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Background and Aims: Strategies to assess patients with suspected acute myocardial infarction (AMI) using a point-of-care (POC) high-sensitivity cardiac troponin I (hs-cTnI) assay may expedite emergency care. A 2-h POC hs-cTnI strategy for emergency patients with suspected AMI was derived and validated., Methods: In two international, multi-centre, prospective, observational studies of adult emergency patients (1486 derivation cohort and 1796 validation cohort) with suspected AMI, hs-cTnI (Siemens Atellica® VTLi) was measured at admission and 2 h later. Adjudicated final diagnoses utilized the hs-cTn assay in clinical use. A risk stratification algorithm was derived and validated. The primary diagnostic outcome was index AMI (Types 1 and 2). The primary safety outcome was 30-day major adverse cardiac events incorporating AMI and cardiac death., Results: Overall, 81 (5.5%) and 88 (4.9%) patients in the derivation and validation cohorts, respectively, had AMI. The 2-h algorithm defined 66.1% as low risk with a sensitivity of 98.8% [95% confidence interval (CI) 89.3%-99.9%] and a negative predictive value of 99.9 (95% CI 99.2%-100%) for index AMI in the derivation cohort. In the validation cohort, 53.3% were low risk with a sensitivity of 98.9% (95% CI 92.4%-99.8%) and a negative predictive value of 99.9% (95% CI 99.3%-100%) for index AMI. The high-risk metrics identified 5.4% of patients with a specificity of 98.5% (95% CI 96.6%-99.4%) and a positive predictive value of 74.5% (95% CI 62.7%-83.6%) for index AMI., Conclusions: A 2-h algorithm using a POC hs-cTnI concentration enables safe and efficient risk assessment of patients with suspected AMI. The short turnaround time of POC testing may support significant efficiencies in the management of the large proportion of emergency patients with suspected AMI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: A majority of acute coronary syndromes (ACS) present without typical ST elevation. One-third of non-ST-elevation myocardial infarction (NSTEMI) patients have an acutely occluded culprit coronary artery [occlusion myocardial infarction (OMI)], leading to poor outcomes due to delayed identification and invasive management. In this study, we sought to develop a versatile artificial intelligence (AI) model detecting acute OMI on single-standard 12-lead electrocardiograms (ECGs) and compare its performance with existing state-of-the-art diagnostic criteria., Methods and Results: An AI model was developed using 18 616 ECGs from 10 543 patients with suspected ACS from an international database with clinically validated outcomes. The model was evaluated in an international cohort and compared with STEMI criteria and ECG experts in detecting OMI. The primary outcome of OMI was an acutely occluded or flow-limiting culprit artery requiring emergent revascularization. In the overall test set of 3254 ECGs from 2222 patients (age 62 ± 14 years, 67% males, 21.6% OMI), the AI model achieved an area under the curve of 0.938 [95% confidence interval (CI): 0.924-0.951] in identifying the primary OMI outcome, with superior performance [accuracy 90.9% (95% CI: 89.7-92.0), sensitivity 80.6% (95% CI: 76.8-84.0), and specificity 93.7 (95% CI: 92.6-94.8)] compared with STEMI criteria [accuracy 83.6% (95% CI: 82.1-85.1), sensitivity 32.5% (95% CI: 28.4-36.6), and specificity 97.7% (95% CI: 97.0-98.3)] and with similar performance compared with ECG experts [accuracy 90.8% (95% CI: 89.5-91.9), sensitivity 73.0% (95% CI: 68.7-77.0), and specificity 95.7% (95% CI: 94.7-96.6)]., Conclusion: The present novel ECG AI model demonstrates superior accuracy to detect acute OMI when compared with STEMI criteria. This suggests its potential to improve ACS triage, ensuring appropriate and timely referral for immediate revascularization., Competing Interests: Conflict of interest: R.H. is the co-founder and Chief Medical Officer of Powerful Medical; M.M., J.B., A.I., B.V., V.B., V.K., and A.D. are employees and shareholders of Powerful Medical. S.W.S., H.P.M., and L.P. are shareholders in Powerful Medical., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Our study addressed the diagnostic performance of the Atellica® IM High-Sensitivity Troponin I (hs-cTnI) assay for the rapid rule-out of myocardial infarction (MI) using a single hs-cTnI measurement at presentation in patients presenting to a US emergency department (ED)., Methods: This was a prospective, observational, cohort study of consecutive ED patients with suspected acute coronary syndrome, using 12-lead electrocardiogram and serial hs-cTnI measurements ordered on clinical indication (SAFETY, NCT04280926). ST-segment elevation MI patients were excluded. The optimal threshold required a sensitivity ≥99% and a negative predictive value (NPV) ≥99.5% for MI during index hospitalization as primary outcome. Type 1 MI (T1MI), myocardial injury, and 30-day adverse events were considered secondary outcomes. Event adjudications were established using the hs-cTnI assay used in clinical care., Results: In 1171 patients, MI occurred in 97 patients (8.3%), 78.3% of which were type 2 MI. The optimal rule out hs-cTnI threshold was <10 ng/L, which identified 519 (44.3%) patients as low risk at presentation, with sensitivity of 99.0% (95% CI, 94.4-100) and NPV of 99.8% (95% CI, 98.9-100). For T1MI, sensitivity was 100% (95% CI, 83.9-100) and NPV 100% (95% CI, 99.3-100). Regarding myocardial injury, the sensitivity and NPV were 99.5% (95% CI, 97.9-100) and 99.8% (95% CI, 98.9-100), respectively. For 30-day adverse events, sensitivity was 96.8% (95% CI, 94.3-98.4) and NPV 97.9% (95% CI, 96.2-98.9)., Conclusions: A single hs-cTnI measurement strategy enabled the rapid identification of patients at low risk of MI and 30-day adverse events, allowing potential discharge early after ED presentation., Clinicaltrials.gov Registration Number: NCT04280926., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: An obstacle in influenza therapeutics development is the lack of clinical endpoints, especially in hospitalized patients. A single time-point binary outcome measure is limited by patients' diverse clinical trajectories and low event rates., Methods: A 6-point ordinal scale with ascending clinical status severity (scoring: discharged; subacute care; acute care without/with respiratory failure; intensive care unit [ICU]; death) was proposed to study outcomes of adults hospitalized with influenza. Individual patient data from 2 active surveillance cohorts' datasets (2015/2016-2017/2018; Edmonton, Hong Kong) was used for evaluation. The impact of neuraminidase inhibitor (NAI) treatment on longitudinal ordinal outcome changes over 30 days was analyzed using mixed-effects ordinal logistic regression and group-based trajectory models., Results: Patient (n = 1226) baseline characteristics included age (mean 68.0 years), virus-type (A 78.1%, B 21.9%), respiratory failure (57.2%), ICU admittance (14.4%), and NAI treatment within 5 days of illness (69.2%). Outcomes at 30 days included discharged (75.2%), subacute care (13.7%), acute care (4.5%), and death (6.6%). Two main clinical trajectories were identified, predictive by baseline scoring (mean ± SD, 4.3 ± 0.6 vs 3.5 ± 0.6, P < .001). Improved outcomes with NAI treatment within 5 days were indicated by significantly lower clinical status scores over time (unadjusted odds ratio [OR], 0.53; 95% confidence interval [CI], .41-.69; P < .001; adjusted OR, 0.62; 95% CI, .50-.77; P < .001, for baseline score, age, and within-patient correlations). In subanalysis, influenza vaccination was also associated with lower scores (adjusted OR, 0.67; 95% CI, .50-.90; P = .007). Analyses of binary endpoints showed insignificant results., Conclusions: The ordinal outcome scale is a potentially useful clinical endpoint for influenza therapeutic trials, which could account for the diverse clinical trajectories of hospitalized patients, warranting further development., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged late in 2019 causing COVID-19 (coronavirus disease-2019) may adversely affect the cardiovascular system. Publications from Asia, Europe, and North America have identified cardiac troponin as an important prognostic indicator for patients hospitalized with COVID-19. We recognized from publications within the first 6 months of the pandemic that there has been much uncertainty on the reporting, interpretation, and pathophysiology of an increased cardiac troponin concentration in this setting., Content: The purpose of this mini-review is: a) to review the pathophysiology of SARS-CoV-2 and the cardiovascular system, b) to overview the strengths and weaknesses of selected studies evaluating cardiac troponin in patients with COVID-19, and c) to recommend testing strategies in the acute period, in the convalescence period and in long-term care for patients who have become ill with COVID-19., Summary: This review provides important educational information and identifies gaps in understanding the role of cardiac troponin and COVID-19. Future, properly designed studies will hopefully provide the much-needed evidence on the path forward in testing cardiac troponin in patients with COVID-19., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

