Diagnostic and prognostic value of cardiac troponins in emergency department patients presenting after a fall: A prospective, multicenter study.

BACKGROUND: Emergency department (ED) presentations after a ground-level fall (GLF) are common. Falls were suggested to be another possible presenting feature of a myocardial infarction (MI), as unrecognized MIs are common in older adults. Elevated high-sensitivity cardiac troponin (hs-cTn) concentrations could help determine the etiology of a GLF in ED. We investigated the prevalence of both MI and elevated high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), as well as the diagnostic accuracy of hs-cTnT and hs-cTnI regarding MI, and their prognostic value in older ED patients presenting after a GLF. METHODS: This was a prospective, international, multicenter, cohort study with a follow-up of up to 1 year. Patients aged 65 years or older presenting to the ED after a GLF were prospectively enrolled. Two outcome assessors independently reviewed all discharge records to ascertain final gold standard diagnoses. Hs-cTnT and hs-cTnI levels were determined from thawed samples for every patient. RESULTS: In total, 558 patients were included. Median (IQR) age was 83 (77-89) years, and 67.7% were female. Elevated hs-cTnT levels were found in 384 (68.8%) patients, and elevated hs-cTnI levels in 86 (15.4%) patients. Three patients (0.5%) were ascertained the gold standard diagnosis MI. Within 30 days, 18 (3.2%) patients had died. Nonsurvivors had higher hs-cTnT and hs-cTnI levels compared with survivors (hs-cTnT 40 [23-85] ng/L in nonsurvivors and 20 [13-33] ng/L in survivors; hs-cTnI 25 [14-54] ng/L in nonsurvivors and 8 [4-16] ng/L in survivors; p < 0.001 for both). CONCLUSIONS: A majority of patients (n = 364, 68.8%) presenting to the ED after a fall had elevated hs-cTnT levels and 86 (15.4%) elevated hs-cTnI levels. However, the incidence of MI in these patients was low (n = 3, 0.5%). Our data do not support the opinion that falls may be a common presenting feature of MI. We discourage routine troponin testing in this population. However, hs-cTnT and hs-cTnI were both found to have prognostic properties for mortality prediction up to 1 year.

Correction: Osterwalder et al. Acute Abdominal Pain: Missed Diagnoses, Extra-Abdominal Conditions, and Outcomes. J. Clin. Med. 2020, 9, 899.

In the original publication [...].

Monocyte Distribution Width as a Diagnostic Marker for Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Monocyte distribution width (MDW) is an emerging biomarker for infection. It is available easily and quickly as part of the CBC count, which is performed routinely on hospital admission. The increasing availability and promising results of MDW as a biomarker in sepsis has prompted an expansion of its use to other infectious diseases. RESEARCH QUESTION: What is the diagnostic performance of MDW across multiple infectious disease outcomes and care settings? STUDY DESIGN AND METHODS: A systematic review of the diagnostic performance of MDW across multiple infectious disease outcomes was conducted by searching PubMed, Embase, Scopus, and Web of Science through February 4, 2022. Meta-analysis was performed for outcomes with three or more reports identified (sepsis and COVID-19). Diagnostic performance measures were calculated for individual studies with pooled estimates created by linear mixed-effects models. RESULTS: We identified 29 studies meeting inclusion criteria. Most examined sepsis (19 studies) and COVID-19 (six studies). Pooled estimates of diagnostic performance for sepsis differed by reference standard (Second vs Third International Consensus Definitions for Sepsis and Septic Shock criteria) and tube anticoagulant used and ranged from an area under the receiver operating characteristic curve (AUC) of 0.74 to 0.94, with mean sensitivity of 0.69 to 0.79 and mean specificity of 0.57 to 0.86. For COVID-19, the pooled AUC of MDW was 0.76, mean sensitivity was 0.79, and mean specificity was 0.59. INTERPRETATION: MDW exhibited good diagnostic performance for sepsis and COVID-19. Diagnostic thresholds for sepsis should be chosen with consideration of reference standard and tube type used. TRIAL REGISTRY: Prospero; No.: CRD42020210074; URL: https://www.crd.york.ac.uk/prospero/.

Monocyte distribution width as a pragmatic screen for SARS-CoV-2 or influenza infection.

