A Systematic Review of Published Physiologically-based Kinetic Models and an Assessment of their Chemical Space Coverage.

Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration-time profile at the target site. Physiologically-based kinetic (PBK) models can predict organ-level concentration-time profiles, however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.

Impact of cell types and culture methods on the functionality of in vitro liver systems - A review of cell systems for hepatotoxicity assessment.

Xenobiotic safety assessment is an area that impacts a multitude of different industry sectors such as medicinal drugs, agrochemicals, industrial chemicals, cosmetics and environmental contaminants. As such there are a number of well-developed in vitro, in vivo and in silico approaches to evaluate their properties and potential impact on the environment and to humans. Additionally, there is the continual investment in multidisciplinary scientists to explore non-animal surrogate technologies to predict specific toxicological outcomes and to improve our understanding of the biological processes regarding the toxic potential of xenobiotics. Here we provide a concise, critical evaluation of a number of in vitro systems utilised to assess the hepatotoxic potential of xenobiotics.

Cost of surviving sepsis: a novel model of recovery from sepsis in Drosophila melanogaster.

BACKGROUND: Multiple organ failure, wasting, increased morbidity, and mortality following acute illness complicates the health span of patients surviving sepsis. Persistent inflammation has been implicated, and it is proposed that insulin signaling contributes to persistent inflammatory signaling during the recovery phase after sepsis. However, mechanisms are unknown and suitable pre-clinical models are lacking. We therefore developed a novel Drosophila melanogaster model of sepsis to recapitulate the clinical course of sepsis, explored inflammation over time, and its relation to impaired mobility, metabolic disturbance, and changes in lifespan. METHODS: We used wild-type (WT), Drosomycin-green fluorescent protein (GFP), and NF-κB-luc reporter male Drosophila melanogaster 4-5 days of age (unmanipulated). We infected Drosophila with Staphylococcus aureus (infected without treatment) or pricked with aseptic needles (sham). Subsets of insects were treated with oral linezolid after the infection (infected with antibiotics). We assessed rapid iterative negative geotaxis (RING) in all the groups as a surrogate for neuromuscular functional outcome up to 96 h following infection. We harvested the flies over the 7-day course to evaluate bacterial burden, inflammatory and metabolic pathway gene expression patterns, NF-κB translation, and metabolic reserve. We also followed the lifespan of the flies. RESULTS: Our results showed that when treated with antibiotics, flies had improved survival compared to infected without treatment flies in the early phase of sepsis up to 1 week (81 %, p = 0.001). However, the lifespan of infected with antibiotics flies was significantly shorter than that of sham controls (p = 0.001). Among infected with antibiotic sepsis survivors, we observed persistent elevation of NF-κB in the absence of any obvious infection as shown by culturing flies surviving sepsis. In the same group, geotaxis had an early (18 h) and sustained decline compared to its baseline. Geotaxis in infected with antibiotics sepsis survivors was significantly lower than that in sham and age-matched unmanipulated flies at 18 and 48 h. Expression of antimicrobial peptides (AMP) remained significantly elevated over the course of 7 days after sepsis, especially drosomycin (5.7-fold, p = 0.0145) on day 7 compared to that of sham flies. Infected with antibiotics flies had a trend towards decreased Akt activation, yet their glucose stores were significantly lower than those of sham flies (p = 0.001). Sepsis survivors had increased lactate levels and LDH activity by 1 week, whereas ATP and pyruvate content was similar to that of the sham group. CONCLUSIONS: In summary, our model mimics human survivors of sepsis with persistent inflammation, impaired motility, dysregulated glucose metabolism, and shortened lifespan.

Increased hospital costs associated with red blood cell transfusion.