From 2014-2019, invasive pulmonary aspergillosis complicated 7.2% (0-23.1% in different influenza seasons) of cases of influenza-associated respiratory failure in Edmonton, Alberta. Disease outcomes ranged from survival without therapy to death despite antifungals. Clinician vigilance, longitudinal local surveillance, and refined criteria to identify patients requiring therapy are needed., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Aims: First, describe how acute myocardial infarction criteria are used to diagnose type 1 (T1MI) and 2 (T2MI) myocardial infarction. Second, determine whether subjective or objective criteria are used for T2MI. Third, examine outcomes for T2MI based on the presence or absence of objective evidence of myocardial ischemia compared with myocardial injury., Methods and Results: Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational, cohort study involving 1640 consecutive emergency department patients with serial high-sensitivity cardiac troponin I among whom 74 (4.5%) had T1MI, 103 (6.3%) T2MI, and 245 (15%) myocardial injury. Compared with T1MI, patients with T2MI were less likely to have ischemic symptoms (97% vs . 83%), Q waves (24% vs . 1%), new ST-T wave changes (74% vs . 51%), new regional wall motion abnormality (64% vs . 11%), and a culprit lesion on coronary angiography (59% vs . 0%) (all p <0.05). T2MIs were more likely to be diagnosed using subjective criteria (symptoms alone) than T1MI (42% vs . 12%, p <0.0001). Patients with objective T2MI, but not subjective T2MI, had a two-fold increase in early mortality compared with myocardial injury, with 30- and 60-day hazard ratios (95% confidence interval) of 2.3 (0.9, 6.2) and 2.0 (0.9, 4.7) respectively., Conclusions: Among patients with T2MI, many cases are diagnosed using subjective criteria. The presence of objective evidence of myocardial ischemia may identify a higher-risk group of T2MI patients in whom early outcomes are worse than myocardial injury. Emphasis on using objective evidence of myocardial ischemia to diagnose T2MI may result in a more precise and specific disease definition.