Monocyte distribution width (MDW) is a novel marker of monocyte activation, which is known to occur in the immune response to viral pathogens. Our objective was to determine the performance of MDW and other leukocyte parameters as screening tests for SARS-CoV-2 and influenza infection. This was a prospective cohort analysis of adult patients who underwent complete blood count (CBC) and SARS-CoV-2 or influenza testing in an Emergency Department (ED) between January 2020 and July 2021. The primary outcome was SARS-CoV-2 or influenza infection. Secondary outcomes were measures of severity of illness including inpatient hospitalization, critical care admission, hospital lengths of stay and mortality. Descriptive statistics and test performance measures were evaluated for monocyte percentage, MDW, white blood cell (WBC) count, and neutrophil to lymphocyte ratio (NLR). 3,425 ED patient visits were included. SARS-CoV-2 testing was performed during 1,922 visits with a positivity rate of 5.4%; influenza testing was performed during 2,090 with a positivity rate of 2.3%. MDW was elevated in patients with SARS-Cov-2 (median 23.0U; IQR 20.5-25.1) or influenza (median 24.1U; IQR 22.0-26.9) infection, as compared to those without (18.9U; IQR 17.4-20.7 and 19.1U; 17.4-21, respectively, P < 0.001). Monocyte percentage, WBC and NLR values were within normal range in patients testing positive for either virus. MDW identified SARS-CoV-2 and influenza positive patients with an area under the curve (AUC) of 0.83 (95% CI 0.79-0.86) and 0.83 (95% CI 0.77-0.88), respectively. At the accepted cut-off value of 20U for MDW, sensitivities were 83.7% (95% CI 76.5-90.8%) for SARS-CoV-2 and 89.6% (95% CI 80.9-98.2%) for influenza, compared to sensitivities below 45% for monocyte percentage, WBC and NLR. MDW negative predictive values were 98.6% (95% CI 98.0-99.3%) and 99.6% (95% CI 99.3-100.0%) respectively for SARS-CoV-2 and influenza. Monocyte Distribution Width (MDW), available as part of a routine complete blood count (CBC) with differential, may be a useful indicator of SARS-CoV-2 or influenza infection.

Monocyte distribution width as part of a broad pragmatic sepsis screen in the emergency department.

STUDY OBJECTIVE: Enhancement of a routine complete blood count (CBC) for detection of sepsis in the emergency department (ED) has pragmatic utility for early management. This study evaluated the performance of monocyte distribution width (MDW) alone and in combination with other routine CBC parameters as a screen for sepsis and septic shock in ED patients. METHODS: A prospective cohort analysis of adult patients with a CBC collected at an urban ED from January 2020 through July 2021. The performance of MDW, white blood count (WBC) count, and neutrophil-to-lymphocyte-ratio (NLR) to detect sepsis and septic shock (Sepsis-3 Criteria) was evaluated using diagnostic performance measures. RESULTS: The cohort included 7952 ED patients, with 180 meeting criteria for sepsis; 43 with septic shock and 137 without shock. MDW was highest for patients with septic shock (median 24.8 U, interquartile range [IQR] 22.0-28.1) and trended downward for patients with sepsis without shock (23.9 U, IQR 20.2-26.8), infection (20.4 U, IQR 18.2-23.3), then controls (18.6 U, IQR 17.1-20.4). In isolation, MDW detected sepsis and septic shock with an area under the receiver operator characteristic curve (AUC) of 0.80 (95% confidence interval [CI] 0.77-0.84) and 0.85 (95% CI 0.80-0 .91), respectively. Optimal performance was achieved in combination with WBC count and NLR for detection of sepsis (AUC 0.86, 95% CI 0.83-0.89) and septic shock (0.86, 95% CI 0.80-0.92). CONCLUSION: A CBC differential panel that includes MDW demonstrated strong performance characteristics in a broad ED population suggesting pragmatic value as a rapid screen for sepsis and septic shock.

Prevalence and Prognosis of Fever Symptoms, Hypo-, and Hyperthermia in Unselected Emergency Patients.

Assessments of history and body temperature are cornerstones of the diagnostic workup in all patients presenting to emergency departments (ED). Yet, the objective measurement of temperature and the subjective perception of fever can differ. This is a secondary exploratory analysis of a consecutive all-comer study, performed at an adult ED in Switzerland. Trained medical students interviewed all patients if fever was present. Altered temperature (>38.0 °C/<36.0 °C) measured at triage using an ear thermometer was used as the reference standard for diagnostic performance. In case of a disagreement between fever symptoms and altered temperature, discordance was noted. Outcome measures for case severity (acute morbidity, hospitalization, intensive care, and in-hospital mortality) were extracted from the electronic health records. Odds ratios (OR) for discordance between signs and symptoms and outcomes were calculated. Among 2183 patients, 325 patients reported fever symptoms. The sensitivity of fever symptoms as a test for altered temperature was 36.3%. Specificity was 91.5%. The negative predictive value was 84.1%, positive likelihood ratio was 4.2 and negative likelihood ratio was 0.7. The adjusted OR for discordance between fever symptoms and altered temperature was 1.71 (95% CI: 1.2-2.44) for acute morbidity, 1.56 (95% CI: 1.13-2.15) for hospitalization, and 1.12 (95% CI: 0.64-1.59) for intensive care. Unadjusted OR for mortality was 1.5 (95% CI: 0.69-3.25). Fever symptoms and altered temperature broadly overlap, but presentations can be stratified according to concordance between signs and symptoms. In case of discordance, the odds for acute morbidity and hospitalization are increased. Discordance may therefore be further investigated as a red flag for a serious outcome.