BACKGROUND: Red blood cell (RBC) transfusion is independently associated in a dose-dependent manner with increased intensive care unit stay, total hospital length of stay, and hospital-acquired complications. Since little is known of the cost of these transfusion-associated adverse outcomes our aim was to determine the total hospital cost associated with RBC transfusion and to assess any dose-dependent relationship. STUDY DESIGN AND METHODS: A retrospective cohort study of all multiday acute care inpatients discharged from a five hospital health service in Western Australia between July 2011 and June 2012 was conducted. Main outcome measures were incidence of RBC transfusion and mean inpatient hospital costs. RESULTS: Of 89,996 multiday, acute care inpatient discharges, 4805 (5.3%) were transfused at least 1 unit of RBCs. After potential confounders were adjusted for, the mean inpatient cost was 1.83 times higher in the transfused group compared with the nontransfused group (95% confidence interval, 1.78-1.89; p < 0.001). The estimated total hospital-associated cost of RBC transfusion in this study was AUD $77 million (US $72 million), representing 7.8% of total hospital expenditure on acute care inpatients. There was a significant dose-dependent association between the number of RBC units transfused and increased costs after adjusting for confounders. CONCLUSION: RBC transfusions were independently associated with significantly higher hospital costs. The financial implication to hospital budgets will assist in prioritizing areas to reduce the rate of RBC transfusions and in implementing patient blood management programs.

Patient comfort in the intensive care unit: a multicentre, binational point prevalence study of analgesia, sedation and delirium management.

OBJECTIVE: To measure the prevalence of assessment and management practices for analgesia, sedation and delirium in patients in Australian and New Zealand intensive care units. MATERIALS AND METHODS: We developed survey items from a modified Delphi panel and included them in a binational, point prevalence study. We used a standard case report form to capture retrospective patient data on management of analgesia, sedation and delirium at the end of a 4-hour period on the study day. Other data were collected during independent assessment of patient status and medication requirements. RESULTS: Data were collected on 569 patients in 41 ICUs. Pain assessment was documented in the 4 hours before study observation in 46% of patients. Of 319 assessable patients, 16% had moderate pain and 6% had severe pain. Routine sedation assessment using a scale was recorded in 63% of intubated and ventilated patients. When assessed, 38% were alert and calm, or drowsy and rousable, 22% were lightly to moderately sedated, 31% were deeply sedated (66% of these had a documented indication), and 9% were agitated or restless. Sedatives were titrated to a target level in 42% of patients. Routine assessment of delirium occurred in 3%, and at study assessment 9% had delirium. Wrist or arm restraints were used for 7% of patients. CONCLUSIONS: Only two-thirds of sedated patients had their sedation levels formally assessed, half had pain assessed and very few had formal assessment of delirium. Our description of current practices, and other observational data, may help in planning further research in this area.

Comparison of physician prediction with 2 prognostic scoring systems in predicting 2-year mortality after intensive care admission: a linked-data cohort study.

PURPOSE: Patients who survive an episode of critical illness continue to experience significant mortality after hospital discharge. This study assessed the accuracy of physician prediction of 2-year mortality and compared it with 2 objective prognostic models. METHODS: Sensitivity (probability of a prediction of death in patients who died within 2 years) and specificity (probability of a prediction of survival in patients who survived at least 2 years) of physicians' 2-year prediction were compared with those from 2 objective prognostic models, Acute Physiology and Chronic Health Evaluation (APACHE) II and Predicted Risk Existing Disease Intensive Care Therapy (PREDICT). RESULTS: Physician prediction of 2-year mortality was available for 2497 (94.8%) intensive care unit admissions. Specificity was high (85.2%; 95% confidence interval [CI], 83.7-86.4), but sensitivity (65.0%; 95% CI, 61.1-68.8) and positive predictive value (57.4%; 95% CI, 53.6-61.2) were relatively low, suggesting overpessimistic prediction of 2-year mortality. Age, Charlson comorbidity index, and APACHE score were independent risk factors for an inaccurate physician prediction. The diagnostic odds ratio for the physician predictions was at least comparable with the APACHE and PREDICT models, which both had very good discrimination of mortality at 2-year follow-up. CONCLUSIONS: Physicians tended to overpredict the risk of 2-year mortality of critically ill patients, but accuracy was comparable with 2 objective prognostic models.

