Optimal cutoff-value of Siemens cardiac troponin I assay in patients with kidney disease for the early diagnosis of acute myocardial infarction

Purpose: The recent introduction of more sensitive cardiac troponin (cTn) assays improved the early diagnosis of acute myocardial infarction (AMI). However, its diagnostic utility has never been tested in patients with kidney disease (KD), who are known to have elevated levels of cTn already in the absence of AMI, which may lead to a lower diagnostic value of more sensitive cTn in this high-risk subgroup. Methods: We conducted an international multicenter study to examine the diagnostic accuracy of the Siemens cTnI Ultra assay in 1997 consecutive patients presenting to the emergency department with symptoms suggestive of AMI, of whom 343 (17%) were determined to have KD (MDRD GFR <60ml/min/1.73m2) and to derive the optimal cutoff-value for the diagnosis of AMI in patients with KD. The diagnostic accuracy was further compared to a conventional cTn assay (Roche Troponin T fourth generation). The final diagnosis was adjudicated by two independent cardiologists based on hs-cTnT. Results: AMI was the final diagnosis in 35% (n=120) of all KD-patients as compared to 18% in patients with normal kidney function (p<0.001). Among KD-patients with other diagnoses than AMI, baseline hs-cTnI-levels were elevated above the 99thpercentile in 20%, In patients with KD the diagnostic accuracy at presentation, quantified by the area under the receiver-operator-characteristic curve (AUC), was significantly greater for Siemens cTnI as compared to the standard cTnT assay (AUC for cTnI, 0.88 vs. AUC for the standard assay, 0.82, p=0.013). In patients presenting within three hours after the onset of chest pain, the superiority of Siemens cTnI over conventional cTnT was even more pronounced (AUC 0.86 vs. 0.72, p=0.005). In KD, the optimal hs-cTnI cutoff derived from the ROC curve was 46 ng/l compared to 19 ng/l in patients with normal kidney function (standard 99th percentile 40 ng/l, provided by the manufacturer). Conclusions: The Siemens cTnI Ultra assay has a very high diagnostic accuracy also in KD-patients and is superior to a conventional cTnT-assay. Mild cTnI elevations are common in non-AMI patients. The optimal cutoff-level in KD-patients seems to be around the 99th percentile of a standard population, whereas the optimal cutoff-level in patients with normal kidney function tends to be only half of the suggested cutoff-value. ClinicalTrials.gov number, NCT0047058

Quantum measurement problem and cluster separability

A modified Beltrametti-Cassinelli-Lahti model of measurement apparatus that satisfies both the probability reproducibility condition and the objectification requirement is constructed. Only measurements on microsystems are considered. The cluster separability forms a basis for the first working hypothesis: the current version of quantum mechanics leaves open what happens to systems when they change their separation status. New rules that close this gap can therefore be added without disturbing the logic of quantum mechanics. The second working hypothesis is that registration apparatuses for microsystems must contain detectors and that their readings are signals from detectors. This implies that separation status of a microsystem changes during both preparation and registration. A new rule that specifies what happens at these changes and that guarantees the objectification is formulated and discussed. A part of our result has certain similarity with 'collapse of the wave function'.Comment: 31 pages, no figure. Published versio

A Cryogenic Underground Observatory for Rare Events: Cuore, an Update

CUORE is a proposed tightly packed array of 1000 TeO_{2} bolometers, each being a cube 5 cm on a side with a mass of 750 gms. The array consists of 25 vertical towers, arranged in a square, of 5 towers by 5 towers, each containing 10 layers of 4 crystals. The design of the detector is optimized for ultralow- background searches for neutrinoless double beta decay of ^{130}Te (33.8% abundance), cold dark matter, solar axions, and rare nuclear decays. A preliminary experiment involving 20 crystals of various sizes (MIBETA) has been completed, and a single CUORE tower is being constructed as a smaller scale experiment called CUORICINO. The expected performance and sensitivity, based on Monte Carlo simulations and extrapolations of present results, are reported.Comment: in press: Nucl. Phys. of Russian Academy of Sc

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.

Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Primary Funding Source: Emergency Care Foundation

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Cardiac biomarkers of acute coronary syndrome: from history to high-sensitivity cardiac troponin

The role of cardiac troponins as diagnostic biomarkers of myocardial injury in the context of acute coronary syndrome (ACS) is well established. Since the initial 1st-generation assays, 5th-generation high-sensitivity cardiac troponin (hs-cTn) assays have been developed, and are now widely used. However, its clinical adoption preceded guidelines and even best practice evidence. This review summarizes the history of cardiac biomarkers with particular emphasis on hs-cTn. We aim to provide insights into using hs-cTn as a quantitative marker of cardiomyocyte injury to help in the differential diagnosis of coronary versus non-coronary cardiac diseases. We also review the recent evidence and guidelines of using hs-cTn in suspected ACS

Diagnostic Accuracy of a High-Sensitivity Cardiac Troponin Assay with a Single Serum Test in the Emergency Department.

OBJECTIVES: We sought to evaluate diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay for acute coronary syndromes (ACS) in the emergency department (ED). The assay has high precision at low concentrations and can detect cTnI in 96.8% of healthy individuals. METHODS: In successive prospective multicenter studies ("testing" and "validation"), we included ED patients with suspected ACS. We drew blood for hs-cTnI [Singulex Clarity® cTnI; 99th percentile, 8.67 ng/L; limit of detection (LoD), 0.08 ng/L] on arrival. Patients also underwent hs-cTnT (Roche Elecsys) testing over ≥3 h. The primary outcome was an adjudicated diagnosis of ACS, defined as acute myocardial infarction (AMI; prevalent or incident), death, or revascularization within 30 days. RESULTS: The testing and validation studies included 665 and 2470 patients, respectively, of which 94 (14.1%) and 565 (22.9%) had ACS. At a 1.5-ng/L cutoff, hs-cTnI had good sensitivity for AMI in both studies (98.7% and 98.1%, respectively) and would have "ruled out" 40.1% and 48.9% patients. However, sensitivity was lower for ACS (95.7% and 90.6%, respectively). At a 0.8-ng/L cutoff, sensitivity for ACS was higher (97.5% and 97.9%, ruling out 28.6% patients in each cohort). The hs-cTnT assay had similar performance at the LoD (24.6% ruled out; 97.2% sensitivity for ACS). CONCLUSIONS: The hs-cTnI assay could immediately rule out AMI in 40% of patients and ACS in >25%, with similar accuracy to hs-cTnT at the LoD. Because of its high precision at low concentrations, this hs-cTnI assay has favorable characteristics for this clinical application