Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Activation of innate sensors by self-antigen contributes to autoimmunity, although how intracellular sensors are chronically exposed to self-antigen has remained unknown. Here, we identify a previously unidentified defect in which lupus-prone macrophages fail to mature the lysosome, promoting the accumulation of apoptotic debris-containing IgG–immune complexes (IgG-ICs). Interestingly, macrophages from other autoimmune diseases accumulate IgG-ICs, indicating that lysosomal defects may underlie multiple autoimmune diseases. Furthermore, the prolonged intracellular residency chronically activates Toll-like receptors and permeabilizes the phagolysosomal membrane, allowing activation of cytosolic sensors. These findings identify lysosomal maturation as a unique defect in MRL/lpr mice that impacts multiple events known to underlie SLE, including pathogenic cytokine secretion

Prospective validation of a checklist to predict short-term death in older patients after emergency department admission in Australia and Ireland

Abstract Background Emergency departments (EDs) are pressured environment where patients with supportive and palliative care needs may not be identified. We aimed to test the predictive ability of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist to flag patients at risk of death within 3 months who may benefit from timely end-of-life discussions. Methods Prospective cohorts of >65-year-old patients admitted for at least one night via EDs in five Australian hospitals and one Irish hospital. Purpose-trained nurses and medical students screened for frailty using two instruments concurrently and completed the other risk factors on the CriSTAL tool at admission. Postdischarge telephone follow-up was used to determine survival status. Logistic regression and bootstrapping techniques were used to test the predictive accuracy of CriSTAL for death within 90 days of admission as primary outcome. Predictability of in-hospital death was the secondary outcome. Results A total of 1,182 patients, with median age 76 to 80 years (IRE-AUS), were included. The deceased had significantly higher mean CriSTAL with Australian mean of 8.1 (95% confidence interval [CI] = 7.7–8.6) versus 5.7 (95% CI = 5.1–6.2) and Irish mean of 7.7 (95% CI = 6.9–8.5) versus 5.7 (95% CI = 5.1–6.2). The model with Fried frailty score was optimal for the derivation (Australian) cohort but prediction with the Clinical Frailty Scale (CFS) was also good (areas under the receiver-operating characteristic [AUROC] = 0.825 and 0.81, respectively). Values for the validation (Irish) cohort were AUROC = 0.70 with Fried and 0.77 using CFS. A minimum of five of 29 variables were sufficient for accurate prediction, and a cut point of 7+ or 6+ depending on the cohort was strongly indicative of risk of death. The most significant independent predictor of short-term death in both cohorts was frailty, carrying a twofold risk of death. CriSTAL's accuracy for in-hospital death prediction was also good (AUROC = 0.795 and 0.81 in Australia and Ireland, respectively), with high specificity and negative predictive values. Conclusions The modified CriSTAL tool (with CFS instead of Fried's frailty instrument) had good discriminant power to improve certainty of short-term mortality prediction in both health systems. The predictive ability of models is anticipated to help clinicians gain confidence in initiating earlier end-of-life discussions. The practicalities of embedding screening for risk of death in routine practice warrant further investigation

Baseline hospital performance and the impact of medical emergency teams: Modelling vs. conventional subgroup analysis

<p>Abstract</p> <p>Background</p> <p>To compare two approaches to the statistical analysis of the relationship between the baseline incidence of adverse events and the effect of medical emergency teams (METs).</p> <p>Methods</p> <p>Using data from a cluster randomized controlled trial (the MERIT study), we analysed the relationship between the baseline incidence of adverse events and its change from baseline to the MET activation phase using quadratic modelling techniques. We compared the findings with those obtained with conventional subgroup analysis.</p> <p>Results</p> <p>Using linear and quadratic modelling techniques, we found that each unit increase in the baseline incidence of adverse events in MET hospitals was associated with a 0.59 unit subsequent reduction in adverse events (95%CI: 0.33 to 0.86) after MET implementation and activation. This applied to cardiac arrests (0.74; 95%CI: 0.52 to 0.95), unplanned ICU admissions (0.56; 95%CI: 0.26 to 0.85) and unexpected deaths (0.68; 95%CI: 0.45 to 0.90). Control hospitals showed a similar reduction only for cardiac arrests (0.95; 95%CI: 0.56 to 1.32). Comparison using conventional subgroup analysis, on the other hand, detected no significant difference between MET and control hospitals.</p> <p>Conclusions</p> <p>Our study showed that, in the MERIT study, when there was dependence of treatment effect on baseline performance, an approach based on regression modelling helped illustrate the nature and magnitude of such dependence while sub-group analysis did not. The ability to assess the nature and magnitude of such dependence may have policy implications. Regression technique may thus prove useful in analysing data when there is a conditional treatment effect.</p