The term unstable angina has been conventionally applied to patients with myocardial ischemia without myocardial necrosis. However, while the clinical context has remained constant over time, the biomarkers of myocardial injury and acute myocardial infarction have evolved. High-sensitivity cardiac troponin assays have several key analytical differences from prior cardiac troponin assay generations, which may alter the diagnosis and frequency of unstable angina, as well as affect our understanding of previously developed risk stratification strategies. This document reviews the current challenges in regards to unstable angina when using high-sensitivity cardiac troponin I and T assays.

Background: We examined the diagnostic performance of high-sensitivity cardiac troponin I (hs-cTnI) vs contemporary cTnI with use of the 99th percentile alone and with a normal electrocardiogram (ECG) to rule out acute myocardial infarction (MI) and serial changes (deltas) to rule in MI., Methods: We included consecutive patients presenting to a US emergency department with serial cTnI onclinical indication. Diagnostic performance for acute MI, including MI subtypes, and 30-day outcomes were examined., Results: Among 1631 patients, MI was diagnosed in 12.9% using the contemporary cTnI assay and in 10.4% using the hs-cTnI assay. For ruling out MI, contemporary cTnI ≤99th percentile at 0, 3, and 6 h and a normal ECG had a negative predictive value (NPV) of 99.5% (95% CI, 98.6-100) and a sensitivity of 99.1% (95% CI, 97.4-100) for diagnostic and safety outcomes. Serial hs-cTnI measurements ≤99th percentile at 0 and 3 h and a normal ECG had an NPV and sensitivity of 100% (95% CI, 100-100) for diagnostic and safety outcomes. For ruling in MI, contemporary cTnI measurements had specificities of 84.4% (95% CI, 82.5-86.3) at presentation and 78.7% (95% CI, 75.4-82.0) with serial testing at 0, 3, and 6 h, improving to 89.2% (95% CI, 87.1-91.3) by using serial cTnI changes (delta, 0 and 6 h) >150%. hs-cTnI had specificities of 86.9% (95% CI, 85.1-88.6) at presentation and 85.7% (95% CI, 83.5-87.9) with serial testing at 0 and 3 h, improving to 89.3% (95% CI, 87.3-91.2) using a delta hs-cTnI (0 and 3 h) >5 ng/L., Conclusions: hs-cTnI and contemporary cTnI assays are excellent in ruling out MI following recommendations predicated on serial testing and the 99th percentile with a normal ECG. For ruling in MI, deltas improve the specificity. ClinicalTrials.gov Identifier: NCT02060760., (© 2017 American Association for Clinical Chemistry.)

Background: Corticosteroids are the basis of treatment for nephrotic syndrome due to minimal change disease (MCD), but 25% of patients have frequently relapsing nephrotic syndrome (FRNS) and 30% become steroid dependent. Prolonged use of conventional immunosuppressants causes significant toxicity. Rituximab (RTX) is now included in guidelines for childhood MCD. Evidence for use in adult MCD is limited. We describe a single-centre experience of RTX use in adult MCD., Methods: Outcomes of all adult MCD patients treated with RTX for FRNS between 2008 and 2015 were retrospectively analysed., Results: Thirteen patients received RTX; 11/13 had childhood-onset MCD. All had FRNS and 10 were steroid dependent. Eleven patients experienced one or more major treatment side effect from conventional therapy. At the time of RTX treatment, six patients were relapsing. All entered remission after RTX. The median length of follow-up after the first RTX treatment was 20 months (range 6-85). After RTX, the rate of relapse was reduced from 4 to 0.4/year (Wilcoxon signed rank P ≤ 0.05). Seven patients relapsed after RTX after a median of 10 months (range 1-11). All seven relapsing patients were successfully re-treated with RTX and none developed RTX-resistant nephrosis. The median number of courses of RTX per patient was 1 (range 1-5). The number of additional immunosuppressants, steroid dependency and antihypertensive agents were also reduced. At the last follow-up, two patients remained on low-dose steroids. No RTX-related adverse events were observed., Conclusion: RTX is safe and effective in adults with FRNS due to MCD. The median rate of relapse is significantly reduced following RTX treatment and additional immunosuppressant exposure is minimized.