Acute Abdominal Pain: Missed Diagnoses, Extra-Abdominal Conditions, and Outcomes.

Abdominal pain (AP) is a common reason for presentation to an emergency department (ED). With this prospective, observational all-comer study, we aimed to answer three questions: Which diagnoses are most often missed? What is the incidence of extra-abdominal causes? What is the prognosis of abdominal pain in a tertiary urban European ED? Participants were systematically interviewed for the presence of 35 predefined symptoms. For all patients with abdominal pain, the index visit diagnoses were recorded. Related representation was defined as any representation, investigation, or surgery related to the index visit (open time frame). If a diagnosis changed between index visit and representation, it was classified as missed diagnosis. Among 3960 screened presentations, 480 (12.1%) were due to AP. Among 63 (13.1%) related representations, the most prevalent causes were cholelithiasis, gastroenteritis, and urinary retention. A missed diagnosis was attributed to 27 (5.6%) presentations. Extra-abdominal causes were identified in 162 (43%) presentations. Thirty-day mortality was comparable to that of all other ED patients (2.2% vs. 2.1%). Patients with abdominal pain had a low risk of representation, and the majority of representations due to missed diagnoses were of benign origin. The high incidence of extra-abdominal causes is noteworthy, as this may induce change to differential diagnosis of abdominal pain.

Modification of the Emergency Severity Index Improves Mortality Prediction in Older Patients.

INTRODUCTION: Older patients frequently present to the emergency department (ED) with nonspecific complaints (NSC), such as generalized weakness. They are at risk of adverse outcomes, and early risk stratification is crucial. Triage using Emergency Severity Index (ESI) is reliable and valid, but older patients are prone to undertriage, most often at decision point D. The aim of this study was to assess the predictive power of additional clinical parameters in NSC patients. METHODS: Baseline demographics, vital signs, and deterioration of activity of daily living (ADL) in patients with NSC were prospectively assessed at four EDs. Physicians scored the coherence of history and their first impression. For prediction of 30-day mortality, we combined vital signs at decision point D (heart rate, respiratory rate, oxygen saturation) as "ESI vital," and added "ADL deterioration," "incoherence of history," or "first impression," using logistic regression models. RESULTS: We included 948 patients with a median age of 81 years, 62% of whom were female. The baseline parameters at decision point D (ESI vital) showed an area under the curve (AUC) of 0.64 for predicting 30-day mortality in NSC patients. AUCs increased to 0.67 by adding ADL deterioration to 0.66 by adding incoherence of history, and to 0.71 by adding first impression. Maximal AUC was 0.73, combining all parameters. CONCLUSION: Adding the physicians' first impressions to vital signs at decision point D increases predictive power of 30-day mortality significantly. Therefore, a modified ESI could improve predictive power of triage in older patients presenting with NSCs.

Construct validity of acute morbidity as a novel outcome for emergency patients.

OBJECTIVES: Validation of acute morbidity as a novel outcome in emergency medicine. METHODS: Construct validity of acute morbidity was established by comparison to other outcomes using linear and logistic regression models. RESULTS: Data of 4608 patients were analysed. 1869 patients (40.6%) fulfilled the criteria for acute morbidity. Using multivariate analyses, acute morbidity was associated with outcomes such as hospitalisation (OR: 11, 95%-CI 9-13), mortality (OR 15, 95%-CI 6-49), and ICU admission (OR: 46, 95%-CI 25-96). Reliability of the construct "acute morbidity" was estimated using Cohens Kappa, which was 0.96 for intra-rater and 0.94 for inter-rater reliability. CONCLUSION: Reliability of the framework for acute morbidity was high. Construct validity was shown by associations with hospitalisation, mortality, and ICU admission.

Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer.

BACKGROUND: The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. METHODS: We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. RESULTS: Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. CONCLUSIONS: In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.

Symptoms at presentation to the emergency department: Predicting outcomes and changing clinical practice?

