Assessment of a Comparative Bayesian-Enhanced Population-Based Decision Model for COVID-19 Critical Care Prediction in the Dominican Republic Social Security Affiliates

Introduction: The novel coronavirus disease 2019 (COVID-19) has been a major health concern worldwide. This study aims to develop a Bayesian model to predict critical outcomes in patients with COVID-19. Methods: Sensitivity and specificity were obtained from previous meta-analysis studies. The complex vulnerability index (IVC-COV2 index for its abbreviation in Spanish) was used to set the pretest probability. Likelihood ratios were integrated into a Fagan nomogram for posttest probabilities, and IVC-COV2 + National Early Warning Score (NEWS) values and CURB-65 scores were generated. Absolute and relative diagnostic gains (RDGs) were calculated based on pretest and posttest differences. Results: The IVC-COV2 index was derived from a population of 1,055,746 individuals and was based on mortality in high-risk (71.97%), intermediate-risk (26.11%), and low-risk (1.91%) groups. The integration of models in which IVC-COV2 intermediate + NEWS ≥ 5 and CURB-65 \u3e 2 led to a number needed to (NNT) diagnose that was slightly improved in the CURB-65 model (2 vs. 3). A comparison of diagnostic gains revealed that neither the positive likelihood ratio (P = 0.62) nor the negative likelihood ratio (P = 0.95) differed significantly between the IVC-COV2 NEWS model and the CURB-65 model. Conclusion: According to the proposed mathematical model, the combination of the IVC-COV2 intermediate score and NEWS or CURB-65 score yields superior results and a greater predictive value for the severity of illness. To the best of our knowledge, this is the first population-based/mathematical model developed for use in COVID-19 critical care decision-making

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strateg

Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis

OBJECTIVE: Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis. DESIGN: G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. G9a and DNMT1 expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-β1 (TGFβ1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl4 administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology. RESULTS: G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGFβ1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGFβ1 fibrogenic responses in hHSC. TGFβ1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity. CONCLUSIONS: Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis

Time and Origin of Cichlid Colonization of the Lower Congo Rapids

Most freshwater diversity is arguably located in networks of rivers and streams, but, in contrast to lacustrine systems riverine radiations, are largely understudied. The extensive rapids of the lower Congo River is one of the few river stretches inhabited by a locally endemic cichlid species flock as well as several species pairs, for which we provide evidence that they have radiated in situ. We use more that 2,000 AFLP markers as well as multilocus sequence datasets to reconstruct their origin, phylogenetic history, as well as the timing of colonization and speciation of two Lower Congo cichlid genera, Steatocranus and Nanochromis. Based on a representative taxon sampling and well resolved phylogenetic hypotheses we demonstrate that a high level of riverine diversity originated in the lower Congo within about 5 mya, which is concordant with age estimates for the hydrological origin of the modern lower Congo River. A spatial genetic structure is present in all widely distributed lineages corresponding to a trisection of the lower Congo River into major biogeographic areas, each with locally endemic species assemblages. With the present study, we provide a phylogenetic framework for a complex system that may serve as a link between African riverine cichlid diversity and the megadiverse cichlid radiations of the East African lakes. Beyond this we give for the first time a biologically estimated age for the origin of the lower Congo River rapids, one of the most extreme freshwater habitats on earth

Assessment of Three Mitochondrial Genes (16S, Cytb, CO1) for Identifying Species in the Praomyini Tribe (Rodentia: Muridae)

The Praomyini tribe is one of the most diverse and abundant groups of Old World rodents. Several species are known to be involved in crop damage and in the epidemiology of several human and cattle diseases. Due to the existence of sibling species their identification is often problematic. Thus an easy, fast and accurate species identification tool is needed for non-systematicians to correctly identify Praomyini species. In this study we compare the usefulness of three genes (16S, Cytb, CO1) for identifying species of this tribe. A total of 426 specimens representing 40 species (sampled across their geographical range) were sequenced for the three genes. Nearly all of the species included in our study are monophyletic in the neighbour joining trees. The degree of intra-specific variability tends to be lower than the divergence between species, but no barcoding gap is detected. The success rate of the statistical methods of species identification is excellent (up to 99% or 100% for statistical supervised classification methods as the k-Nearest Neighbour or Random Forest). The 16S gene is 2.5 less variable than the Cytb and CO1 genes. As a result its discriminatory power is smaller. To sum up, our results suggest that using DNA markers for identifying species in the Praomyini tribe is a largely valid approach, and that the CO1 and Cytb genes are better DNA markers than the 16S gene. Our results confirm the usefulness of statistical methods such as the Random Forest and the 1-NN methods to assign a sequence to a species, even when the number of species is relatively large. Based on our NJ trees and the distribution of all intraspecific and interspecific pairwise nucleotide distances, we highlight the presence of several potentially new species within the Praomyini tribe that should be subject to corroboration assessments