Introduction: Despite their widespread use, measures of classification accuracy (i.e. sensitivity and specificity) have several limitations that conceals relevant information and may bias decision-making. Assessing the predictive ability of clinical tools instead may provide more useful prognostic information to support decision-making, particularly in an Emergency setting. We sought to contrast classification accuracy versus predictive ability of the Systemic Inflammatory Response Syndrome (SIRS) and quick Sepsis-related Organ Failure Assessment (qSOFA) Sepsis scores for determining mortality risk among patients with infection transported by paramedics. Methods: A one-year cohort of patients with infections transported to the Emergency Department by paramedics was linked to in-hospital administrative databases. Hospital mortality was determined for each patient at the time of discharge. We calculated sensitivity and specificity of SIRS and qSOFA for classifying hospital mortality across different score thresholds, and estimated discrimination (assessed using the C statistic) and calibration (assessed visually) of prediction. Prediction models for hospital mortality were constructed using the aggregated SIRS or qSOFA scores for each patient as a predictor, while accounting for clustering by institution and adjusting for differences in patient age and sex. Predicted and observed risk were plotted to assess calibration and change in risk across levels of each score. Results: A total of 10,409 patients with infection who were transported by paramedics were successfully linked, with an overall mortality rate of 9.2%. The median SIRS score among non-survivors was 2, while the median qSOFA score was 1. SIRS score had higher sensitivity estimates than qSOFA for classifying hospital mortality at all thresholds (0.11 – 0.83 vs. 0.08 – 0.80), but the qSOFA score had better discrimination (C statistic 0.76 vs. 0.71) and calibration. The risk of hospital mortality predicted by the SIRS score ranged from 6.6-24% across score values, whereas the risk predicted by the qSOFA score ranged from 8.6-53%. Conclusion: Assessing the SIRS and qSOFA scores predictive ability reveals that the qSOFA score provides more information to clinicians about a patient's mortality risk despite having worse sensitivity. This study highlights important limitations of classification accuracy for diagnostic test studies and supports a shift toward assessing predictive ability instead. Character count 2490

Introduction: The quick Sepsis-related Organ Failure Assessment (qSOFA) score was developed to provide clinicians with a quick assessment for patients with latent organ failure possibly consistent with sepsis at high-risk for mortality. With the clinical heterogeneity of patients presenting with sepsis, a Bayesian validation approach may provide a better understanding of its clinical utility. This study used a Bayesian analysis to assess the prediction of hospital mortality by the qSOFA score among patients with infection transported by paramedics. Methods: A one-year cohort of adult patients transported by paramedics in a large, provincial EMS system was linked to Emergency Department (ED) and hospital administrative databases, then restricted to those patients with an ED diagnosed infection. A Bayesian binomial regression model was constructed using Hamiltonian Markov-Chain Monte-Carlo sampling, normal priors for each parameter, the calculated score, age and sex as the predictors, and hospital mortality as the outcome. Discrimination was assessed using posterior predictions to calculate a “Bayesian” C statistic, and calibration was assessed with calibration plots of the observed and predicted probability distributions. The independent predictive ability of each measure was tested by including each component measure (respiratory rate, Glasgow Coma Scale, and systolic blood pressure) as continuous predictors in a second model. Results: A total of 9,920 patients with ED diagnosed infection were included. 264 (2.7%) patients were admitted directly to the ICU, and 955 (9.6%) patients died in-hospital. As independent predictors, the probability of mortality increased as each measure became more extreme, with the Glasgow Coma Scale predicting the greatest change in mortality risk from a high to low score; however, no dramatic change in the probability supporting a single decision threshold was seen for any measure. For the calculated score, the C statistic for predicting mortality was 0.728. The calibration curve had no overlap of predictions, with a probability of 0.5 (50% credible interval 0.47-0.53) for patients with a qSOFA score of 3. Conclusion: Although no single decision threshold was identified for each component measure, a calculated qSOFA score provides good prediction of mortality for patients with ED diagnosed infection. When validating clinical prediction scores, a Bayesian approach may be used to assess probabilities of interest for clinicians to support better clinical decision making. Character count 2494

