The impact of age on predictive performance of national early warning score at arrival to emergency departments: development and external validation

Study objective: To investigate how age affects the predictive performance of the National Early Warning Score (NEWS) at arrival to the emergency department (ED) regarding inhospital mortality and intensive care admission.Methods: International multicenter retrospective cohorts from 2 Danish and 3 Dutch ED. Development cohort: 14,809 Danish patients aged >= 18 years with at least systolic blood pressure or pulse measured from the Danish Multicenter Cohort. External validation cohort: 50,448 Dutch patients aged >18 years with all vital signs measured from the Netherlands Emergency Department Evaluation Database (NEED). Multivariable logistic regression was used for model building. Performance was evaluated overall and within age categories: 18 to 64 years, 65 to 80 years, and more than 80 years.Results: In the Danish Multicenter Cohort, a total of 2.5% died inhospital, and 2.8% were admitted to the ICU, compared with 2.8% and 1.6%, respectively, in the NEED. Age did not add information for the prediction of intensive care admission but was the strongest predictor for inhospital mortality. For NEWS alone, severe underestimation of risk was observed for persons above 80 while overall Area Under Receiver Operating Characteristic (AUROC) was 0.82 (confidence interval [CI] 0.80 to 0.84) in the Danish Multicenter Cohort versus 0.75 (CI 0.75 to 0.77) in the NEED. When combining NEWS with age, underestimation of risks was eliminated for persons above 80, and overall AUROC increased significantly to 0.86 (CI 0.85 to 0.88) in the Danish Multicenter Cohort versus 0.82 (CI 0.81 to 0.83) in the NEED.Conclusion: Combining NEWS with age improved the prediction performance regarding inhospital mortality, mostly for persons aged above 80, and can potentially improve decision policies at arrival to EDs

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

UNLABELLED: Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7-7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4-5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46-103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1-2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. TRIAL REGISTRATION: clinicaltrials.gov NTC02092116

The association between systolic blood pressure and heart rate in emergency department patients: a multicenter cohort study

BackgroundGuidelines and textbooks assert that tachycardia is an early and reliable sign of hypotension, and an increased heart rate (HR) is believed to be an early warning sign for the development of shock, although this response may change by aging, pain, and stress.ObjectiveTo assess the unadjusted and adjusted associations between systolic blood pressure (SBP) and HR in emergency department (ED) patients of different age categories (18–50 years; 50–80 years; > 80 years).MethodsA multicenter cohort study using the Netherlands Emergency department Evaluation Database (NEED) including all ED patients ≥ 18 years from three hospitals in whom HR and SBP were registered at arrival to the ED. Findings were validated in a Danish cohort including ED patients. In addition, a separate cohort was used including ED patients with a suspected infection who were hospitalized from whom measurement of SBP and HR were available prior to, during, and after ED treatment. Associations between SBP and HR were visualized and quantified with scatterplots and regression coefficients (95% confidence interval [CI]).ResultsA total of 81,750 ED patients were included from the NEED, and a total of 2358 patients with a suspected infection. No associations were found between SBP and HR in any age category (18–50 years: −0.03 beats/min/10 mm Hg, 95% CI −0.13–0.07, 51–80 years: −0.43 beats/min/10 mm Hg, 95% CI −0.38 to −0.50, > 80 years: −0.61 beats/min/10 mm Hg, 95% CI −0.53 to −0.71), nor in different subgroups of ED patient. No increase in HR existed with a decreasing SBP during ED treatment in ED patients with a suspected infection.ConclusionNo association between SBP and HR existed in ED patients of any age category, nor in ED patients who were hospitalized with a suspected infection, even during and after ED treatment. Emergency physicians may be misled by traditional concepts about HR disturbances because tachycardia may be absent in hypotension.Development and application of statistical models for medical scientific researc

Development and external validation of the International Early Warning Score for improved age- and sex-adjusted in-hospital mortality prediction in the emergency department

