Background Circulating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. However, the source and mechanism of release of cfDNA in trauma is not well understood. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. The primary objective of our study was to determine if cfDNA has prognostic utility in trauma. The secondary objective of this study was to determine the source of cfDNA in trauma compared to sepsis. Methods We studied trauma patients from two prospective observational cohort studies: the DNA as a Prognostic Marker in ICU Patients (DYNAMICS) study and the Endotoxin in Polytrauma (ENPOLY) study. We also studied septic patients from the DYNAMICS study. Citrated plasma samples were collected longitudinally from the patients (days 1 to 7). The following molecules were measured in the plasma samples: cfDNA, protein C (PC), myeloperoxidase (MPO) (a marker of neutrophil activation), citrullinated Histone H3 (H3Cit, a marker of NETosis), cyclophilin A (a marker of necrosis), and caspase-cleaved K18 (a marker of apoptosis). Results A total of 77 trauma patients were included ( n = 38 from DYNAMICS and n = 39 from ENPOLY). The median age was 49 years; 27.3% were female, and mortality was 16.9% at 28 days. Levels of cfDNA were elevated compared to healthy values but not significantly different between survivors and non-survivors. There was a positive correlation between MPO and cfDNA in septic patients ( r = 0.424, p < 0.001). In contrast, there was no correlation between MPO and cfDNA in trauma patients ( r = – 0.192, p = 0.115). Levels of H3Cit, a marker of NETosis, were significantly elevated in septic patients compared to trauma patients ( p < 0.01) while apoptosis and necrosis markers did not differ between the two groups. Conclusion Our studies suggest that the source and mechanism of release of cfDNA differ between trauma and sepsis patients. In sepsis, cfDNA is likely primarily released by activated neutrophils via the process of NETosis. In contrast, cfDNA in trauma appears to originate mainly from injured or necrotic cells. Although cfDNA is elevated in trauma and sepsis patients compared to healthy controls, cfDNA does not appear to have prognostic utility in trauma patients. Trial registration ClinicalTrials.gov Identifier: NCT01355042 . Registered May 17, 2011 Electronic supplementary material The online version of this article (10.1186/s40635-019-0251-4) contains supplementary material, which is available to authorized users.

This study indicates that HEWS at ED triage has limited utility for identifying patients at risk of experiencing a critical event. However, HEWS may allow earlier identification of septic patients. Prospective studies are needed to further delineate the utility of the HEWS to identify septic patients in the ED.

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.

BACKGROUND AND PURPOSEExenatide is a 39-amino-acid peptide widely used to manage type 2 diabetes mellitus. However, it has a short plasma half-life and requires a twice daily injection regime. To overcome these drawbacks we used maleimide-polyethylene glycol to induce site-specific PEGylation. EXPERIMENTAL APPROACHThe analogue PB-105 (ExC39) was produced by replacing cysteine at position 39 of exenatide to provide a free thiol group. PB-105 showed the same glucoregulatory activity as exenatide in mice. Site-specific PEGylation of PB-105 was performed to produce PB-110 (ExC39PEG5kDa), PB-106 (ExC39PEG20kDa), PB-107 (ExC39PEG30kDa) and PB-108 (ExC39PEG40kDa). Their effects on intracellular cAMP, acute glucoregulatory activity and pharmacokinetic profile were compared in mice and rats. KEY RESULTSPEGylation shifted the concentration-response curve of PB-105 to the right in a parallel, polyethylene glycol mass-dependent manner but with an inflexion point of at least 20 kDa. The activities of PB-107 and PB-108 but not PB-106 were reduced by 90% and 99%. PEGylation affected in vivo glucoregulatory activity in the same 'Inflexion-Shift' fashion at least at 20 kDa, but linearly increased plasma duration and systemic exposure without inflexion. PB-106 had a plasma t1/2 approximately 10-fold that of PB-105, and exhibited superior glucoregulatory activity compared with PB-105 in normal and diabetic mice. CONCLUSIONS AND IMPLICATIONSSite-specific PEGylation of exenatide with a permanent amide linkage affects its activity in a new type of 'Inflexion-Shift' fashion. PB-106 is a putative new analogue for treating diabetes; it possesses no loss of in vitro activity, prolonged plasma duration and superior, improved in vivo glucoregulatory activity compared with exenatide.

IntroductionMultiple early warning scores (EWS) have been developed and implemented to reduce cardiac arrests on hospital wards. Case–control observational studies that generate an area under the receiver operator curve (AUROC) are the usual validation method, but investigators have also generated EWS with algorithms with no prior clinical knowledge. We present a protocol for the validation and comparison of our local Hamilton Early Warning Score (HEWS) with that generated using decision tree (DT) methods.Methods and analysisA database of electronically recorded vital signs from 4 medical and 4 surgical wards will be used to generate DT EWS (DT-HEWS). A third EWS will be generated using ensemble-based methods. Missing data will be multiple imputed. For a relative risk reduction of 50% in our composite outcome (cardiac or respiratory arrest, unanticipated intensive care unit (ICU) admission or hospital death) with a power of 80%, we calculated a sample size of 17 151 patient days based on our cardiac arrest rates in 2012. The performance of the National EWS, DT-HEWS and the ensemble EWS will be compared using AUROC.Ethics and disseminationEthics approval was received from the Hamilton Integrated Research Ethics Board (#13-724-C). The vital signs and associated outcomes are stored in a database on our secure hospital server. Preliminary dissemination of this protocol was presented in abstract form at an international critical care meeting. Final results of this analysis will be used to improve on the existing HEWS and will be shared through publication and presentation at critical care meetings.

The HEARTSMAP tool can be reliably used to assess pediatric psychosocial assessment documentation across a diverse range of EDs. Current documentation practices are variable and often inadequate, and the HEARTSMAP tool can aid in quality improvement initiatives to standardize and optimize care for the growing burden of pediatric mental illness.

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents is increasing. This has spurred the development and publication of clinical practice guidelines (CPGs) for the management of paediatric T2DM. Given the long-term complications of T2DM, optimal management is important to prevent or delay these complications. However, the quality of published CPGs has not yet been empirically evaluated.Our objective is to systematically appraise all published CPGs for the management of T2DM in children and adolescents.MethodsWe will identify all published CPGs that address T2DM in children and adolescents through MEDLINE, Embase, CINAHL, Trip, and the National Guideline Clearinghouse and will screen diabetes and paediatric societies and associations’ websites. Search records will be screened in duplicate for inclusion. Grey literature will be covered by systematically searching publications of all relevant diabetes societies and associations and other health organizations for CPGs that meet our inclusion criteria. CPGs deemed eligible for inclusion will be retrieved. Quality assessment will be conducted using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool by a team of four appraisers. Scaled scores of the AGREE II will be used to gauge the overall quality of CPGs.DiscussionThe results of this review will be disseminated through presentations at local, national, and international conferences and publication in a peer-reviewed journal. The results of this review can help improve the reporting of future guidelines, inform decisions of policy-makers to endorse CPGs, and affect the choice of guideline use in clinical practice.Systematic review registrationPROSPERO CRD42016034187

No abstract