Background: Rapid rule-out strategies using high-sensitivity cardiac troponin assays are largely supported by studies performed outside the US in selected cohorts of patients with chest pain that are atypical of US practice, and focused exclusively on ruling out acute myocardial infarction (AMI), rather than acute myocardial injury, which is more common and associated with a poor prognosis., Methods: Prospective, observational study of consecutive patients presenting to emergency departments [derivation (n = 1647) and validation (n = 2198) cohorts], where high-sensitivity cardiac troponin I (hs-cTnI) was measured on clinical indication. The negative predictive value (NPV) and diagnostic sensitivity of an hs-cTnI concentration

Background: International Classification of Diseases (ICD) coding is the standard diagnostic tool for healthcare management. At present, type 2 myocardial infarction (T2MI) classification by the Universal Definition of Myocardial Infarction (MI) remains ignored in the ICD system. We determined the concordance for the diagnosis of MI using ICD-9 coding vs the Universal Definition., Methods: Cardiac troponin I (cTnI) was measured by both contemporary (cTnI) and high-sensitivity (hs-cTnI) assays in 1927 consecutive emergency department (ED) patients [Use of TROPonin In Acute coronary syndromes (UTROPIA) cohort] who had cTnI ordered on clinical indication. All patients were adjudicated using both contemporary and hs-cTnI assays. The Kappa index and McNemar test were used to assess concordance between ICD-9 code 410 and type 1 MI (T1MI) and type 2 MI (T2MI)., Results: Among the 249 adjudicated MIs using the contemporary cTnI, only 69 (28%) were ICD-coded MIs. Of 180 patients not ICD coded as MI, 34 (19%) were T1MI and 146 (81%) were T2MI. For the ICD-coded MIs, 79% were T1MI and 21% were T2MI. A fair Kappa index, 0.386, and a McNemar difference of 0.0892 (P < 0.001) were found. Among the 207 adjudicated MIs using the hs-cTnI assay, 67 (32%) were ICD coded as MI. Of the 140 patients not ICD coded as MI, 27 (19%) were T1MI and 113 (81%) were T2MI. For the ICD-coded MIs, 85% were T1MI and 15% T2MI. A moderate Kappa index, 0.439, and a McNemar difference of 0.0674 (P < 0.001) were found., Conclusions: ICD-9-coded MIs captured only a small proportion of adjudicated MIs, primarily from not coding T2MI. Our findings emphasize the need for an ICD code for T2MI., (© 2016 American Association for Clinical Chemistry.)

Introduction: We compared the incidence of undetectable [below the limit of detection (LoD)], measurable (LoD to 99th percentile), and increased cardiac troponin I (cTnI) concentrations above the 99th percentile between Abbott high-sensitivity cTnI (hs-cTnI) and contemporary cTnI assays in a US emergency department population., Methods: Patients (n = 2100) presenting to the emergency department who had serial cTnI (0, 3, 6, 9 h) measurements ordered on clinical indication were enrolled. Contemporary cTnI [Abbott Architect used clinically; 99th percentile: 0.030 μg/L (30 ng/L)] and hs-cTnI [Abbott investigational; sex-specific 99th percentiles: female (F) 16 ng/L, male (M) 34 ng/L] assays simultaneously measured fresh EDTA plasma., Results: The hs-cTnI assay measured fewer undetectable cTnI concentrations compared to the contemporary cTnI assay across baseline (F: 31% vs 47%, M: 22% vs 40%) and serial (F: 21% vs 46%; M: 19% vs 54%) measurements. Conversely, the proportion of measurable cTnI concentrations was higher using hs-cTnI compared to contemporary cTnI assay across both baseline (F: 46% vs 31%; M: 60% vs 33%) and serial (F: 48% vs 28%; M: 83% vs 40%) measurements. The overall proportion of patients with increased cTnI concentrations above the 99th percentile was not significantly different between the contemporary (31%) and hs-cTnI (26%) assays (P = 0.09)., Conclusions: In patients presenting to the emergency department, the use of the Abbott hs-cTnI assay provides clinicians with more numeric cTnI concentrations. This occurs via a shift from results below the LoD to those between the LoD and the 99th percentile and does not increase in the number of cTnI concentrations above the 99th percentile., (© 2016 American Association for Clinical Chemistry.)