Objectives: Early Warning Scores (EWSs) have a great potential to assist clinical decision-making in the emergency department (ED). However, many EWS contain methodological weaknesses in development and validation and have poor predictive performance in older patients. The aim of this study was to develop and externally validate an International Early Warning Score (IEWS) based on a recalibrated National Early warning Score (NEWS) model including age and sex and evaluate its performance independently at arrival to the ED in three age categories (18–65, 66–80, > 80 yr).Design: International multicenter cohort study.Setting: Data was used from three Dutch EDs. External validation was performed in two EDs in Denmark.Patients: All consecutive ED patients greater than or equal to 18 years in the Netherlands Emergency department Evaluation Database (NEED) with at least two registered vital signs were included, resulting in 95,553 patients. For external validation, 14,809 patients were included from a Danish Multicenter Cohort (DMC).Measurements and Main Results: Model performance to predict in-hospital mortality was evaluated by discrimination, calibration curves and summary statistics, reclassification, and clinical usefulness by decision curve analysis. In-hospital mortality rate was 2.4% (n = 2,314) in the NEED and 2.5% (n = 365) in the DMC. Overall, the IEWS performed significantly better than NEWS with an area under the receiving operating characteristic of 0.89 (95% CIs, 0.89–0.90) versus 0.82 (0.82–0.83) in the NEED and 0.87 (0.85–0.88) versus 0.82 (0.80–0.84) at external validation. Calibration for NEWS predictions underestimated risk in older patients and overestimated risk in the youngest, while calibration improved for IEWS with a substantial reclassification of patients from low to high risk and a standardized net benefit of 5–15% in the relevant risk range for all age categories.Conclusions: The IEWS substantially improves in-hospital mortality prediction for all ED patients greater than or equal to18 years.Development and application of statistical models for medical scientific researchAnalysis and support of clinical decision makin

Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): Immune responses to Vacc-4x regions on p24 and changes in HIV reservoirs.

The REDUC clinical study Part B investigated Vacc-4x/rhuGM-CSF therapeutic vaccination prior to HIV latency reversal using romidepsin. The main finding was a statistically significant reduction from baseline in viral reservoir measurements. Here we evaluated HIV-specific functional T-cell responses following Vacc-4x/rhuGM-CSF immunotherapy in relation to virological outcomes on the HIV reservoir. This study, conducted in Aarhus, Denmark, enrolled participants (n = 20) with CD4>500 cells/mm <sup>3</sup> on cART. Six Vacc-4x (1.2 mg) intradermal immunizations using rhuGM-CSF (60 μg) as adjuvant were followed by 3 weekly intravenous infusions of romidepsin (5 mg/m <sup>2</sup> ). Immune responses were determined by IFN-γ ELISpot, T-cell proliferation to p24 15-mer peptides covering the Vacc-4x region, intracellular cytokine staining (ICS) to the entire HIV <sup>Gag</sup> and viral inhibition. The frequency of participants with CD8+ T-cell proliferation assay positivity was 8/16 (50%) at baseline, 11/15 (73%) post-vaccination, 6/14 (43%) during romidepsin, and 9/15 (60%)post-romidepsin. Participants with CD8+ T-cell proliferation assay positivity post-vaccination showed reductions in total HIV DNA post-vaccination (p = 0.006; q = 0.183), post-latency reversal (p = 0.005; q = 0.183), and CA-RNA reductions post-vaccination (p = 0.015; q = 0.254). Participants (40%) were defined as proliferation 'Responders' having ≥2-fold increase in assay positivity post-baseline. Robust ELISpot baseline responses were found in 87.5% participants. No significant changes were observed in the proportion of polyfunctional CD8+ T-cells to HIV <sup>Gag</sup> by ICS. There was a trend towards increased viral inhibition from baseline to post-vaccination (p = 0.08). In this 'shock and kill' approach supported by therapeutic vaccination, CD8+ T-cell proliferation represents a valuable means to monitor functional immune responses as part of the path towards functional HIV cure