; in Armenia it was 88,7%, in Calarcá, 81,5%, in Montenegro, 91,8% and in La Tebaida 97,8%. IgM was 14, 2% in Quindío; in Armenia it was 11,5%, in Calarcá, 13,0%, in Montenegro, 13,1% and in La Tebaida, 28,9%. CONCLUSIONS: We found a high prevalence of both IgG and IgM in the four municipalities. We had positive results for IgM in all age groups, which suggests recent infection. We also found simultaneous seropositivity for IgG and IgM (12.9%), which may indicate infection by another serotype or presence of infection in the past three months. A multisectoral approach is necessary for dengue control in Quindío.

Validation of the Spanish Short Self-Regulation Questionnaire (SSSRQ) through Rasch Analysis.

Background: The aim of the study was to psychometrically characterize the Spanish Short Self-Regulation Questionnaire (SSSRQ) through Rasch analysis. Materials and Methods: 831 Spaniard university students (262 men), between 17 and 39 years of age and ranging from the first to the 5th year of studies, completed the SSSRQ questionnaire. Confirmatory factor analysis (CFA) was carried out in order to establish structural adequacy. Afterward, by means of the Rasch model, a study of each sub scale was conducted to test for dimensionality, fit of the sample questions, functionality of the response categories, reliability and estimation of Differential Item Functioning by gender and course. Results: The four sub-scales comply with the unidimensionality criteria, the questions are in line with the model, the response categories operate properly and the reliability of the sample is acceptable. Nonetheless, the test could benefit from the inclusion of additional items of both high and low difficulty in order to increase construct validity, discrimination and reliability for the respondents. Several items with differences in gender and course were also identified. Discussion: The results evidence the need and adequacy of this complementary psychometric analysis strategy, in relation to the CFA to enhance the instrument.

Seroprevalencia de la infección por dengue en los municipios de Armenia, Calarcá, La Tebaida y Montenegro en el departamento del Quindío, 2014 / Seroprevalence of dengue infection in the municipalities of Armenia, Calarcá, La Tebaida and Montenegro in Quindío, 2014

Resumen Introducción: El dengue representa un grave problema de salud pública para Colombia y, en el departamento del Quindío, afecta el 90 % de los municipios. Se necesitan estudios actualizados sobre la seroprevalencia en la población general para reforzar las acciones de salud pública. Objetivo: Determinar la seroprevalencia de la infección por dengue en barrios con alta incidencia de dengue en cuatro municipios del departamento del Quindío: Armenia, Calarcá, La Tebaida y Montenegro, en 2014. Materiales y métodos: Se hizo un estudio de prevalencia mediante muestreo probabilístico estratificado y bietápico. Se hizo una encuesta a 658 sujetos residentes del área urbana de los municipios seleccionados y se les tomó una muestra de sangre por venopunción para determinar anticuerpos IgG e IgM contra el virus del dengue. Resultados: La seroprevalencia de anticuerpos IgG en el Quindío fue de 89,4 %; en Armenia fue de 88,7 %, en Calarcá, de 81,5 %, en Montenegro, de 91,8 %, y en La Tebaida, de 97,8 %. La seroprevalencia de anticuerpos IgM en Quindío fue de 14,2 %; en Armenia, de 11,5 %, en Calarcá, de 13,0 %, en Montenegro, de 13,1%, y en La Tebaida, de 28,9 %. Conclusiones: Se evidenció una alta prevalencia de anticuerpos IgG e IgM en los cuatro municipios. En todos los grupos de edad se encontraron personas seropositivas para IgM, lo cual indicaría infección reciente. La seropositividad simultánea para IgM e IgG (12,9 %) puede indicar infección secundaria por otro serotipo del virus o una infección en los tres meses anteriores. Es necesario impulsar estrategias multisectoriales para el control de la transmisión del dengue en el Quindío.

Abstract Introduction: Dengue is a serious public health problem in Colombia; it is prevalent in 90% of the municipalities in Quindío. Studies on its seroprevalence are required to address public health interventions. Objective: To establish the seroprevalence of dengue infection in neighborhoods with high incidence in the municipalities of Armenia, Calarcá, La Tebaida and Montenegro, Quindío, in 2014. Materials and methods: We conducted a probabilistic, stratified, two-stage prevalence study. We interviewed 658 residents in the urban area of the selected municipalities. After they signed the informed consent, we took a blood sample to determine dengue IgG and IgM antibodies. Results: Seroprevalence of IgG in Quindío was 89,4%; in Armenia it was 88,7%, in Calarcá, 81,5%, in Montenegro, 91,8% and in La Tebaida 97,8%. IgM was 14, 2% in Quindío; in Armenia it was 11,5%, in Calarcá, 13,0%, in Montenegro, 13,1% and in La Tebaida, 28,9%. Conclusions: We found a high prevalence of both IgG and IgM in the four municipalities. We had positive results for IgM in all age groups, which suggests recent infection. We also found simultaneous seropositivity for IgG and IgM (12.9%), which may indicate infection by another serotype or presence of infection in the past three months. A multisectoral approach is necessary for dengue control in Quindío.

Identification of novel mutation in cathepsin C gene causing Papillon-Lefèvre Syndrome in Mexican patients.

BACKGROUND: Papillon-Lefèvre Syndrome (PLS) is a type IV genodermatosis caused by mutations in cathepsin C (CTSC), with a worldwide prevalence of 1-4 cases per million in the general population. In México, the prevalence of this syndrome is unknown, and there are few case reports. The diagnosis of twenty patients in the state of Sinaloa highlights the need to characterize this syndrome in Mexicans. METHODS: To understand the basis of PLS in Mexicans, the gene expression, enzymatic activity and mutational analysis of CTSC were assayed in nine PLS patients and their relatives. Frequencies of CTSC gene polymorphisms and HLA alleles were determined in these patients, their relatives, and the population. RESULTS: Patients showed normal CTSC gene expression, but a deep reduction (up to 85%) in enzymatic activity in comparison to unrelated healthy individuals. A novel loss-of-function mutation, c.203 T > G (p.Leu68Arg), was found in all patients, and some carried the polymorphism c.458C > T (p.Thr153Ile). Allelic frequencies in patients, relatives and controls were 88.89%, 38.24% and 0.25% for G (c.203 T > G); and 11.11%, 8.82% and 9.00% for T (c.458C > T). HLA-DRB1*11 was found significantly more frequent (P = 0.0071) in patients than controls (33.33% vs. 7.32%), with an estimated relative risk of 6.33. CONCLUSIONS: The novel loss-of function mutation of CTSC gene (c.203 T > G) found in patients correlated with their diminished enzymatic activity, and HLA-DRB1*11 was found to be associated with PLS. The study of more PLS patients may give more insights into the etiology of the disease as well as its prevalence in México.