A prospective, observational study of the performance of MEWS, NEWS, SIRS and qSOFA for early risk stratification for adverse outcomes in patients with suspected infections at the emergency department.

BACKGROUND: Many patients with suspected infection are presented to the emergency Department. Several scoring systems have been proposed to identify patients at high risk of adverse outcomes. METHODS: We compared generic early warning scores (MEWS and NEWS) to the (SIRS) criteria and quick Sequential Organ Failure Assessement (qSOFA), for early risk stratification in 1400 patients with suspected infection in the ED. The primary study end point was 30-day mortality. RESULTS: The AUROC of the NEWS score for predicting 30-day mortality was 0.740 (95% Confidence Interval 0.682- 0.798), higher than qSOFA (AUROC of 0.689, 95% CI 0.615- 0.763), MEWS (AUROC 0.643 (95% CI 0.583-0.702) and SIRS (AUROC 0.586, 95%CI 0.521 - 0.651). The sensitivity was also highest for NEWS⋝ 5 (sensitivity 75,8% specificity of 67,4%). CONCLUSION: Among patients presenting to the ED with suspected infection, early risk stratification with NEWS (cut-off of ⋝5) is more sensitive for prediction of mortality than qSOFA, MEWS or SIRS, with adequate specificity.

Predicting poor outcome in patients with suspected COVID-19 presenting to the Emergency Department (COVERED) - Development, internal and external validation of a prediction model.

BACKGROUND: A recent systematic review recommends against the use of any of the current COVID-19 prediction models in clinical practice. To enable clinicians to appropriately profile and treat suspected COVID-19 patients at the emergency department (ED), externally validated models that predict poor outcome are desperately needed. OBJECTIVE: Our aims were to identify predictors of poor outcome, defined as mortality or ICU admission within 30 days, in patients presenting to the ED with a clinical suspicion of COVID-19, and to develop and externally validate a prediction model for poor outcome. METHODS: In this prospective, multi-center study, we enrolled suspected COVID-19 patients presenting at the EDs of two hospitals in the Netherlands. We used backward logistic regression to develop a prediction model. We used the area under the curve (AUC), Brier score and pseudo-R2 to assess model performance. The model was externally validated in an Italian cohort. RESULTS: We included 1193 patients between March 12 and May 27 2020, of whom 196 (16.4%) had a poor outcome. We identified 10 predictors of poor outcome: current malignancy (OR 2.774; 95%CI 1.682-4.576), systolic blood pressure (OR 0.981; 95%CI 0.964-0.998), heart rate (OR 1.001; 95%CI 0.97-1.028), respiratory rate (OR 1.078; 95%CI 1.046-1.111), oxygen saturation (OR 0.899; 95%CI 0.850-0.952), body temperature (OR 0.505; 95%CI 0.359-0.710), serum urea (OR 1.404; 95%CI 1.198-1.645), C-reactive protein (OR 1.013; 95%CI 1.001-1.024), lactate dehydrogenase (OR 1.007; 95%CI 1.002-1.013) and SARS-CoV-2 PCR result (OR 2.456; 95%CI 1.526-3.953). The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75). CONCLUSION: The COVERED risk score showed excellent discriminatory ability, also in an external validation. It may aid clinical decision making, and improve triage at the ED in health care environments with high patient throughputs.

Prehospital accuracy of (H)EMS pelvic ring injury assessment and the application of non-invasive pelvic binder devices.

