Multivariate time-series analysis of biomarkers from a dengue cohort offers new approaches for diagnosis and prognosis

Dengue is a major public health problem worldwide with distinct clinical manifestations: an acute presentation (dengue fever, DF) similar to other febrile illnesses (OFI) and a more severe, life-threatening form (severe dengue, SD). Due to nonspecific clinical presentation during the early phase of dengue infection, differentiating DF from OFI has remained a chal-lenge, and current methods to determine severity of dengue remain poor early predictors. We present a prospective clinical cohort study conducted in Caracas, Venezuela from 2001–2005, designed to determine whether clinical and hematological parameters could distinguish DF from OFI, and identify early prognostic biomarkers of SD. From 204 enrolled suspected dengue patients, there were 111 confirmed dengue cases. Piecewise mixed effects regression and nonparametric statistics were used to analyze longitudinal records. Decreased serum albumin and fibrinogen along with increased D-dimer, thrombin-anti-thrombin complex, activated partial thromboplastin time and thrombin time were prognostic of SD on the day of defervescence. In the febrile phase, the day-to-day rates of change in serum albumin and fibrinogen concentration, along with platelet counts, were significantly decreased in dengue patients compared to OFI, while the day-to-day rates of change of lym-phocytes (%) and thrombin time were increased. In dengue patients, the absolute lympho-cytes to neutrophils ratio showed specific temporal increase, enabling classification of dengue patients entering the critical phase with an area under the ROC curve of 0.79. Secondary dengue patients had elongation of Thrombin time compared to primary cases while the D-dimer formation (fibrinolysis marker) remained always lower for secondary compared to primary cases. Based on partial analysis of 31 viral complete genomes, a high frequency of C-to-T transitions located at the third codon position was observed, suggesting deamina-tion events with five major hot spots of amino acid polymorphic sites outside in non-structural proteins. No association of severe outcome was statistically significant for any of the five major polymorphic sites found. This study offers an improved understanding of dengue hemostasis and a novel way of approaching dengue diagnosis and disease prognosis using piecewise mixed effect regression modeling. It also suggests that a better discrimination of the day of disease can improve the diagnostic and prognostic classification power of clinical variables using ROC curve analysis. The piecewise mixed effect regression model corroborated key early clinical determinants of disease, and offers a time-series approach for future vaccine and pathogenesis clinical studies

Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency–causing KNG1 variants, and estimated prevalence

Background: Severe high-molecular-weight kininogen (HK) deficiency is a poorly studied autosomal recessive contact system defect caused by pathogenic, biallelic KNG1 variants. Aim: We performed the first comprehensive analysis of diagnostic, clinical, genetic, and epidemiological aspects of HK deficiency. Methods: We collected clinical information and blood samples from a newly detected HK-deficient individual and from published cases identified by a systematic literature review. Activity and antigen levels of coagulation factors were determined. Genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. The frequency of HK deficiency was estimated considering truncating KNG1 variants from GnomAD. Results: We identified 48 cases of severe HK deficiency (41 families), of these 47 have been previously published (n = 19 from gray literature). We genotyped 3 cases and critically appraised 10 studies with genetic data. Ten HK deficiency-causing variants (one new) were identified. All of them were truncating mutations, whereas the only known HK amino acid substitution with a relevant phenotype instead causes hereditary angioedema. Conservative estimates suggest an overall prevalence of severe HK deficiency of approximately one case per 8 million population, slightly higher in Africans. Individuals with HK deficiency appeared asymptomatic and had decreased levels of prekallikrein and factor XI, which could lead to misdiagnosis. Conclusion: HK deficiency is a rare condition with only few known pathogenic variants. It has an apparently good prognosis but is prone to misdiagnosis. Our understanding of its clinical implications is still limited, and an international prekallikrein and HK deficiency registry is being established to fill this knowledge gap. Keywords: blood coagulation disorders; diagnosis; epidemiology; high-molecular-weight; kallikrein-kinin system; kininogen; partial thromboplastin tim

Análisis comparativo de las pautas del consejo de organizaciones internacionales de ciencias médicas (CIOMS) 2016. (Parte 1 de 3)

To carry out scientific research on human beings, compliance with the Declaration of Helsinki, whose last update was published in 2013, is essential. For Latin American countries, this statement was adopted as the CIOMS Guidelines, which were last updated and published in 2016. As part of the evaluation of the subject Bioethics and Research, students of the VI Cohort of the Master in Bioethics of the Faculty of Medicine, UCV, were asked to perform a comparative analysis of these with the guidelines contemplated in the previous edition of 2002 to provide researchers with a contribution in their training and a rapid adaptation to the new proposal. For the development of these works, the guidelines were grouped into large related topics and presented in three installments.Para la realización de investigaciones científicas en seres humanos es fundamental el cumplimiento de la Declaración de Helsinki, cuya última actualización se publicó en el 2013. Para los países de América Latina esta declaración se adaptó como las Pautas CIOMS, por lo que también fue necesario actualizar y su publicación ocurrió en el 2016. Como parte de la evaluación de la asignatura Bioética e Investigación, se solicitó a los estudiantes de la VI Cohorte de la Maestría en Bioética de la Facultad de Medicina, UCV, que realizarán un análisis comparativo de éstas con las pautas contempladas en la edición anterior del 2002 a fin de proporcionar a los investigadores un aporte en su formación y una rápida adaptación a la nueva propuesta. Para el desarrollo de estos trabajos se agruparon las pautas en grandes temas afines y se presentan en tres entregas