BACKGROUND: The type and number of symptoms in emergency patients differ widely. It remains unclear, if outcomes can be predicted by the number of symptoms. Furthermore, it is unknown, whether clinical practice could be influenced by presenting symptoms. METHODS: Prospective observational study, performed in the emergency department of the University Hospital Basel, a tertiary hospital. A consecutive sample of patients was interviewed at presentation for a predefined set of 35 symptoms. The number of symptoms was correlated with outcomes using linear and logistic regression models. Clinical practice was observed using prospective data on disease severity ratings, triage category, use of resources, length-of-stay and follow-up presentations. RESULTS: Data of 3472 patients were analysed. The number of symptoms ranged between 1 and 25, the mean being 2.74. Women reported more symptoms than men. Age and comorbidity indices were not associated with the number of symptoms. After adjusting for age and gender, there was no correlation between the number of symptoms and adverse outcomes, such as ICU-admission or in-hospital mortality (OR: 1.03, CI: 0.88-1.18, P = .68). The number of symptoms at presentation was associated with hospitalisation, disease severity rating by patients and emergency physicians, triage categories, use of resources, length-of-stay and follow-up presentations. CONCLUSION: The number of symptoms did not correlate with the main adverse outcomes (ICU-admission and in-hospital mortality). However, clinical practice was influenced by the nature and number of symptoms. This was shown by associations with hospitalisation, length-of-stay, use of resources and follow-up presentations. Furthermore, the number of symptoms correlated with the caregivers' disease severity ratings and the attributed triage categories. This may indicate that caregivers respond to the number of symptoms by a higher investment in their immediate work-ups and later follow-ups.

Risk of adverse outcome in patients referred by emergency medical services in Switzerland.

AIMS OF THE STUDY: Comparison of outcomes between different emergency medical services (EMS) is difficult and lacking in Switzerland. Therefore, knowledge about the inherent risks of EMS-referred patients is important. Targeted interventions may benefit these patients by optimising resource allocation. We therefore aimed to study outcomes in EMS-referred patients presenting to a Swiss emergency department (ED). METHODS: Prospective observational study in all patients presenting to the ED of Basel University Hospital. Mode of referral was recorded (EMS or other). Univariate and multivariate linear, Poisson and logistic regression models were used. Crude and age/gender adjusted associations between mode of referral and outcomes were calculated. Outcomes were shown for admission, length of stay (LOS), in-hospital, and 1-year mortality. RESULTS: Of 5634 patients presenting in the inclusion period, 4703 were screened, 4544 were included and 4287 were followed up for 365 days. Associations between EMS referral and several adverse outcomes were found and expressed as odds ratios (ORs) and geometric mean ratios (GMRs): hospital admission (OR 3.8, 95% CI 3.2-4.5; p <0.001), intensive care unit (ICU) admission (OR 4.2, 95% CI 3.2-5.5, p <0.001), ED-LOS (GMR 1.2, 95% CI 1.1-1.2; p <0.001), in-hospital mortality (OR 6.4, 95% CI 2.9-15.6; p <0.001) and 1-year mortality (OR 2.3, 95% CI 1.7-3.0; p <0.001). CONCLUSION: Patients referred by EMS have higher odds of admission to hospital and ICU, a longer ED LOS, and higher short- and long-term mortalities than the general ED population.

[Adverse drug events of older patients presenting in the emergency department]. / Notfall-Präsentation von älteren Erwachsenen mit unerwünschten Arzneimittelwirkungen.

The effect of medication is always a balance between their beneficial effects and any adverse reactions they might elicit. The main risk for adverse drug events {ADEs) is polypharmacy, which is the simultaneous use of multiple drugs.This often applies to older patients, who suffer from multiple diseases and therefore take multiple medications. Thus, itis not surprising, that ADEs are frequention older patients and account up to 16% of emergency visits. It is still under discussion, whether age is an independent risk factor for ADEs. However, there are some age-related changes in the pharmacokinetic and pharmacodynamics properties of many drugs, which may influence the highly fragile balance between benefit and harm in older patients. Though there are multiple risk factors for and causes of ADEs, it could be shown that a lot of ADEs are preventable and even predictable: Budnitz eta/. showed that almost two thirds of emergency hospitalisations occur due to four medication classes: warfarin, oral antiplatelet agents, insulin and oral hypoglycaemic agents. Nevertheless, only 40-60% ofA DEs are recognized in the emergency department. This might be explained by the broad clinical symptoms, ranging from bleeding due to anticoagulants to the more nonspecific symptom of weakness due to hyponatraemia secondary to thiazide diuretics. Detecting and avoiding ADEs could be aided by using lists such as Beers criteria or STOPP/FART which list medications which are potentially inappropriate for older patients.

Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.

The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK-RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.