BACKGROUND: Pre-hospital application of a non-invasive pelvic binder device (NIPBD) is essential to increase chances of survival by limiting blood loss in patients with an unstable pelvic ring injury. However, unstable pelvic ring injuries are often not recognized during prehospital assessment. We investigated the prehospital (helicopter) emergency medical services ((H)EMS)' accuracy of the assessment of unstable pelvic ring injuries and NIPBD application rate. METHODS: We performed a retrospective cohort study on all patients with a pelvic injury transported by (H)EMS to our level one trauma centre between 2012 and 2020. Pelvic ring injuries were included and radiographically categorized using the Young & Burgess classification system. Lateral Compression (LC) type II/III -, Anterior-Posterior (AP) type II/III - and Vertical Shear (VS) injuries were considered as unstable pelvic ring injuries. (H)EMS charts and in-hospital patient records were evaluated to determine the sensitivity, specificity and diagnostic accuracy of the prehospital assessment of unstable pelvic ring injuries and prehospital NIPBD application. RESULTS: A total of 634 patients with pelvic injuries were identified, of whom 392 (61.8%) had pelvic ring injuries and 143 (22.6%) had unstable pelvic ring injuries. (H)EMS personnel suspected a pelvic injury in 30.6% of the pelvic ring injuries and in 46.9% of the unstable pelvic ring injuries. An NIPBD was applied in 108 (27.6%) of the patients with a pelvic ring injury and in 63 (44.1%) of the patients with an unstable pelvic ring injury. (H)EMS prehospital diagnostic accuracy measured in pelvic ring injuries alone was 67.1% for identifying unstable pelvic ring injuries from stable pelvic ring injuries and 68.1% for NIPBD application. CONCLUSION: The (H)EMS prehospital sensitivity of unstable pelvic ring injury assessment and NIPBD application rate is low. (H)EMS did not suspect an unstable pelvic injury nor applied an NIPBD in roughly half of all unstable pelvic ring injuries. We advise future research on decision tools to aid the routine use of an NIPBD in any patient with a relevant mechanism of injury.

Non-canonical kinase signaling by the death ligand TRAIL in cancer cells: discord in the death receptor family.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapy is currently evaluated in clinical studies as a tumor cell selective pro-apoptotic approach. However, besides activating canonical caspase-dependent apoptosis by binding to TRAIL-specific death receptors, the TRAIL ligand can activate non-canonical cell survival or proliferation pathways in resistant tumor cells through the same death receptors, which is counterproductive for therapy. Even more, recent studies indicate metastases-promoting activity of TRAIL. In this review, the remarkable dichotomy in TRAIL signaling is highlighted. An overview of the currently known mechanisms involved in non-canonical TRAIL signaling and the subsequent activation of various kinases is provided. These kinases include RIP1, IκB/ NF-κB, MAPK p38, JNK, ERK1/2, MAP3K TAK1, PKC, PI3K/Akt and Src. The functional consequences of their activation, often being stimulation of tumor cell survival and in some cases enhancement of their invasive behavior, are discussed. Interestingly, the non-canonical responses triggered by TRAIL in resistant tumor cells resemble that of TRAIL-induced signals in non-transformed cells. Better knowledge of the mechanism underlying the dichotomy in TRAIL receptor signaling may provide markers for selecting patients who will likely benefit from TRAIL-based therapy and could provide a rationalized basis for combination therapies with TRAIL death receptor-targeting drugs.

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells.

Thymidine phosphorylase (TP) is often overexpressed in cancer and potentially plays a role in the stimulation of angiogenesis. The exact mechanism of angiogenesis induction is unclear, but is postulated to be related to thymidine-derived sugars. TP catalyzes the conversion of thymidine (TdR) to thymine and deoxyribose-1-phosphate (dR-1-P), which can be converted to dR-5-P, glyceraldehyde-3-phosphate (G3P) or deoxyribose (dR). However, it is unclear which sugar accumulates in this reaction. Therefore, in the TP overexpressing Colo320 TP1 and RT112/TP cells we determined by LC-MS/MS which sugars accumulated, their subcellular localization (using (3)H-TdR) and whether dR was secreted from the cells. In both TP-overexpressing cell lines, dR-1-P and dR-5-P accumulated intracellularly at high levels and dR was secreted extensively by the cells. A specific inhibitor of TP completely blocked TdR conversion, and thus no sugars were formed. To examine whether these sugars may be used for the production of angiogenic factors or other products, we determined with (3)H-TdR in which subcellular location these sugars accumulated. TdR-derived sugars accumulated in the cytoskeleton and to some extent in the cell membrane, while incorporation into the DNA was responsible for trapping in the nucleus. In conclusion, various metabolic routes were entered, of which the TdR-derived sugars accumulated in the cytoskeleton and membrane. Future studies should focus on which exact metabolic pathway is involved in the induction of angiogenesis.