Identifying Priorities in Intensive Care : a description of a system for collecting intensive care data, an analysis of the data collected, a critique of aspects of severity scoring systems used to compare intensive care outcome, identification of priorities in intensive care and proposals to improve outcome for intensive care patients.

MDThis thesis reviews the requirements for intensive care audit data and describes the development of ICARUS (Intensive Care Audit and Resource Utilisation System), a system to collect and analyse intensive care audit information. By the end of 1998 ICARUS contained information on over 45,000 intensive care admissions. A study was performed to determine the accuracy of the data collection and entry in ICARUS. The data in ICARUS was used to investigate some limitations of the APACHE II severity scoring system. The studies examined the effect of changes in physiological values and post-intensive care deaths, and the effect of casemix adjustment on mortality predicted by APACHE II. A hypothesis is presented that excess intensive care mortality in the United Kingdom may be concealed by intensive care mortality prediction models. A critical analysis of ICARUS data was undertaken to identify patient groups most likely to benefit from intensive care. This analysis revealed a high mortality in critically ill patients admitted from the wards to the intensive care unit. To help identify critically ill ward patients, the physiological values and procedures in the 24 hours before intensive care admission from the ward were recorded: examination of the results suggested that management of these patients could be improved. This led to the setting up of a patient at risk team (PART). Two studies report the effect of the PART on patients on the wards and on the patients admitted from the wards to the intensive care unit. Additional care for surgical patients on the wards is suggested as a way of improving the management of high-risk postoperative patients. The thesis concludes by discussing the benefits of the ICARUS system and speculating on the direction that should be taken for intensive care audit in the future

Optimal prediction of mortality after abdominal aortic aneurysm repair with statistical models

Objective: To identify the best method for the prediction of postoperative mortality in individual abdominal aortic aneurysm surgery (AAA) patients by comparing statistical modelling with artificial neural networks' (ANN) and clinicians' estimates. Methods: An observational multicenter study was conducted of prospectively collected postoperative Acute Physiology and Chronic Health Evaluation II data for a 9-year period from 24 intensive care units (ICU) in the Thames region of the United Kingdom. The study cohort consisted of 1205 elective and 546 emergency AAA patients. Four independent physiologic variables-age, acute physiology score, emergency operation, and chronic health evaluation-were used to develop multiple regression and ANN models to predict in-hospital mortality. The models were developed on 75% of the patient population and their validity tested on the remaining 25%. The results from these two models were compared with the observed outcome and clinicians' estimates by using measures of calibration, discrimination, and subgroup analysis

The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets

SARS-CoV-2 entry requires sequential cleavage of the spike glycoprotein at the S1/S2 and the S2ʹ cleavage sites to mediate membrane fusion. SARS-CoV-2 has a polybasic insertion (PRRAR) at the S1/S2 cleavage site that can be cleaved by furin. Using lentiviral pseudotypes and a cell-culture-adapted SARS-CoV-2 virus with an S1/S2 deletion, we show that the polybasic insertion endows SARS-CoV-2 with a selective advantage in lung cells and primary human airway epithelial cells, but impairs replication in Vero E6, a cell line used for passaging SARS-CoV-2. Using engineered spike variants and live virus competition assays and by measuring growth kinetics, we find that the selective advantage in lung and primary human airway epithelial cells depends on the expression of the cell surface protease TMPRSS2, which enables endosome-independent virus entry by a route that avoids antiviral IFITM proteins. SARS-CoV-2 virus lacking the S1/S2 furin cleavage site was shed to lower titres from infected ferrets and was not transmitted to cohoused sentinel animals, unlike wild-type virus. Analysis of 100,000 SARS-CoV-2 sequences derived from patients and 24 human postmortem tissues showed low frequencies of naturally occurring mutants that harbour deletions at the polybasic site. Taken together, our findings reveal that the furin cleavage site is an important determinant of SARS-CoV-2 transmission