IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab.

BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109.

Multicultural emergency medicine epidemiology: A health economic analysis of patient visits.

OBJECTIVE: There is growing evidence to suggest that culturally and linguistically diverse (CALD) patients cost the health system more than non-CALD patients because of a higher burden of disease and increased resource consumption. The present study aimed to compare the ED resource utilisation of CALD and non-CALD patients at a tertiary hospital in Sydney, Australia. METHODS: The total ED resource utilisation was calculated by separating each visit into diagnostic test cost and time spent in ED components. The time component was calculated using the product of the total length of stay and a resource cost per unit time measure. Diagnostic tests were costed using the Australian Medicare Benefit Schedule. A generalised additive model was developed to estimate the isolated effect of CALD status on the resource utilisation during an ED visit. RESULTS: CALD patients had a higher median resource utilisation than non-CALD patients ($736.93 vs $701.36, P < 0.0001); however, the generalised additive model demonstrated that CALD status was not independently associated with increased resource utilisation. CONCLUSION: CALD status is not an independent influence on ED resource utilisation but other explanatory variables such as increased age and altered case-mix appear to have a much greater influence. There may, however, be other reasons to consider CALD loading such as equity in healthcare and to address poorer overall health outcomes for CALD patients.

Routine screening of emergency admissions at risk of chronic hepatitis (SEARCH) identifies and links hepatitis B cases to care.

BACKGROUND AND AIMS: Significant barriers exist with hepatitis B (HBV) case detection and effective linkage to care (LTC). The emergency department (ED) is a unique healthcare interaction where hepatitis screening and LTC could be achieved. We examined the efficacy and utility of automated ED HBV screening for Overseas Born (OB) patients. METHODS: A novel-automated hepatitis screening service "SEARCH" (Screening Emergency Admissions at Risk of Chronic Hepatitis) was piloted at a metropolitan hospital. A retrospective and comparative analysis of hepatitis testing during the SEARCH pilot compared to a period of routine testing was conducted. RESULTS: During the SEARCH pilot, 4778 OB patients were tested for HBV (86% of eligible patient presentations), compared with 1.9% of eligible patients during a control period of clinician-initiated testing. SEARCH detected 108 (2.3%) hepatitis B surface antigen positive patients including 20 (19%) in whom the diagnosis was new. Among 88 patients with known HBV, 57% were receiving medical care, 33% had become lost to follow-up and 10% had never received HBV care. Overall, 30/88 (34%) patients with known HBV were receiving complete guideline-based care prior to re-engagement via SEARCH. Following SEARCH, LTC was successful achieved in 48/58 (83%) unlinked patients and 19 patients were commenced on anti-viral therapy. New diagnoses of cirrhosis and hepatocellular carcinoma were made in five and one patient(s) respectively. CONCLUSIONS: Automated ED screening of OB patients is effective in HBV diagnosis, re-diagnosis and LTC. Prior to SEARCH, the majority of patients were not receiving guideline-based care.

Finding Cases of Hepatitis C for Treatment Using Automated Screening in the Emergency Department is Effective, but What Is the Cost?

Case detection remains a major challenge for hepatitis C virus (HCV) elimination. We have previously published results from a pilot of an emergency department (ED) semiautomated screening program, SEARCH; Screening Emergency Admissions at Risk of Chronic HCV. Several refinements to SEARCH have been developed to streamline and reduce cost. All direct costs of HCV testing until direct-acting antiviral (DAA) therapy initiation were calculated. Cost was assessed in 2018 Australian Dollars. A cost analysis of the initial program and refinements are presented. Sensitivity analysis to understand impact of variation in staff time, laboratory test cost, changes in HCV antibody (Ab) prevalence, RNA positivity percentage, and rate of linkage to care was conducted. Impact of refinements (SEARCH (2)) to cost is presented. The total SEARCH pilot, testing 5000 patients was estimated to cost $110,549.52 (range $92,109.79-$129,581.24) comprising of $68,278.67 for HCV Ab testing, $21,568.99 for follow-up and linkage to care of positive patients and $20,701.86 to prepare HCV RNA positive patients for treatment. Internal program refinements resulted in a 25% cost reduction. Following refinements, the cost of HCV antibody screening was $8.46 per test and the total cost per positive HCV Ab, positive HCV RNA, and per treated patient were $611.77, $2,168.64, and $3,566.11, respectively. Our sensitivity analysis indicates costs per HCV case found are modest so long as HCV Ab prevalence was at least 1%. ED screening is an affordable strategy for HCV case detection and elimination.

Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation.

Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.

Screening Emergency Admissions at Risk of Chronic Hepatitis C (SEARCH) to diagnose or 're-diagnose' infections is effective in Australia.

The World Health Organization has set ambitious viral hepatitis elimination targets; however, difficulties in identifying and engaging patients remain. The emergency visit is an opportunity for enhanced linkage to care (LTC). We assessed the effectiveness of an automated Emergency Department (ED) screening service in identifying patients with hepatitis C (HCV) and achieving LTC. A retrospective evaluation was undertaken, analysing the first 5000 patients screened through an automatic Australian service termed 'Screening Emergency Admissions at Risk of Chronic Hepatitis' (SEARCH). Screening was performed for those recommended in the Australian national testing policy, specifically overseas born (OB) and Aboriginal or Torres Strait Islanders (ATSI). Healthcare worker education, patient information materials and opt-out informed consent were used to test sera already collected for biochemistry assays. 5000 of 5801 (86.2%) consecutive eligible patients were screened (OB: 4778, ATSI: 222) from 14 093 ED presentations. HCV antibody was positive in 181 patients (3.6%); 51 (1.0%) were HCV RNA positive. Of 51 HCV RNA-positive patients, 12 were new diagnoses, 32 were 're-diagnoses' (aware but lost to follow-up [LTFU]), and 7 were previously known but treatment contraindicated. LTC was successful in 38 viraemic patients (7 deceased, 4 LTFU, 1 treatment ineligible and 1 declined). Of RNA-negative patients, 75 were previously treated and 49 had presumed spontaneous clearance. Opt-out consent was acceptable to all patients and staff involved. ED screening can lead to additional diagnosing and 're-diagnosing' of HCV, with high rates of LTC. Opt-out consent and automation removed major obstacles to testing.

Impact of therapeutic drug level monitoring on outcomes of patients with Crohn's disease treated with Infliximab: real world data from a retrospective single centre cohort study.

BACKGROUND: Therapeutic drug monitoring (TDM) by measuring infliximab (IFX) trough levels and antibodies to infliximab (ATI) is used to optimise treatment in inflammatory bowel disease. We aimed to explore the clinical outcomes of TDM for patients with Crohn's disease on IFX in real life setting. METHODS: This is a retrospective observational study. Primary outcomes were the clinicians' response to each TDM result and the rate of IFX discontinuation due to secondary loss of response or serious adverse event. Secondary outcomes included the intestinal surgery rate after IFX initiation and remission 6 months after TDM. Multivariate logistic regression was performed to identify factors associated with IFX discontinuation and abdominal surgery. RESULTS: 291 patients were included. 238 (81.8%) patients were tested for TDM at least once during their follow-up with 672 TDM results. 95/238 patients (39.9%) had undetectable levels and 76 (31.9%) had positive ATI at least once. The median infliximab trough level was 3.4 µg/mL. IFX was discontinued in 109 patients (37.5%). 526/672 (78.3%) TDMs results were not followed by altered patient management. Treatment was discontinued in 40 (75.5%) patients never tested for TDM compared with 69 (29.0%) of those tested (p<0.01). Fewer TDM tested patients (29; 12.2%) required intestinal surgery post IFX initiation compared with TDM not-tested (15; 28.3%). Not being TDM tested was independently associated with IFX discontinuation and abdominal surgery. CONCLUSIONS: IFX discontinuation and intestinal surgery were significantly less frequent with TDM. TDM requested to investigate loss of response resulted in change in patient management.

Temporal map of the pig polytrauma plasma proteome with fluid resuscitation and intravenous vitamin C treatment.

