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Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (-0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.

Two criteria of alcoholic drinking behaviorinelasticity of demand and dissociation of intake from normal eating and drinking-are illustrated by study of alcohol-preferring C57BL/6J mice. Although these mice drink enough to become intoxicated for brief periods each night, they do not meet the more rigorous criteria for pharmacologically motivated drinking. In these respects the animals resemble human alcoholics and appear to provide an opportunity to analyze the disease under laboratory conditions. On the other hand, there are reasons to question the relevance of these phenomena to the human disease. Heavy drinking does not harm the animals in any obvious way. It neither disables them acutely, nor does it produce significant organ damage (4), even after months of ingesting the equivalent for humans of two quarts of whiskey per day. The rapid metabolism of alcohol in mice protects them from the toxicity that a man would experience from comparable drinking. While it is conceivable that mice might be found that would drink enough alcohol voluntarily to produce the toxic effects that are so prominent in human alcoholics, it is perhaps unnecessary to demand this of a model since toxicity is a result, not the cause, of excessive drinking.Essentially, the problem in alcoholism is abnormal appetite-a compulsion to drink alcohol at inappropriate times and to continue drinking to the stage of gross impairment. Of course, not all motivation to drink alcohol is pathological. It is a food as well as a drug (5, 6), and studies of drinking by animals must make this distinction (7,8). For human alcoholics, the substance appears to act as an addictive drug, while the caloric effects are motivationally irrelevant. The question implicit in any proposed model of the disease is whether the animal's motivation is similarly drug-oriented or simply nutritive.The present report discusses two tests that make this distinction: elasticity of appetite for beverage-concentration alcohol and temporal correlations of eating and drinking. Elasticity is exhibited by a reduction in the quantity of alcohol consumed when alternative sources of calories are provided. Correlations compare intake patterns of food and drink. By both criteria, the mice in the present study appeared to be consuming alcohol as a food rather than a drug. It is possible that other strains or species being studied as models of alcoholism would exhibit evidence of pharmacologically motivated drinking when evaluated by these criteria. Since such testing is not difficult, and the result is critical to issues of clinical relevance, it might be useful to subject all putative models to these criteria. MATERIALS AND METHODSMale mice of the C57BL/6J strain were housed individually in plastic cages, located in a temperature-controlled (22 ± 10C) room with a light/dark cycle of 12:12 hr. The equipment used for continuous monitoring of fluid consumption and details of feeding and animal care have been described (9). In addition, a device for monitoring consumption of dry food wa...