Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect.

Background Low nurse staffing levels are associated with adverse patient outcomes from hospital care, but the causal relationship is unclear. Limited capacity to observe patients has been hypothesised as a causal mechanism. Objectives This study determines whether or not adverse outcomes are more likely to occur after patients experience low nurse staffing levels, and whether or not missed vital signs observations mediate any relationship. Design Retrospective longitudinal observational study. Multilevel/hierarchical mixed-effects regression models were used to explore the association between registered nurse (RN) and health-care assistant (HCA) staffing levels and outcomes, controlling for ward and patient factors. Setting and participants A total of 138,133 admissions to 32 general adult wards of an acute hospital from 2012 to 2015. Main outcomes Death in hospital, adverse event (death, cardiac arrest or unplanned intensive care unit admission), length of stay and missed vital signs observations. Data sources Patient administration system, cardiac arrest database, eRoster, temporary staff bookings and the Vitalpac system (System C Healthcare Ltd, Maidstone, Kent; formerly The Learning Clinic Limited) for observations. Results Over the first 5 days of stay, each additional hour of RN care was associated with a 3% reduction in the hazard of death [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.94 to 1.0]. Days on which the HCA staffing level fell below the mean were associated with an increased hazard of death (HR 1.04, 95% CI 1.02 to 1.07), but the hazard of death increased as cumulative staffing exposures varied from the mean in either direction. Higher levels of temporary staffing were associated with increased mortality. Adverse events and length of stay were reduced with higher RN staffing. Overall, 16% of observations were missed. Higher RN staffing was associated with fewer missed observations in high-acuity patients (incidence rate ratio 0.98, 95% CI 0.97 to 0.99), whereas the overall rate of missed observations was related to overall care hours (RN + HCA) but not to skill mix. The relationship between low RN staffing and mortality was mediated by missed observations, but other relationships between staffing and mortality were not. Changing average skill mix and staffing levels to the levels planned by the Trust, involving an increase of 0.32 RN hours per patient day (HPPD) and a similar decrease in HCA HPPD, would be associated with reduced mortality, an increase in staffing costs of £28 per patient and a saving of £0.52 per patient per hospital stay, after accounting for the value of reduced stays. Limitations This was an observational study in a single site. Evidence of cause is not definitive. Variation in staffing could be influenced by variation in the assessed need for staff. Our economic analysis did not consider quality or length of life. Conclusions Higher RN staffing levels are associated with lower mortality, and this study provides evidence of a causal mechanism. There may be several causal pathways and the absolute rate of missed observations cannot be used to guide staffing decisions. Increases in nursing skill mix may be cost-effective for improving patient safety. Future work More evidence is required to validate approaches to setting staffing levels. Other aspects of missed nursing care should be explored using objective data. The implications of findings about both costs and temporary staffing need further exploration. Trial registration This study is registered as ISRCTN17930973. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 6, No. 38. See the NIHR Journals Library website for further project information.

The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor ␣-1-antitrypsin result from point mutations in its gene. In addition, ␣-2-macroglobulin competes with ␣-1-antitrypsin for proteinases, and the ␣-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of ␣-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either ␣-1-antitrypsin or ␣-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 m into the tissue before becoming sequestered. We have shown that proteinases sequestered to ␣-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with ␣-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all ␣-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to ␣-2-macroglobulin where it retains proteolytic activity.␣-1-antitrypsin; chronic obstructive pulmonary disease; reaction-diffusion model; enzyme kinetics; serine proteinase CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is a major cause of morbidity and mortality worldwide (40) and creates a significant economic burden (60). Several pulmonary phenotypes have been recognized, including chronic bronchitis, which affects the large airways and is associated with chronic mucus hypersecretion (28a), and emphysema, which is associated with destruction of alveolar walls and enlargement of airspaces distal to the terminal bronchioles (38). Although the main risk factor for the development of COPD is cigarette smoking (10), only around 20% of smokers develop clinically significant disease (49), indicating that other environmental and genetic risk factors are important in the etiology. To date, deficiency of the serine proteinase inhibitor (serpin) ␣-1-antitrypsin (A1AT) is the only widely recognized genetic predisposition.A1AT is secreted by hepatocytes (16), enters the lungs primarily by passive diffusion, and inhibits neutrophil serine proteinases (NSPs) irreversibly with 1:1 stoichiometry. Circulating levels of A1AT are in the range of 20 -53 M in individuals with the normal (protease inhibitor MM, PiMM) genotype (5). Over 100 naturally occurring genetic variants...