BACKGROUND: Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems. OBJECTIVES: We applied quantitative mass spectrometry-based proteomics [liquid chromatography-mass spectrometry (LC-MS/MS)] to map the effects of fluid resuscitation and intravenous vitamin C (VitC) in a pig model of polytrauma (hemorrhagic shock, tissue injury, liver reperfusion, hypothermia, and comminuted bone fracture). The goal was to determine the effects of VitC on plasma protein expression, with respect to changes associated with coagulation and trauma-induced coagulopathy (TIC). METHODS: Longitudinal blood samples were drawn from nine male Sinclair pigs at baseline, 2 h post trauma, and 0.25, 2, and 4 h post fluid resuscitation with 500 mL hydroxyethyl starch. Pigs were treated intravenously (N = 3/treatment group) with saline, 50 mg VitC/kg (Lo-VitC), or 200 mg VitC/kg (Hi-VitC) during fluid resuscitation. RESULTS: A total of 436 plasma proteins were quantified of which 136 changed following trauma and resuscitation; 34 were associated with coagulation, complement cascade, and glycolysis. Unexpectedly, Lo-VitC and Hi-VitC treatments stabilized ADAMTS13 levels by ~4-fold (P = .056) relative to saline and enhanced ADAMTS13/von Willebrand factor (VWF) cleavage efficiency based on LC-MS/MS evidence for the semitryptic VWF cleavage product (VWF1275-1286 ). CONCLUSIONS: This study provides the first comprehensive map of trauma-induced changes to the plasma proteome, especially with respect to proteins driving the development of TIC.

Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model.

BACKGROUND: Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage. METHODS: Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung. RESULTS: Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1ß, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours. CONCLUSION: Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries. LEVEL OF EVIDENCE: Prospective randomized controlled blinded trial study, Preclinical (animal-based).

Metformin selectively targets redox control of complex I energy transduction.

Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

A Comparison of a New Ultrasound-Based Whole Blood Viscoelastic Test (SEER Sonorheometry) Versus Thromboelastography in Cardiac Surgery.

BACKGROUND: Viscoelastic thromboelastography tests such as TEG™ are now routine for assessing the coagulation status of cardiac surgery patients. We compared TEG™ with a new technology, sonic estimation of elasticity via resonance (SEER) sonorheometry, to compare measures of coagulation dynamics of whole blood and assess its potential for rapid, near-point-of-care monitoring of hemostasis during cardiac surgery. METHODS: Whole blood coagulation assessment of a prospective cohort of 50 cardiac surgery patients was performed using SEER sonorheometry and blood samples collected at 4 time points during cardiac surgery: baseline before anesthetic induction, during cardiopulmonary bypass on rewarming, 10 minutes after heparin reversal by protamine, and on patient transfer to the intensive care unit. Clot strength trajectories (G, measured by TEG™; and clot stiffness measured by SEER sonorheometry) and clot times were assessed by repeated-measures mixed models. Strength of association between the 2 methods (clot stiffness and clot times) was assessed using a modified Bland-Altman method for repeated measures; Deming (orthogonal) regression was used to quantify method concordance (constant and proportional bias). RESULTS: Clot strength/stiffness and clot time measures for both techniques showed similar tracking of trajectories. Strength of association between methods was acceptable (correlations, 0.8-0.9); however, Deming regression detected substantial deviation (bias) between techniques. SEER clot stiffness values averaged approximately 10 hPa higher than corresponding G at all time points. Reaction time (TEG™) was 1 to 2.5 minutes longer than corresponding clot times (SEER). Laboratory times (from sample drop-off to results) were substantially less for SEER sonorheometry (median time, 11-17 minutes) compared with nonautomated kaolin TEG™ (median time, 42 minutes). CONCLUSIONS: Currently, no viscoelastic hemostatic analyzer system can be considered the "gold standard"; therefore, differences observed between TEG™ and SEER are of importance only because they show that the methods are not perfectly substitutable. Measurements of clot stiffness determined by the 2 methods were correlated but not interchangeable. Reasons for discrepancies include the substantial difference in the physical methods of inducing coagulation activation in samples and the mathematical assumptions underlying calculations of G. Future studies will be required to evaluate SEER sonorheometry's abilities to identify bleeding diatheses (sensitivity/specificity) or to develop treatment algorithms based on the new tests.

