Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit.

Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies.

Cost-Effectiveness of Plasma Microbial Cell-Free DNA Sequencing When Added to Usual Care Diagnostic Testing for Immunocompromised Host Pneumonia.

Introduction: Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value.

Aim: The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients.

Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

Background: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia.

Methods: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing.

Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection.

Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8Tc, NKT, and epithelial cells.

Hypothesis-Agnostic Network-Based Analysis of Real-World Data Suggests Ondansetron is Associated with Lower COVID-19 Any Cause Mortality.

Background: The COVID-19 pandemic generated a massive amount of clinical data, which potentially hold yet undiscovered answers related to COVID-19 morbidity, mortality, long-term effects, and therapeutic solutions.

Objectives: The objectives of this study were (1) to identify novel predictors of COVID-19 any cause mortality by employing artificial intelligence analytics on real-world data through a hypothesis-agnostic approach and (2) to determine if these effects are maintained after adjusting for potential confounders and to what degree they are moderated by other variables.

Methods: A Bayesian statistics-based artificial intelligence data analytics tool (bAIcis) within the Interrogative Biology platform was used for Bayesian network learning and hypothesis generation to analyze 16,277 PCR+ patients from a database of 279,281 inpatients and outpatients tested for SARS-CoV-2 infection by antigen, antibody, or PCR methods during the first pandemic year in Central Florida.

Altered methylation of specific DNA loci in the liver of -null mice results in repression of and and is associated with development of preneoplastic foci.

Folate B-dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway-catalyzed by betaine-homocysteine methyltransferase (BHMT)-for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J (betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk ( = 8) and observed elevation of -adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione -transferase and cytokeratin 8-18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed.

Genetic and epigenetic transgenerational implications related to omega-3 fatty acids. Part II: maternal FADS2 rs174575 genotype and DNA methylation predict toddler cognitive performance.

Maternal transfer of fatty acids is important to fetal brain development. The prenatal environment may differentially affect the substrates supporting declarative memory abilities, as the level of fatty acids transferred across the placenta may be affected by the maternal fatty acid desaturase 2 (FADS2) rs174575 single nucleotide polymorphism. In this study, we hypothesized that toddler and maternal rs174575 genotype and FADS2 promoter methylation would be related to the toddlers' declarative memory performance.

Genetic and epigenetic transgenerational implications related to omega-3 fatty acids. Part I: maternal FADS2 genotype and DNA methylation correlate with polyunsaturated fatty acid status in toddlers: an exploratory analysis.

Polyunsaturated fatty acid metabolism in toddlers is regulated by a complex network of interacting factors. The contribution of maternal genetic and epigenetic makeup to this milieu is not well understood. In a cohort of mothers and toddlers 16 months of age (n = 65 mother-child pairs), we investigated the association between maternal genetic and epigenetic fatty acid desaturase 2 (FADS2) profiles and toddlers' n-6 and n-3 fatty acid metabolism.

Perinatal α-linolenic acid availability alters the expression of genes related to memory and to epigenetic machinery, and the Mecp2 DNA methylation in the whole brain of mouse offspring.

Many animal and human studies indicated that dietary ω-3 fatty acids could have beneficial roles on brain development, memory, and learning. However, the exact mechanisms involved are far from being clearly understood, especially for α-linolenic acid (ALA), which is the precursor for the ω-3 elongation and desaturation pathways. This study investigated the alterations induced by different intakes of flaxseed oil (containing 50% ALA), during gestation and lactation, upon the expression of genes involved in neurogenesis, memory-related molecular processes, and DNA methylation, in the brains of mouse offspring at the end of lactation (postnatal day 19, P19).

Perinatal epigenetic determinants of cognitive and metabolic disorders.

Multiple cues from the environment of our indirect and immediate ancestors, which often persist throughout the prenatal period and adulthood, are shaping our phenotypes through either direct, parent-to-child influences, or transgenerational inheritance. These effects are due to gene-environment interactions, which are intended to be a predictive tool and a mechanism of quick adaptation to the environment, as compared with genetic variations that are inherited over many generations. In certain circumstances the influences induced by the gene-environment interactions can have deleterious effects upon the health status, in the context of a radical change in the environment that does not fit with the predicted conditions, via epigenetic alterations.

Perinatal manipulation of α-linolenic acid intake induces epigenetic changes in maternal and offspring livers.

Previous studies indicated that the intake of α-linolenic acid (ALA) can alter the concentration of both ω-6 and ω-3 fatty acids in both mother and offspring, with consequences on postnatal brain development. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in the Fads2 DNA methylation in both maternal and offspring livers, at the end of lactation period. Both Fads2 promoter and intron 1 DNA methylation were increased in the groups receiving postnatal flaxseed oil containing 50% ALA (mothers or pups), while bivariate analysis indicated a significant association of the Fads2 epigenetic status in the liver between each mother and its offspring.

Maternal α-linolenic acid availability during gestation and lactation alters the postnatal hippocampal development in the mouse offspring.

The availability of ω-3 polyunsaturated fatty acids is essential for perinatal brain development. While the roles of docosahexaenoic acid (the most abundant ω-3 species) were extensively described, less is known about the role of α-linolenic acid (ALA), which is the initial molecular species undergoing elongation and desaturation within the ω-3 pathways. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in hippocampal development (dentate gyrus) in the mouse male offspring, at the end of lactation (postnatal day 19, P19).

Nutritional influence on epigenetics and effects on longevity.

Purpose Of Review: This review synthesizes recently published information regarding nutrition and its impact upon epigenetically mediated mechanisms involved in longevity and aging.

Recent Findings: Recent studies enriched considerably our understanding of the relationship between aging and gene-nutrient interactions that continuously shape our phenotype. Epigenetic mechanisms play an important role in mediating between the nutrient inputs and the ensuing phenotypic changes throughout our entire life and seem to be responsible, in part, for the biological changes that occur during aging.

High fat diet-induced maternal obesity alters fetal hippocampal development.

The importance of maternal nutrition for fetal brain development is increasingly recognized. Previous studies have suggested that maternal obesity or maternal exposure to obesogenic diets may permanently alter brain structure and function in the offspring. To test whether maternal exposure to a high-fat diet, prior and during gestation, alters fetal hippocampal development, we fed 8-week old C57BL/6 females with a high-fat diet (60% calories from fat) for 10 weeks prior to matting and 17 days after.