The effect of socioeconomic status on outcomes for seriously ill patients: a linked data cohort study.

OBJECTIVE: To investigate the association between socioeconomic status (SES) and outcomes for seriously ill patients. DESIGN AND SETTING: A retrospective cohort study based on data from an intensive care unit clinical database linked with data from the Western Australian hospital morbidity and mortality databases over a 16-year period (1987-2002). MAIN OUTCOME MEASURES: In-hospital and long-term mortality. RESULTS: Data on 15,619 seriously ill patients were analysed. The in-hospital mortality rate for all seriously ill patients was 14.8%, and the incidence of death after critical illness was 7.4 per 100 person-years (4.8 per 100 person-years after hospital discharge). Patients from the most socioeconomically disadvantaged areas were more likely to be younger, to be Indigenous, to live in a remote area, to be admitted non-electively, and to have more severe acute disease and comorbidities. SES was not significantly associated with in-hospital mortality, but long-term mortality was significantly higher in patients from the lowest SES group than in those from the highest SES group, after adjusting for age, ethnicity, comorbidities, severity of acute illness, and geographical accessibility to essential services (hazard ratio for death in lowest SES group v highest SES group was 1.21 [95% CI, 1.04-1.41]; P = 0.014). The attributable incidence of death after hospital discharge between patients from the lowest and highest SES groups was 1.0 per 100 person-years (95% CI, 0.3-1.6 per 100 person-years). CONCLUSION: Lower SES was associated with worse long-term survival after critical illness over and above the background effects of age, acuity of acute illness, comorbidities, Indigenous status and geographical access to essential services.

Spatially extended host-parasite interactions: the role of recovery and immunity.

Techniques for determining the long-term dynamics of host-parasite systems are well established for mixed populations. The field of spatial modelling in ecology is more recent but a number of key advances have been made. In this paper, we use state-of-the-art approximation techniques, supported by simulations, in order to investigate the role of recovery and immunity in spatially structured populations. Our approach is to use correlation models, namely pair-wise models, to capture the spatial relationships of contacts and interactions between individuals. We use the pair-wise framework to address a number of key ecological questions; including, the persistence of endemic limit cycles and regions of parasite-driven extinction--features which differentiate spatial from non-spatial models--and the effects on invasion fitness. We demonstrate a loss of limit cycle behaviour, in addition to an increase in the critical transmissibility and extinction thresholds, when recovery is included. This approach allows for a better analytical understanding of the dynamics of host-parasite interactions and demonstrates the importance of recovery and immunity in local interactions.

Cefepime versus ceftazidime: considerations for empirical use in critically ill patients.

Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated.

The next 15 years: taking plant-made vaccines beyond proof of concept.

Significant potential advantages are associated with the production of vaccines in transgenic plants; however, no commercial product has emerged. An analysis of the strengths, weaknesses, opportunities and threats for plant-made vaccine technology is provided. The use of this technology for human vaccines will require significant investment and developmental efforts that cannot be supported entirely by the academic sector and is not currently supported financially by industry. A focus on downstream aspects to define potential products, conduct of additional basic clinical testing, and the incorporation of multidisciplinary strategic planning would accelerate the potential for commercialization in this field. Estimates of production cost per dose and volume of production are highly variable for a model vaccine produced in transgenic tomato, and can be influenced by the optimization of many factors. Commercialization of plant-made vaccine technology is likely to be led by the agricultural biotechnology sector rather than the pharmaceutical sector due to the disruptive nature of the technology and the complex intellectual property landscape. The next major milestones will be conduct of a phase II human clinical trial and demonstration of protection in humans. The achievement of these milestones would be accelerated by further basic investigation into mucosal immunity, the codevelopment of oral adjuvants, and the integration of quality control standards and good manufacturing practices for the production of preclinical and clinical batch materials.