What causes adverse events in prehospital care? A human-factors approach.

BACKGROUND: The last decade has seen a vast amount of work directed at the investigation of patient harm events. Unfortunately, little of it has pertained to prehospital care and as such, risk remains unquantified and poorly understood in this setting. We hypothesised that adverse patient events occurring during the prehospital phase may fall into discernible patterns, and that an understanding of these patterns would be valuable in the development of mitigation strategies. METHODS: A survey tool was developed with reference to the human factors literature. Paramedics in a large Australian ambulance service were asked to recall an adverse event and to nominate factors that may have contributed to its occurrence. Responses were analysed using principal components analysis in order to identify contributory factors that could be statistically grouped together in meaningful patterns. RESULTS: The survey yielded 370 responses. Eight key single contributors and 14 groups of contributory factors were identified. Of the groups, only two were strongly associated with serious patient outcomes, such as reported significant deterioration or death. CONCLUSIONS: The deteriorating patient was identified as the leading single contributor to prehospital adverse events, and two perfect storm patient harm scenarios were found to contribute materially to adverse outcomes. This approach to identifying both single factors contributing to an incident and factors which could be grouped together in a pattern, appears useful in delineating risk in the acute prehospital setting, and warrants further exploration in this and other areas of patient safety.

Do clinical safety charts improve paramedic key performance indicator results? (A clinical improvement programme evaluation).

INTRODUCTION: Is the Clinical Safety Chart clinical improvement programme (CIP) effective at improving paramedic key performance indicator (KPI) results within the Ambulance Service of New South Wales? METHODS: The CIP intervention area was compared with the non-intervention area in order to determine whether there was a statistically significant improvement in KPI results. RESULTS: The CIP was associated with a statistically significant improvement in paramedic KPI results within the intervention area. CONCLUSIONS: The strategies used within this CIP are recommended for further consideration.

Fingertip photoplethysmographic waveform variability and systemic vascular resistance in intensive care unit patients.

Low frequency variability in the fingertip photoplethysmogram (PPG) waveform has been utilized for inferring sympathetic vascular control, but its relationship with a quantitative measure of vascular tone has not been established. In this study, we examined the association between fingertip PPG waveform variability (PPGV) and systemic vascular resistance (SVR) obtained from thermodilution cardiac output (CO) and intra-arterial pressure measurements in 48 post cardiac surgery intensive care unit patients. Among the hemodynamic measurements, both CO (P < 0.05) and SVR (P < 0.0001) had statistically significant relationships with the normalized low frequency power (LF(nu)) of PPGV. The LF(nu) of baseline PPGV had moderate but significant positive correlation with SVR (r = 0.54, P < 0.0001), and a value below 52.5 nu was able to identify SVR < 900 dyn s cm⁻5 with sensitivity of 59% and specificity of 95%. The results have provided quantitative evidence to confirm the link between fingertip PPGV and sympathetic vascular control. Suppression of LF vasomotor waves leading to dominance of respiration-related HF fluctuations in the fingertip circulation was a specific (though not sensitive) marker of systemic vasodilatation, which could be potentially utilized for the assessment of critical care patients.

Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users.

RATIONALE: Although some aspects of memory functions are known to be acutely impaired by delta(9)-tetrahydrocannabinol (delta(9)-THC; the main active constituent of marijuana), effects on other aspects of memory are not known and the time course of functional impairments is unclear. OBJECTIVE: The present study aimed to detail the acute and residual cognitive effects of delta(9)-THC in infrequent cannabis users. METHODS: A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg delta(9)-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. RESULTS: Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact. The higher dose of delta(9)-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by delta(9)-THC. In several tasks, delta(9)-THC increased both speed and error rates, reflecting "riskier" speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as "stoned" for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal. CONCLUSIONS: These data demonstrate that oral delta(9)-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory.