ABSTRACT
The transmission risk of SARS-CoV-2 within hospitals can exceed that in the general community because of more frequent close proximity interactions (CPIs). Heterogeneity of risk across wards is still poorly described. We measured CPIs in 15 clinical wards across three hospitals using wearable sensors over 36 hours in spring 2020. This data was combined with a transmission model to estimate and compare transmission risks across wards. We found a four-fold range of epidemic risk between wards, with patients frequently presenting high risk to patients and healthcare workers (HCWs). Using a simulation study, we then assessed the potential impact on global risk of targeting individuals for prevention based on their contact patterns. We found that targeting individuals with the highest cumulative contact hours was most impactful. This study reveals patterns of interactions between individuals in hospital during a pandemic and opens new routes for research into airborne nosocomial risk. One Sentence SummaryWe measured contacts between staff, patients and visitors in 15 hospital wards, and used models to predict epidemic risk and evaluate interventions.
ABSTRACT
Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
ABSTRACT
"The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy about hydroxychloroquine and the retrospective nature of their study, they intend to revise the manuscript after peer review"
ABSTRACT
New treatments are being developed for myotonic dystrophy type 1 (DM1). To evaluate their efficacy, knowledge about the natural history of respiratory dysfunction and its relationship with the genotype will be crucial. Also needed is information on factors predicting the time-course of respiratory function in DM1. Using data from 283 patients, we built a segmented linear mixed-effects regression model to assess respiratory function changes over time. Respiratory variables associated with the CTG repeat number were identified by multivariate linear regression analysis. Cox proportional-hazards regression was used to estimate hazard ratios (HRs) for starting non-invasive ventilation (NIV). Higher CTG repeat number was associated with peak cough flow impairment (p = 0.007) and with lower values for maximal inspiratory pressure (p <0.0001) and upright vital capacity. A vital capacity decline over time was associated with older age at first evaluation (p <0.0001), higher CTG repeat number (p <0.0001), and higher baseline body mass index (p = 0.0004). NIV initiation was associated with lower peak cough flow (p <0.001) after age and PaCO2 adjustment. Earlier and closer monitoring with routine peak cough flow determination in adults with congenital DM1, combined with weight control, may diminish the risk of respiratory complications and optimise other aspects of management.