Background: The frequency and characteristics of myocardial infarction (MI) subtypes per the Third Universal Definition of MI (TUDMI) classification system using high-sensitivity (hs) cardiac troponin assays with sex-specific cutoffs is not well known. We sought to describe the diagnostic characteristics of type 1 (T1MI) and type 2 (T2MI) MI using an hs-cardiac troponin I (hs-cTnI) assay with sex-specific cutoffs., Methods: A total of 310 consecutive patients with serial cTnI measurements obtained on clinical indication were studied with contemporary and hs-cTnI assays. Ninety-ninth percentile sex-specific upper reference limits (URLs) for the hs-cTnI assay were 16 ng/L for females and 34 ng/L for males. The TUDMI consensus recommendations were used to define and adjudicate MI based on each URL., Results: A total of 127 (41%) patients had at least 1 hs-cTnI exceeding the sex-specific 99th percentiles, whereas 183 (59%) had hs-cTnI within the reference interval. Females had more myocardial injury related to supply/demand ischemia than males (39% vs 18%, P = 0.01), whereas males had more multifactorial or indeterminate injury (52% vs 33%, P = 0.05). By hs-cTnI, there were 32 (10%) acute MIs, among which 10 (3%) were T1MI and 22 (7%) were T2MI. T2MI represented 69% (22 out of 32) of all acute MIs, whereas T1MI represented 31% (10 out of 32). Ninety-five patients (31%) had an increased hs-cTnI above the 99th percentile but did not meet criteria for acute MI. The most common triggers for T2MI were tachyarrhythmias, hypotension/shock, and hypertension. By contemporary cTnI, more MIs (14 T1MI and 29 T2MI) were diagnosed. By contemporary cTnI, there were 43 MIs, 14 T1MI, and 29 T2MI., Conclusions: Fewer MI diagnoses were found with the hs-cTnI assay, contrary to the commonly accepted idea that hs-cTnI will lead to excessive false-positive diagnoses., (© 2015 American Association for Clinical Chemistry.)

Background: We assessed the utilization rationale behind provider ordering of cardiac troponin I (cTnI) testing for the diagnosis of myocardial infarction after implementation of a hospital-wide serial order protocol., Methods: During 2 months in 2013, any request for additional cTnI testing within 30 days of the initial serial cTnI order prompted an electronic health record best practice alert (BPA), which included clinical decision support that could be bypassed by giving a clinical indication. cTnI orders were not limited (timing, number), and upon BPA, trigger data was collected for clinical indications and actions, patient stay (duration, location), International Classification of Diseases, Revision 9 diagnosis, cTnI orders, and timing of cTnI measurements., Results: The BPA was triggered 1477 times by 423 providers who cared for 702 patients. There were a mean of 3.6 cTnI results per patient, 2.1 BPAs per patient, and 1.2 visits per patient. Providers (42% of whom were residents) acknowledged and overrode the BPA 97% of the time. In response to the BPA, 65% of providers selected a prepared rationale: 64% acute coronary syndrome/ST-elevation myocardial infarction/non-ST-elevation myocardial infarction; 30% demand ischemia; and 6% non-ACS myocardial necrosis. Of the remaining 35% of providers, 71% listed no rationale for their additional cTnI orders. Of patients with a BPA, 93% had non-ACS-related primary International Classification of Diseases, Revision 9 diagnosis, and 58% of the time, patients' cTnI results never increased during their stay. In 53% of cases, BPAs were generated by a request for an additional cTnI series when <2 results were available., Conclusions: Providers largely ignored the BPA that warned of potential overutilization of cTnI testing independent of diagnosis, including ACS., (© 2014 American Association for Clinical Chemistry.)

This article will explore the role of conscience in cases which are not subject to a predictable, generalisable rule-based conscientious objection. These claims arise in cases where doctors, who might have previously provided the treatment at issue, determine that the specific facts of a case mean that they cannot morally provide treatment. In legal cases, the courts have tended to act as if these conscience refusals are part of the best interests analysis. They claim that the treatment, as requested, simply is not in the best interests of the patient. However, the courts have used this analysis even when it appears clear that the refusal of treatment is not in what the patient thinks is his or her best interests. Indeed, in recent cases such as Aintree v James, the court has made it clear that determining what is in the best interests of patients usually relies more on the advice of healthcare professionals than it does on the patient's views. It is not, then, about what patients think they need or want, but what doctors and other medical staff think they can morally provide under the circumstances. This article will explore how re-conceptualising these sorts of claims as ones about conscience provides a more stable footing for understanding the legal and ethical issues which are of importance to the courts and what this might mean for these sorts of decisions in the future., (© The Author [2015]. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: To determine the ability of serial cardiac troponin (cTnI) changes (delta) to distinguish type 1 and type 2 myocardial infarction (MI) (excluding all ST-segment elevation MIs (STEMIs)) and describe the diagnostic accuracy and 180-day mortality in MI versus no-MI patients., Methods and Results: Serial cTnIs were measured in 1112 consecutive patients without STEMI and within 6h of presentation to a United States emergency department: 856 (77%) with no MI, 66 (6%) type 1 MI, and 190 (17%) type 2 MI. Of the 0 to 3h and 0 to 6h absolute and relative cTnI changes, only the distribution of absolute change from 0 to 6h was significantly different between type 1 and type 2 MI: median (interquartile range) 311 (1430) ng/l vs. 80 (330) ng/l, p=0.03. Neither the absolute concentration change nor the absolute percent change from either 0 h to 3h (areas under the curves (AUCs) 0.57 and 0.54 respectively) or 0 h to 6h (AUCs 0.60 and 0.51) improved on the performance of the individual cTnI results at 3h (AUC 0.60) or 6h (AUC 0.62), respectively. After adjusting for age, and histories of heart failure and renal insufficiency, those with type 2 MI (hazard ratio 2.9, 95% confidence interval (CI) 1.4-5.9, p=0.004) and those with no index MI and cTnI(max0-6h) > 34 ng/l (2.5, CI 1.1-6.0, p=0.04) had increased risk of death within 180 days compared with those with no MI and cTnI(max 0-6h) ≤ 34 ng/l., Conclusion: Delta cTnI did not aid in distinguishing type 1 MI from the more common type 2 MI. Patients diagnosed with type 2 MIs, which represented more than half of all index MIs, had increased risk of death after discharge., (© The European Society of Cardiology 2014.)

High-dose methotrexate (MTX) can produce acute kidney injury, impairing MTX elimination. Continuous venovenous hemofiltration (CVVH) may enhance elimination in this setting, although its use is largely unstudied. A 79-year-old man received IV MTX for central nervous system lymphoma, and over a 34-h period his serum creatinine increased from 1.09 to 2.24 mg/dL. His serum MTX concentration (sMTX) at the end of this time period was 59.05 µmol/L. After urinary alkalinization and leucovorin and glucarpidase (CPDG2) treatment, sMTX decreased. Fluid overload ensued and CVVH was initiated. The initial MTX extraction ratio and clearance were 0.22 and 47.0 mL/min, respectively. No MTX extraction occurred at an sMTX of 0.15 µmol/L. Continuous venovenous hemodialysis was initiated, and sMTX further declined. CVVH may help eliminate MTX and provide renal replacement at moderate sMTX.

Objective: To model inconsistencies or distortions among three realities: patients' physical reality; clinicians' mental models of patients' conditions, laboratories, etc; representation of that reality in electronic health records (EHR). To serve as a potential tool for quality improvement of EHRs., Methods: Using observations, literature, information technology (IT) logs, vendor and US Food and Drug Administration reports, we constructed scenarios/models of how patients' realities, clinicians' mental models, and EHRs can misalign to produce distortions in comprehension and treatment. We then categorized them according to an emergent typology derived from the cases themselves and refined the categories based on insights gained from the literature of interactive sociotechnical systems analysis, decision support science, and human computer interaction. Typical of grounded theory methods, the categories underwent repeated modifications., Results: We constructed 45 scenarios of misalignment between patients' physical realities, clinicians' mental models, and EHRs. We then identified five general types of misrepresentation in these cases: IT data too narrowly focused; IT data too broadly focused; EHRs miss critical reality; data multiplicities-perhaps contradictory or confusing; distortions from data reflected back and forth across users, sensors, and others. The 45 scenarios are presented, organized by the five types., Conclusions: With humans, there is a physical reality and actors' mental models of that reality. In healthcare, there is another player: the EHR/healthcare IT, which implicitly and explicitly reflects many mental models, facets of reality, and measures thereof that vary in reliability and consistency. EHRs are both microcosms and shapers of medical care. Our typology and scenarios are intended to be useful to healthcare IT designers and implementers in improving EHR systems and reducing the unintended negative consequences of their use.

Aims: Clinical and medico-legal decisions often require knowledge of alcohol impairment that is not necessarily revealed by an individual's appearance, and in turn, may not necessarily reflect level of blood alcohol. This study compares clinical signs and symptoms with measured and estimated blood alcohol concentrations (BACs)., Method: Individuals (n = 384) perceived to be under the influence of alcohol at presentation to an emergency department were assessed by physicians and nurses for clinical features of alcohol intoxication (alcohol symptom checklist, ASC), who were asked to estimate the patient's BAC. Relation to measured BACs was assessed by correlation., Results: BACs ranged from 0 to 418 mg/100 ml. The correlation between the estimated BAC and measured BAC was r = 0.513. Measured BAC correlated with ASC r = 0.250. In subjects without a history of chronic drinking (n = 134) there was a better (P < 0.05) correlation with the ASC score (r = 0.363) versus measured BAC compared with that for chronic drinkers (r = 0.154). The positive predictive value of estimating BAC at or above a particular BAC cut-off decreased from 93.2% at 100 mg/100 ml to 37.7% at 300 mg/100 ml (P < 0.05)., Conclusions: Measured BAC does not correlate well with the outward physical signs of intoxication, especially for chronic drinkers. There is a need for further education on how tolerance masks clinical signs of intoxication for the chronic drinker. BACs should be measured especially in the obtunded where no history (symptoms) can be given by the patient.

Background: We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value., Methods: We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan-Meier method and compared with the log-rank statistic., Results: At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values., Conclusions: A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal.