Introduction: The Prehospital Evidence-Based Practice (PEP) program is an online, freely accessible, continuously updated Emergency Medical Services (EMS) evidence repository. This summary describes the research evidence for the identification and management of adult patients suffering from sepsis syndrome or septic shock. Methods: PubMed was searched in a systematic manner. One author reviewed titles and abstracts for relevance and two authors appraised each study selected for inclusion. Primary outcomes were extracted. Studies were scored by trained appraisers on a three-point Level of Evidence (LOE) scale (based on study design and quality) and a three-point Direction of Evidence (DOE) scale (supportive, neutral, or opposing findings based on the studies’ primary outcome for each intervention). LOE and DOE of each intervention were plotted on an evidence matrix (DOE x LOE). Results: Eighty-eight studies were included for 15 interventions listed in PEP. The interventions with the most evidence were related to identification tools (ID) (n = 26, 30%) and early goal directed therapy (EGDT) (n = 21, 24%). ID tools included Systematic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA) and other unique measures. The most common primary outcomes were related to diagnosis (n = 30, 34%), mortality (n = 40, 45%) and treatment goals (e.g. time to antibiotic) (n = 14, 16%). The evidence rank for the supported interventions were: supportive-high quality (n = 1, 7%) for crystalloid infusion, supportive-moderate quality (n = 7, 47%) for identification tools, prenotification, point of care lactate, titrated oxygen, temperature monitoring, and supportive-low quality (n = 1, 7%) for vasopressors. The benefit of prehospital antibiotics and EGDT remain inconclusive with a neutral DOE. There is moderate level evidence opposing use of high flow oxygen. Conclusion: EMS sepsis interventions are informed primarily by moderate quality supportive evidence. Several standard treatments are well supported by moderate to high quality evidence, as are identification tools. However, some standard in-hospital therapies are not supported by evidence in the prehospital setting, such as antibiotics, and EGDT. Based on primary outcomes, no identification tool appears superior. This evidence analysis can guide selection of appropriate prehospital therapies.

Introduction: Early and accurate diagnosis of critical conditions is essential in emergency medical services (EMS). Serum lactate testing may be used to identify patients with worse prognosis, including sepsis. Recently, the use of a point-of-care lactate (POCL) test has been evaluated in guiding treatment in patients with sepsis. Operating as part of the Prehospital Evidence Based Practice (PEP) Program, the authors sought to identify and describe the body of evidence for POCL use in EMS and the emergency department (ED) for patients with sepsis. Methods: Following PEP methodology, in May 2018, PubMed was searched in a systematic manner. Title and abstract screening were conducted by the program coordinator. These studies were collected, appraised and added to the existing body of literature contained within the PEP database. Evidence appraisal was conducted by two reviewers who assigned both a level of evidence (LOE) on a novel three tier scale and a direction of evidence (supportive, neutral or opposing; based on primary outcome). Data on setting and study design were also extracted. Results: Eight studies were included in our analysis. Three of these studies were conducted in the ED setting; each investigating the POCL test's ability to predict severe sepsis, ICU admission or death. All three studies found supportive results for POCL. A systematic review on the use of POCL in the ED determined that this test can also improve time to treatment. Five of the total 8 studies were conducted prehospitally. Two of these studies were supportive of POCL use in the prehospital setting; in terms of feasibility and the ability to predict sepsis. Both of these study sites used this early information as part of initiating a “sepsis alert” pathway. The other three prehospital studies provide neutral support for POCL. One study demonstrated moderate ability of POCL to predict severe illness. Two studies found poor agreement between prehospital POCL and serum lactate values. Conclusion: Limited low and moderate quality evidence suggest POCL may be feasible and helpful in predicting sepsis in the prehospital setting. However, there is sparse and inconsistent support for specific important outcomes, including accuracy.

Respiratory viral infections are a leading cause of disease worldwide. A variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. Standard surveillance systems typically only target severe infections (ED outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. Here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. We enrolled 214 individuals at multiple New York City locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. We combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. Asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. Symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. Upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. These findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population.

Particle loading affects the dynamics of buoyant plumes, since the difference between particle and fluid densities is much greater than that in the fluid alone. In stratified environments, plume rise is density limited; after initial overshoot, the plume reaches a terminal level and spreads radially. Particles dropping from this horizontal intrusion may be re-entrained. This recycling of dense matter reduces plume buoyancy and intrusion height and, for sufficient load, can lead to plume collapse. Entrainment-based formulae yield a steady-state plume rise. We identify a new conserved quantity for such plumes. Integrating paths of particles dropping from the intrusion yields the fraction re-entrained. A simple mathematical model predicts from buoyancy ratio at source ( $P=$  negative particle buoyancy divided by positive fluid buoyancy) whether a particle-laden plume will collapse. Under this model, for small settling velocity, a particle-laden plume will not collapse if $P<0.368$ . Above this, collapse depends also on the amount of particle-free ambient fluid entrained in the overshoot region. For pure plumes, experimental evidence suggests that this is small. For forced plumes, more substantial overshoot and entrainment is shown to increase the critical ratio. An extension, based on successive recycling, estimates time to collapse. To investigate further we develop a simple computational model, coupling a ‘top-hat’ plume model, an analytical formula for radially decaying concentrations in the intrusion and an axisymmetric finite-volume solution for time-dependent settling and entrainment. The model can predict the impact of particle load on final rise, as well as the occurrence and time scales of plume collapse.

We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽−2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score −2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3–99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.

This paper is concerned with some of the properties of arcs in the real affine plane which are met by every parabola at not more than four points. Many of the properties of arcs of parabolic order four which we consider here are analogous to the corresponding properties of arcs of cyclic order three in the conformai plane which are described in (1). The paper (2), on parabolic differentiation, provides the background for the present discussion.

In Section 2, general tangent, osculating, and superosculating parabolas are introduced. The concept of strong differentiability is introduced in Section 3; cf. Theorem 1. Section 4 deals with arcs of finite parabolic order, and it is proved (Theorem 2) that an end point p of an arc A of finite parabolic order is twice parabolically differentiable.

The purpose of this paper is the study of parabolically differentiable points of arcs in the real affine plane. In Section 2, two different definitions of convergence of a family of parabolas are given and it is observed (Theorem 1) that these are equivalent. In Section 3, tangent parabolas at a point p of an arc A are discussed and it is proved (Theorem 2) that all the non-degenerate non-tangent parabolas of A through p intersect A at p or that all of them support. In Section 4, osculating parabolas are introduced and the condition that an arc be twice parabolically differentiable at a point p is stated.

In (2) Lane and Scherk discussed differentiate points of arcs in the conformai (inversive) plane. Arcs A3 of cyclic order three were discussed in (3; 4). In the present note we give necessary and sufficient conditions for the union of two A3's to be an A 3 (Theorem 1), and for an A3 to be extensible to a larger one (Theorem 2). The related problem of extending arcs in projective n-space was dealt with by Haupt in (1) and Sauter in (5; 6).

This paper follows naturally a note on parabolic differentiation (2) in which the parabolically differentiable points in the real affine plane were discussed. In the parabolic case, the four-parameter family of parabolas in the affine plane led to three differentiability conditions. In the present paper, the five-parameter family of conies in the real projective plane gives rise to four differentiability conditions and a point of an arc in the projective plane is called conically differentiable if these four conditions are satisfied. The differentiable points are classified by the nature of their families of osculating conies, superosculating conies, and their ultraosculating conies.

Introduction. This paper is a generalization of the classification of the differentiable points in the conformai plane given in (1). The main tools are the intersection and support properties of all the spheres through a differentiable point of an arc in conformal 3-space.

The purpose of this note is the classification of thedifferentiable points on curves in the conformai plane. We introduce tangent and osculating circles at such points and study the intersection and support properties of these circles.

Let F(z, u) denote

1

where F 1(z),… , F n(z) are rational functions of z with complex coefficients. We shall speak of F (z, u) = 0 as the fundamental algebraic equation and shall adopt z as the independent variable and u as the dependent, except in § 4, where we use x and y instead of them, and where it is understood that x and y are connected birationally with z and u.