Delivering safe and effective test-result communication, management and follow-up : a mixed-methods study protocol

Introduction: The failure to follow-up pathology and medical imaging test results poses patient-safety risks which threaten the effectiveness, quality and safety of patient care. The objective of this project is to: (1) improve the effectiveness and safety of test-result management through the establishment of clear governance processes of communication, responsibility and accountability; (2) harness health information technology (IT) to inform and monitor test-result management; (3) enhance the contribution of consumers to the establishment of safe and effective test-result management systems. Methods and analysis: This convergent mixed-methods project triangulates three multistage studies at seven adult hospitals and one paediatric hospital in Australia. Study 1 adopts qualitative research approaches including semistructured interviews, focus groups and ethnographic observations to gain a better understanding of test-result communication and management practices in hospitals, and to identify patient-safety risks which require quality-improvement interventions. Study 2 analyses linked sets of routinely collected healthcare data to examine critical test-result thresholds and test-result notification processes. A controlled before-and-after study across three emergency departments will measure the impact of interventions (including the use of IT) developed to improve the safety and quality of test-result communication and management processes. Study 3 adopts a consumer-driven approach, including semistructured interviews, and the convening of consumer-reference groups and community forums. The qualitative data will identify mechanisms to enhance the role of consumers in test-management governance processes, and inform the direction of the research and the interpretation of findings. Ethics and dissemination: Ethical approval has been granted by the South Eastern Sydney Local Health District Human Research Ethics Committee and Macquarie University. Findings will be disseminated in academic, industry and consumer journals, newsletters and conferences

Binary systems and their nuclear explosions

Peer ReviewedPreprin

The changing nature of the population of intensive-care patients

Background: The increase in the number of Australia’s frail, very elderly ( 80 years of age) population will have an impact on admissions to intensive care. As the number of very elderly patients increase, it will be important to have information about what the impact of increasing age will have on aspects such as: the impact of age and chronic health conditions on intensive care treatment, and the impact on prognosis in the short and longer-term as well as how we should be involving the very elderly in determining their own goals of care. Objective: To evaluate the long-term trend in the rates of the very elderly ( 80 years of age) admitted to intensive care, as well as describe their chronic health conditions, length of stay, and mortality rates. Methods: This study was a retrospective review that used a database from a 40-bed, multidisciplinary, adult intensive care unit (ICU), located in South-Western Sydney, Australia. The setting is an 877-bed tertiary hospital that has medical and surgical specialties; including a referral trauma unit, with approximately 80,000 admissions a year. Data were acquired over 15-years, from January 1st, 2000 to December 31st, 2015. Results: Data were available for 32,796 patients, and of these, 4,137 (12.5%) were aged ≥ 80 years. The percentage of the very elderly admitted to ICU progressively increased from 8.6% in 2000 to (14.5% in 2015, p < .001). Overall, the median length of stay (LOS) in the ICU was 2-days (interquartile range: 1.2-4.1), and increased from 2.0 to 2.3 (p < .001). Similarly, the median hospital LOS increased over time from 9 to 11 days (p < .001). Intensive care and hospital death rates decreased over time from 19.9% to 9.8% (p < .001), and 31.8% to 19.9% (p < .001), respectively. The majority of the very elderly were admitted from the emergency department (ED) (38.1%), other sources of admission being from the operating theatres (OT) (33.5%), and the general ward (18.1%). Conclusions: The number and percentage of very elderly patients being managed in ICU is increasing, representing a different population from the one that much of our practice has been previously based. For example, we may need to review the way we estimate severity of illness on admission to the ICU with more weight given to the chronic health component of the very elderly. The acute indications for admission to ICU such as falls and infections are relatively straightforward to manage and usually have a good outcome. However, because age and the chronic health status of the very elderly are largely progressive and irreversible, we as health care professionals working in intensive care may have to consider longer-term post hospital outcomes as a basis for evaluating the effectiveness of the interventions in ICU