Mitochondrial antioxidants abate SARS-COV-2 pathology in mice.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.

SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19.

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

The Carer Assessment of MedicaTion Management GuidanCe for People With Dementia at Hospital Discharge (CATCH) Tool: Exploratory Factor Analysis.

PURPOSE: The Carer Assessment of medicaTion management guidanCe for people with dementia at Hospital discharge (CATCH) tool was developed to examine the carer's experiences of medication management guidance delivery at discharge. This study explored its factor structure, characterized carers' experiences at discharge, and identified predictors of carer preparedness to manage medications at discharge. METHODS: A cross-sectional survey of carers across Australia was distributed. Survey responses were analyzed descriptively, and exploratory factor and regression analyses were performed. RESULTS: A total of 185 survey responses were completed. Exploratory factor analysis revealed 2 factors in the CATCH tool: (1) shared and supported decision-making in medication management (16 items loading 0.47 to 0.93); 2) provision of medication management guidance that is easy to understand (4 items loading (0.48 to 0.82). Internal consistency was acceptable (Cronbach alpha >0.8). Almost 18% of participants stated that they were not included in decisions about medications for people with dementia. The carer reported that the measure of how guidance is provided was positively related to their confidence in the management of medications postdischarge and satisfaction ( P < 0.05 for both). CONCLUSIONS: The CATCH tool can give the patient and carer an opportunity to provide feedback on key elements of medication management guidance delivered at discharge.

Secretome profiling reveals acute changes in oxidative stress, brain homeostasis, and coagulation following short-duration spaceflight.

As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated "spaceflight secretome profiles," which showed significant differences in coagulation, oxidative stress, and brain-enriched proteins. While >93% of differentially abundant proteins (DAPs) in vesicles and metabolites recovered within six months, the majority (73%) of plasma DAPs were still perturbed post-flight. Moreover, these proteomic alterations correlated better with peripheral blood mononuclear cells than whole blood, suggesting that immune cells contribute more DAPs than erythrocytes. Finally, to discern possible mechanisms leading to brain-enriched protein detection and blood-brain barrier (BBB) disruption, we examined protein changes in dissected brains of spaceflight mice, which showed increases in PECAM-1, a marker of BBB integrity. These data highlight how even short-duration spaceflight can disrupt human and murine physiology and identify spaceflight biomarkers that can guide countermeasure development.

Availability and evaluation of medication management resources for carers of people with dementia: a scoping review with an environmental scan.

INTRODUCTION: There is a need for resources to guide informal carers in medication management for people with dementia. Availability of resources on medication management guidance has yet to be explored. AREAS COVERED: A systematic search of MEDLINE, Embase, CINAHL and PsycINFO was performed in May 2022 to identify and evaluate resources for carers of people with dementia that provide guidance in medication management. Google and known repositories were also searched. Readability of text-based resources was examined using the Flesch-Kincaid reading level, the Flesch reading ease and the Gunning-Fog index. Resources were further evaluated using the Patient Education Material Assessment Tool (PEMAT or PEMAT-A/V). EXPERT OPINION: Fifteen resources were identified, which largely focused on medication administration with limited discussion of shared decision-making. Current resources do not appear to have included people living with dementia or their carers in their development and did not address high-risk care settings. Codesign of resources with carers and people with dementia would ensure that resources are comprehensive and target their needs. Future research should therefore focus on development of readily available and understandable resources that provide medication management guidance for carers across different health settings, to comprehensively address the multi-faceted nature of dementia.

SARS-CoV-2 Orphan Gene ORF10 Contributes to More Severe COVID-19 Disease.

The orphan gene of SARS-CoV-2, ORF10, is the least studied gene in the virus responsible for the COVID-19 pandemic. Recent experimentation indicated ORF10 expression moderates innate immunity in vitro. However, whether ORF10 affects COVID-19 in humans remained unknown. We determine that the ORF10 sequence is identical to the Wuhan-Hu-1 ancestral haplotype in 95% of genomes across five variants of concern (VOC). Four ORF10 variants are associated with less virulent clinical outcomes in the human host: three of these affect ORF10 protein structure, one affects ORF10 RNA structural dynamics. RNA-Seq data from 2070 samples from diverse human cells and tissues reveals ORF10 accumulation is conditionally discordant from that of other SARS-CoV-2 transcripts. Expression of ORF10 in A549 and HEK293 cells perturbs immune-related gene expression networks, alters expression of the majority of mitochondrially-encoded genes of oxidative respiration, and leads to large shifts in levels of 14 newly-identified transcripts. We conclude ORF10 contributes to more severe COVID-19 clinical outcomes in the human host.