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Objectives: To determine if a set of time-varying biological indicators can be used to: 1) predict the sepsis mortality risk over time and 2) generate mortality risk profiles. Design: Prospective observational study. Setting: Nine Canadian ICUs. Subjects: Three-hundred fifty-six septic patients. Interventions: None. Measurements and Main Results: Clinical data and plasma levels of biomarkers were collected longitudinally. We used a complementary log-log model to account for the daily mortality risk of each patient until death in ICU/hospital, discharge, or 28 days after admission. The model, which is a versatile version of the Cox model for gaining longitudinal insights, created a composite indicator (the daily hazard of dying) from the “day 1” and “change” variables of six time-varying biological indicators (cell-free DNA, protein C, platelet count, creatinine, Glasgow Coma Scale score, and lactate) and a set of contextual variables (age, presence of chronic lung disease or previous brain injury, and duration of stay), achieving a high predictive power (conventional area under the curve, 0.90; 95% CI, 0.86–0.94). Including change variables avoided misleading inferences about the effects of day 1 variables, signifying the importance of the longitudinal approach. We then generated mortality risk profiles that highlight the relative contributions among the time-varying biological indicators to overall mortality risk. The tool was validated in 28 nonseptic patients from the same ICUs who became septic later and was subject to 10-fold cross-validation, achieving similarly high area under the curve. Conclusions: Using a novel version of the Cox model, we created a prognostic tool for septic patients that yields not only a predicted probability of dying but also a mortality risk profile that reveals how six time-varying biological indicators differentially and longitudinally account for the patient’s overall daily mortality risk.

Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies—defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis—are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical  research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.

Background Although extracellular DNA has been reported to activate coagulation, its direct effects and consequent interpretations have recently been questioned because of silica and polyphosphate (polyP) contaminations when DNA is isolated using common silica‐based kits. Objectives To identify and characterize alternative methods of isolating DNA that is free of silica with functionally undetectable levels of polyP. Methods DNA was isolated from the whole blood or buffy coat using three different DNA isolation kits: (a) the silica‐based QIAGEN QIAMP DNA Blood mini kit (silica‐DNA), (b) the non‐silica‐based QIAGEN PAXgene Blood DNA kit (PAX‐DNA), and (c) the non‐silica‐based QuickGene DNA whole blood kit large (DBL‐DNA). The procoagulant properties of DNA were assessed by thrombin generation and plasma clotting assays. A polyP detection assay was used to detect polyP contamination. Results and Conclusions Unlike the isolated DNA, commercially available calf thymus DNA contains thrombinlike amidolytic activity. The PAX‐DNA and DBL‐DNA did not contain silica nor functionally detectable polyP as contaminants. Both PAX‐ and DBL‐DNA were procoagulant in a dose‐dependent manner, which is neutralized with deoxyribonuclease I (DNase I). Thus, we recommend the use of PAX‐DNA or DBL‐DNA for functional studies to investigate the role of extracellular DNA.