Chiral substances possess a unique architecture such that, despite sharing identical molecular formulas, atom-to-atom linkages, and bonding distances, they cannot be superimposed. Thus, in the environment of living systems, where specific structure-activity relationships may be required for effect (e.g., enzymes, receptors, transporters, and DNA), the physiochemical and biochemical properties of racemic mixtures and individual stereoisomers can differ significantly. In drug development, enantiomeric selection to maximize clinical effects or mitigate drug toxicity has yielded both success and failure. Further complicating genetic polymorphisms in drug disposition, stereoselective metabolism of chiral compounds can additionally influence pharmacokinetics, pharmacodynamics, and toxicity. Optically pure pharmaceuticals may undergo racemization in vivo, negating single enantiomer benefits or inducing unexpected effects. Appropriate chiral antidotes must be selected for therapeutic benefit and to minimize adverse events. Enantiomers may possess different carcinogenicity and teratogenicity. Environmental toxicology provides several examples in which compound bioaccumulation, persistence, and toxicity show chiral dependence. In forensic toxicology, chiral analysis has been applied to illicit drug preparations and biological specimens, with the potential to assist in determination of cause of death and aid in the correct interpretation of substance abuse and "doping" screens. Adrenergic agonists and antagonist, nonsteroidal anti-inflammatory agents, SSRIs, opioids, warfarin, valproate, thalidomide, retinoic acid, N-acetylcysteine, carnitine, penicillamine, leucovorin, glucarpidase, pesticides, polychlorinated biphenyls, phenylethylamines, and additional compounds will be discussed to illustrate important concepts in "chiral toxicology."

Background: We sought to determine the diagnostic accuracy of the cardiac troponin I (cTnI) VITROS(R) Troponin I-ES assay for early detection of acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome (ACS)., Methods: cTnI was measured on admission and approximately 6 h postadmission in 381 patients. The 99th percentile cTnI concentration (0.034 microg/L) and change [delta (delta)] between admission and follow-up concentrations were evaluated in diagnostic sensitivity and specificity calculations. Risk of cardiac event or death within 60 days was evaluated by Cox proportional hazards regression., Results: AMI occurred in 52 patients. Diagnostic sensitivities (95% CI) of admission and follow-up cTnIs for AMI were 69% (55%-81%) and 94% (84%-99%), respectively. The corresponding specificities (95% CI) were 78% (73%-82%) and 81% (77%-85%), and ROC curve areas were 0.82 vs 0.96 (P < 0.001). Deltas between admission and follow-up cTnI >30% had a sensitivity of 75% (95% CI 61%-86%) and a specificity of 91% (95% CI 87%-94%). During follow-up, 1 cardiac death, 2 noncardiac deaths, 52 AMIs, 6 coronary artery bypass grafts, and 43 percutanous coronary interventions occurred in 62 patients. A delta cTnI >30%, when added to either initial cTnI >0.034 microg/L or follow-up cTnI >0.034 microg/L, improved risk stratification for cardiac event or death (P < 0.001)., Conclusions: Admission cTnI measured by the VITROS ES assay is a sensitive biomarker for detection of AMI. Utilizing >30% cTnI delta in addition to either the baseline or follow-up concentration improved both specificity and risk assessment in patients presenting with symptoms of ACS.

Background: Cardiac troponin is the preferred biomarker for detecting acute myocardial injury and infarction (MI). We studied whether multiple biomarkers of numerous pathophysiological pathways would increase the diagnostic accuracy for detecting MI., Methods: Seven biomarkers [myeloperoxidase, soluble CD40 ligand, placental growth factor, matrix metalloproteinase 9 (MMP-9), high-sensitivity C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide] and estimated glomerular filtration rate were measured in 457 patients presenting on admission with symptoms suggestive of acute coronary syndrome. Twenty-five patients (5.4%) received MI diagnoses. Clinical sensitivities and specificities were evaluated from 99th-percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers that were independently predictive of MI., Results: Biomarker sensitivities ranged from 20% to 96%, and specificities ranged from 19% to 89%. MMP-9 had the highest sensitivity, but its specificity was 19%. cTnI demonstrated a sensitivity of 72% (95% CI, 51%-88%) and a specificity of 89% (95% CI, 85%-92%). In multivariate models, cTnI (P < 0.001) and either hsCRP (P = 0.009) or MMP-9 (P = 0.03) were independently predictive of MI. Addition of hsCRP or MMP-9 increased the specificity to 95% (95% CI, 92%-97%) or 91% (95% CI, 88%-94%), respectively, but reduced the sensitivity to 56% (95% CI, 35%-76%) and 68% (95% CI, 47%-85%) relative to cTnI alone., Conclusions: Our findings indicate that the most clinically accurate biomarker for the early diagnosis of MI is the use of cTnI alone, rather than a multiple-biomarker approach, when an analytically robust cardiac troponin assay based on the 99th percentile is used.

