Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics.

Approximately 5 million dengue virus-infected patients progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the FcγR CD64 on myeloid cells, yet a signature of diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage versus enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.

An 8-gene machine learning model improves clinical prediction of severe dengue progression.

BACKGROUND: Each year 3-6 million people develop life-threatening severe dengue (SD). Clinical warning signs for SD manifest late in the disease course and are nonspecific, leading to missed cases and excess hospital burden. Better SD prognostics are urgently needed. METHODS: We integrated 11 public datasets profiling the blood transcriptome of 365 dengue patients of all ages and from seven countries, encompassing biological, clinical, and technical heterogeneity. We performed an iterative multi-cohort analysis to identify differentially expressed genes (DEGs) between non-severe patients and SD progressors. Using only these DEGs, we trained an XGBoost machine learning model on public data to predict progression to SD. All model parameters were "locked" prior to validation in an independent, prospectively enrolled cohort of 377 dengue patients in Colombia. We measured expression of the DEGs in whole blood samples collected upon presentation, prior to SD progression. We then compared the accuracy of the locked XGBoost model and clinical warning signs in predicting SD. RESULTS: We identified eight SD-associated DEGs in the public datasets and built an 8-gene XGBoost model that accurately predicted SD progression in the independent validation cohort with 86.4% (95% CI 68.2-100) sensitivity and 79.7% (95% CI 75.5-83.9) specificity. Given the 5.8% proportion of SD cases in this cohort, the 8-gene model had a positive and negative predictive value (PPV and NPV) of 20.9% (95% CI 16.7-25.6) and 99.0% (95% CI 97.7-100.0), respectively. Compared to clinical warning signs at presentation, which had 77.3% (95% CI 58.3-94.1) sensitivity and 39.7% (95% CI 34.7-44.9) specificity, the 8-gene model led to an 80% reduction in the number needed to predict (NNP) from 25.4 to 5.0. Importantly, the 8-gene model accurately predicted subsequent SD in the first three days post-fever onset and up to three days prior to SD progression. CONCLUSIONS: The 8-gene XGBoost model, trained on heterogeneous public datasets, accurately predicted progression to SD in a large, independent, prospective cohort, including during the early febrile stage when SD prediction remains clinically difficult. The model has potential to be translated to a point-of-care prognostic assay to reduce dengue morbidity and mortality without overwhelming limited healthcare resources.

Perfil de personalidad de hombres condenados por delitos violentos y delitos no violentos recluidos en el establecimiento penitenciario de mediana seguridad y carcelario de la ciudad de Cartagena / Personality profile of convictted men for violent and nonviolent offenses serving time in the in the medium security penal facility and prison of Catagena city

El presente artículo se deriva de una investigación que tuvo como objetivo describir las características de personalidad de hombres condenados por delitos violentos (homicidio – delitos sexuales) y delitos no violentos (tráfico de estupefacientes) recluidos en establecimiento penitenciario de la ciudad de Cartagena, a través de la aplicación del Inventario Clínico Multiaxial de Millon MCMI–III que evalúa trastornos de personalidad e indicadores clínicos en relación con las teorías del DSM (APA). Se utilizó un diseño cuantitativo, descriptivo, no experimental del tipo trasversal. En los resultados obtenidos de la evaluación de los sujetos condenados por el delito de homicidio se encontró predomino de personalidad narcisista, en los sujetos condenados por delitos sexuales se evidenció manipulación de respuestas y personalidad antisocial; en cuanto a los evaluados condenados por delito no violento, personalidad paranoide. En relación con los indicadores clínicos todos los evaluados presentaron ansiedad; la presencia de síntomas ansiosos podría estar relacionada con el ambiente penitenciario, pero no se encontró evidencia científica que apoyará o no este hecho. En los delitos violentos se encontró presencia de consumo de sustancias psicoactivas en contraste con la ausencia de este indicador clínico en los evaluados condenados por tráfico de estupefacientes...

This article stems from an investigation aimed at describing the personality characteristics of men convicted for violent crimes (murder – sexual offenses) and non–violent offenses (drug trafficking) incarcerated in the city of Cartagena, using the Clinical Multiaxial Millon Inventory MCMI– III that evaluates personality disorders and clinical indicators in relation to theories of DSM (APA). A quantitative, descriptive, non–experimental type of transversal design was applied. The research results indicate a predominance of narcissistic personality traits in the subjects convicted for homicide, in individuals convicted for sexual offenses manipulation of responses and an antisocial personality became evident, whilst in subjects convicted for nonviolent crime, a paranoid personality became apparent. As regards the clinical indicators all the subjects researched manifested anxiety. The presence of anxiety symptoms may have been related to the prison environment, but no scientific evidence to support or not to support this fact was found. Violent crime appeared associated with the presence of psychoactive substances in contrast to the absence of this clinical indicator in the evaluated subjects convicted for drug trafficking...

Cloreto de benzalcônio como medicação tópica / Benzalkonium chloride as topical medication

Fontes dos dados: Revisão bibliográfica obtida pela busca nas bases de dados Cochrane, MEDLINE, BIREME, LILACS e SciELO nos últimos 20 anos, utilizando-se os termos: compostos de benzalcônio, mucosa nasal, toxicidade de drogas e rinite. Síntese dos dados: O cloreto de benzalcônio é um composto amônio quaternário que possui ação umectante e detergente, com propriedades emulsificadora e germicida. Os efeitos adversos sobre o organismo têm sido estudados há mais de duas décadas. Ratos tratados com cloreto de benzalcônio por mais de quatro semanas desenvolveram, a partir do sexto dia, hiperemia da região nasal e respiração ruidosa. Em biópsias de tecido nasal de indivíduos saudáveis submetidos ao cloreto de benzalcônio, verificou-se ação deletéria sobre os cílios da mucosa nasal. Outras alterações também foram observadas, como perda da continuidade celular nas amostras de epitélio nasal, defeitos na membrana nuclear, acúmulo de grânulos e perda de organelas. Conclusões: Diferentes efeitos deletérios do cloreto de benzalcônio sobre a mucosa nasal foram demonstrados in vivo e in vitro...

Data sources: Literature review obtained by Cochrane, MEDLINE, BIREME, LILACS and SciELO databases over the last 20 years, using the terms: benzalkonium chloride compounds, nasal mucosa, drug toxicity, and rhinitis. Data synthesis: Benzalkonium chloride is a quaternary ammonium compound that has humectant and detergent actions, and emulsification and germicide properties. The adverse effects on the body have been studied for more than two decades. Mice treated with benzalkonium chloride by more than four weeks, from the sixth day, showed nasal hyperemia and a noisy breathing. In nasal tissue biopsies of healthy individuals treated with benzalkonium chloride a deleterious action on the nasal mucosa cilia was demonstrated. Also, other alterations have been observed: cell loss of continuity in nasal epithelium, nuclear membrane defects, granule accumulation and organelles loss. Conclusions: Different deleterious effects of benzalkonium chloride on the nasal mucosa have been demonstrated in vivo and in vitro. The toxicity was observed even in concentrations below found in commercial preparations and in use for short period of time. Benzalkonium chloride can cause morphological changes in mucous cilia transport; and in immune function possibly clinical implications that may bring injury in the patients...