Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D2 (PGD2)) and a phospholipase (phospholipase A2 group 2D (PLA2G2D)) contributed to poor outcomes in aged mice3,4. mRNA expression of PLA2G2D and prostaglandin D2 receptor (PTGDR), and production of PGD2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA2G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA2G2D–PGD2/PTGDR pathway is a useful target for therapeutic interventions.This work is supported in part by grants from the National Institutes of Health USA (NIH; P01 AI060699 (S.P. and P.B.M.) and R01 AI129269 (S.P.)) and BIOAGE Labs (S.P.). The Pathology Core is partially supported by the Center for Gene Therapy for Cystic Fibrosis (NIH grant P30 DK-54759) and the Cystic Fibrosis Foundation. P.B.M. is supported by the Roy J. Carver Charitable Trust. L.-Y.R.W. is supported by Mechanism of Parasitism Training Grant (T32 AI007511). We thank M. Gelb (University of Washington) for Pla2g2d−/− mice.Peer reviewe

Systemic Problems: A perspective on stem cell aging and rejuvenation.

This review provides balanced analysis of the advances in systemic regulation of young and old tissue stem cells and suggests strategies for accelerating development of therapies to broadly combat age-related tissue degenerative pathologies. Many highlighted recent reports on systemic tissue rejuvenation combine parabiosis with a "silver bullet" putatively responsible for the positive effects. Attempts to unify these papers reflect the excitement about this experimental approach and add value in reproducing previous work. At the same time, defined molecular approaches, which are "beyond parabiosis" for the rejuvenation of multiple old organs represent progress toward attenuating or even reversing human tissue aging

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood.

Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans

Prospective Evaluation of Weight-Based Prophylactic Enoxaparin Dosing in Critically Ill Trauma Patients: Adequacy of AntiXa Levels is Improved.

Venous thromboembolism (VTE) is a leading cause of death in multisystem trauma patients; the importance of VTE prevention is well recognized. Presently, standard dose enoxaparin (30 mg BID) is used as chemical prophylaxis, regardless of weight or physiologic status. However, evidence suggests decreased bioavailability of enoxaparin in critically ill patients. Therefore, we hypothesized that a weight-based enoxaparin dosing regimen would provide more adequate prophylaxis (as indicated by antifactor Xa levels) for patients in our trauma intensive care unit (TICU).These data were prospectively collected in TICU patients admitted over a 5-month period given twice daily 0.6 mg/kg enoxaparin (actual body weight). Patients were compared with a historical cohort receiving standard dosing. Anti-Xa levels were collected at 11.5 hours (trough, goal ≥ 0.1 IU/mL) after each evening administration. Patient demographics, admission weight, dose, and daily anti-Xa levels were recorded. Patients with renal insufficiency or brain, spine, or spinal cord injury were excluded. Data were collected from 26 patients in the standard-dose group and 37 in the weight-based group. Sixty-four trough anti-Xa measurements were taken in the standard dose group and 74 collected in the weight-based group. Evaluating only levels measured after the third dose, the change in dosing of enoxaparin from 30 to 0.6 mg/kg resulted in an increased percentage of patients with goal antifactor Xa levels from 8 per cent to 61 per cent (P \u3c 0.0001). Examining all troughs, the change in dose resulted in an increase in patients with a goal anti-Xa level from 19 to 59 per cent (P \u3c 0.0001). Weight-based dosing of enoxaparin in trauma ICU patients yields superior results with respect to adequate anti-Xa levels when compared with standard dosing. These findings suggest that weight-based dosing may provide superior VTE prophylaxis in TICU patients. Evaluation of the effects of this dosing paradigm on actual VTE rate is ongoing at our institution

“Who’ll take the chair?” Maternal employment effects of a Polish (pre)school reform

This study examines the impact of preschool availability on the employment of mothers of preschool-aged children. We exploit a transitional phase of a 2009 Polish education reform that simultaneously lowered the primary school age from 7 to 6 and provided a statutory right to preschool to 5-year-olds. As a significant share of 6-year-old children moved into primary schools a year earlier, their preschool seats effectively became available for younger children. The reform thereby led to a substantial rise in the number of available preschool seats for 3- to 5-year-olds. Using regional variation in the degree of preschool expansion, we estimate the impact of the increased availability of preschool seats on maternal employment. Our results indicate a significant and sizable employment effect: a 10% points increase in the ratio of preschool seats to preschool-aged children increases maternal employment by around 4.2% points. The effect seems to be concentrated among highly educated mothers and mothers with a youngest child of age three