Wegener's granulomatosis (WG) is a chronic, relapsing, systemic autoimmune disease. Rituximab, a monoclonal antibody against human CD20, has shown promise as a novel treatment for WG. The monitoring of therapeutic B-cell 'depletion' by peripheral blood flow cytometry has been proposed to help monitor rituximab therapy. We report the case of a patient with known WG and granulomatous disease, successfully treated with rituximab, who relapsed whilst peripheral blood monitoring apparently indicated persistent B-cell depletion. Further investigations demonstrated CD20(+) B cells in tissue at sites of active disease. The implications for disease pathogenesis and clinical monitoring of disease are discussed.

Background: We determined the diagnostic accuracy of the Advia Centaur TnI-Ultra assay for detecting myocardial infarction (MI) and assessing risk of adverse events in patients presenting with ischemic symptoms suggestive of acute coronary syndrome., Methods: We measured cardiac troponin I (cTnI) on admission and 6-24 h after admission (follow-up) in plasma specimens from 371 consecutive patients. The end point was the first of cardiac event or death within 60 days. We estimated survival curves using the Kaplan-Meier method and compared groups with the log rank statistic., Results: MI was established in 49 patients (13%). Clinical sensitivities and specificities for MI based on the 99th percentile (0.04 microg/L) were 74% and 84%, respectively, on admission and 94% and 81% at follow-up. ROC curves showed significantly higher accuracy for MI in the follow-up specimen compared with admission (P = 0.001). Overall there were 2 cardiac deaths, 1 noncardiac death, 49 MIs, 7 coronary artery bypass grafts, and 36 percutaneous coronary interventions in 59 patients during follow-up. The event rate in those with cTnI <0.006 microg/L was significantly lower than in groups with cTnI 0.006-0.04 microg/L, >0.04-0.10 microg/L, or >0.10 microg/L (2.8% vs 11.1%, 24.1%, 55.1%, respectively; P <0.0001). Relative risks for the increasing cTnI cutoff groups were 3.9 (95% CI 1.2-13), 8.9 (2.4-34), and 25 (7.3-82) after adjustment for age, diabetes, history of hypertension, previous MI, and estimated glomerular filtration rate., Conclusions: The TnI-Ultra assay is a sensitive, early diagnostic biomarker for MI and an independent predictor of adverse events at any measurable cTnI in patients with symptoms of acute coronary syndrome.

Background: In June 1998, we investigated one of the largest foodborne outbreaks of enterotoxigenic Escherichia coli gastroenteritis reported in the United States., Methods: We conducted cohort studies of 11 catered events to determine risk factors for illness. We used stool cultures, polymerase chain reaction, and serologic tests to determine the etiologic agent, and we conducted an environmental inspection to identify predisposing conditions and practices at the implicated establishment., Results: During 5-7 June, the implicated delicatessen catered 539 events attended by >16,000 people. Our epidemiological study of 11 events included a total of 612 attendees. By applying the median prevalence of illness (20%) among events with ill attendees to the total number of events with any ill attendees, we estimate that at least 3300 persons may have developed gastroenteritis during this outbreak. Multiple food items (potato salad, macaroni salad, egg salad, and watermelon) were associated with illness, all of which required extensive handling during preparation. Enterotoxigenic Escherichia coli serotype O6:H16 producing heat-labile and heat-stable toxins was isolated from the stool specimens from 11 patients. Eight patients with positive stool culture results, 11 (58%) of 19 other symptomatic attendees, and 0 (0%) of 17 control subjects had elevated serum antibody titers to E. coli O6 lipopolysaccharide. The delicatessen had inadequate hand-washing supplies, inadequate protection against back siphonage of wastewater in the potable water system, a poorly draining kitchen sink, and improper food storage and transportation practices., Conclusions: In the United States, where enterotoxigenic Escherichia coli is an emerging cause of foodborne disease, enterotoxigenic Escherichia coli should be suspected in outbreaks of gastroenteritis when common bacterial or viral enteric pathogens are not identified.

An X-Windows-based graphic user interface is presented which allows the seamless integration of numerous existing biomolecular programs into a single analysis environment. This environment is based on a core multiple sequence editor that is linked to external programs by a user-expandable menu system and is supported on Sun and DEC workstations. There is no limitation to the number of external functions that can be linked to the interface. The length and number of sequences that can be handled are limited only by the size of virtual memory present on the workstation. The sequence data itself is used as the reference point from which analysis is done, and scalable graphic views are supported. It is suggested that future software development utilizing this expandable, user-defined menu system and the I/O linkage of external programs will allow biologists to easily integrate expertise from disparate fields into a single environment.

The main active form of atrial natriuretic peptide (ANP) in the circulation is alpha ANP(1-28) [gamma-ANP(99-126)], although some active and inactive metabolites are also though to be present. Some immunoassays for alpha ANP reportedly detect inactive metabolites, as determined by their comparison with results by receptor assay, which would lead to misleading results for alpha ANP(1-28) measurements. Here we compare a radioreceptor assay (RRA) and a radioimmunoassay (RIA) for alpha ANP and show that their results correlate very well with regard to specificity and that the RIA appears to detect only the active circulating form of alpha ANP(1-28).