Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis.

BACKGROUND: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation. METHODS: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use. RESULTS: Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q-value = 7.29 × 10-5. Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001). CONCLUSIONS: Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF.

The Sydney Mental Health Client Mortality Audit: what does it tell us and what are we to do?

OBJECTIVES: To examine the characteristics of those mental health clients of an Australian metropolitan health service who died during a 6 year period, 2005 - 2010. METHODS: The medical records, and where available, coronial post-mortem examinations were audited for 109 people with schizophrenia who died while they were clients of the mental health service. RESULTS: The mean age of death for men was 45 years and for women, 47 years, compared to the general population's male and female life expectancy of 79 and 84 years, respectively. About one-half of the deaths were due to suicide (n = 55), followed by natural causes (n = 42; 39%), undetermined causes (n = 7), and accidents or acts of violence (n = 5). Smoking rates, diagnosed diabetes and hypertension were higher in the group that died from natural causes. Morbid obesity (body mass index (BMI) > 35 kg/m(2)) rates were higher in the group that died of natural causes (38%), compared with the suicide group (5%). CONCLUSIONS: While suicide accounts for the majority of those dying prematurely in this study cohort, it appears that for those who survive the risk of suicide in the earlier period of a chronic psychotic illness, there is yet another threat to life expectancy: death from preventable cardiorespiratory disorders, due to a poor lifestyle and social deprivation.

Blame and accountability 1: understanding blame and blame pathologies.

OBJECTIVE: In this first paper the role and dynamics of blame in the context of medical critical incidents is examined. Blame pathologies are described and the complex nature of medical adverse events and the environment are explored. METHODS: The literature is examined and a case scenario explored. RESULTS: Evidence regarding effects of a 'blame culture' on clinicians and organizations is presented. In an accompanying second paper the place of accountability in relation to clinicians and health organizations is elucidated. CONCLUSIONS: The necessary conditions for an accountable, responsive, fair and transparent health culture are proposed.

Blame and accountability 2: on being accountable.

OBJECTIVE: This second paper follows an exploration of the nature of blame and addresses the balance between a 'blame-free' health culture and appropriate accountability. This paper aims to define and describe accountability as a key component of clinical governance and a responsive, fair and transparent health culture. METHODS: The literature is examined and the concept of a fair and transparent health culture is explored. The case vignette in Part 1 is used to illustrate a particular issue of accountability. RESULTS: The place of accountability in relation to clinicians and health organisations is elucidated. CONCLUSIONS: The necessary conditions for an accountable, responsive, fair and transparent health culture are proposed.