The hs-cTnT 0-hour/1-hour algorithm performs well for early rule-out and rule-in of acute myocardial infarction.
The vertebrate heart possesses autoregulatory mechanisms enabling it first to sense and then to adapt its force of contraction to continually changing demands. The molecular components of the cardiac mechanical stretch sensor are mostly unknown but of immense medical importance, since dysfunction of this sensing machinery is suspected to be responsible for a significant proportion of human heart failure. In the hearts of the ethylnitros-urea (ENU)-induced, recessive embryonic lethal zebrafish heart failure mutant main squeeze (msq), we find stretch-responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) severely down-regulated. We demonstrate through positional cloning that heart failure in msq mutants is due to a mutation in the integrin-linked kinase (ilk) gene. ILK specifically localizes to costameres and sarcomeric Z-discs. The msq mutation (L308P) reduces ILK kinase activity and disrupts binding of ILK to the Z-disc adaptor protein -parvin (Affixin). Accordingly, in msq mutant embryos, heart failure can be suppressed by expression of ILK, and also of a constitutively active form of Protein Kinase B (PKB), and VEGF. Furthermore, antisense-mediated abrogation of zebrafish -parvin phenocopies the msq phenotype. Thus, we provide evidence that the heart uses the Integrin-ILK--parvin network to sense mechanical stretch and respond with increased expression of ANF and VEGF, the latter of which was recently shown to augment cardiac force by increasing the heart's calcium transients.[Keywords: Integrin-linked kinase (ILK); zebrafish; cardiac stretch sensor; -parvin (Affixin)] Supplemental material is available at http://www.genesdev.org.
Aim: Biotin in human serum is a potential interfering factor for streptavidin-biotin-based assays. We aimed to evaluate the effective half-life of biotin and biotin metabolites, and establish a pharmacokinetic (PK) model to simulate the time taken for the biotin concentration to fall below a series of thresholds. Materials & methods: PK properties of biotin (5, 10 and 20 mg daily) were evaluated in healthy participants. Biotin serum concentrations were simulated for high-dose regimens (1 mg daily to 300 mg q.i.d.) using a population PK model. Results: Washout periods required for biotin concentrations to reach thresholds ranging from 10 to 100 ng/ml were successfully simulated. Conclusion: Our simulations provide valuable guidance on biotin washout periods necessary to avoid false assay results. Immunoassays that allow rapid measurement of analytes can be vital for the correct diagnosis of a broad range of diseases [1]. The interaction of streptavidin and biotin has been utilized for the development of robust and highly sensitive immunoassays by many manufacturers (Abbott, Beckman Coulter, Ortho Clinical Diagnostics, Roche Diagnostics, Siemens Healthcare Diagnostics and others). Biotin, a water-soluble vitamin, is a small and stable molecule that can be conjugated to many proteins without significantly affecting their biological activity; this interaction is the strongest known noncovalent binding between a protein and a ligand [2].Exogenous biotin has the potential to interfere with streptavidin-biotin-based assay results. The impact of interference on test results can be the generation of falsely high values, obtained when using a competitive assay design, whereby an excess of biotin in the specimen competes with biotinylated analog for binding sites on streptavidin. Alternatively, when using a sandwich assay design, an excess of biotin in the specimen can displace biotinylated antibodies, which can generate falsely low values [3]. Reports of biotin interference leading to incorrect biochemical diagnoses in both adults and children have been published previously, along with warnings to clinicians and pathologists to interpret unexpected assay results with caution and consider the potential effect of biotin interference before making a diagnosis [4][5][6][7].The normal serum concentration of biotin is very low; published average values range from below 0.1 to 0.8 ng/ml [8,9]. The adequate daily intake of biotin is 30 μg/day [10] and biotin deficiency is rare as the majority of diets contain enough biotin for this to be reached. However, biotin is increasingly being marketed as a lifestyle supplement which is claimed to strengthen hair and nails, despite no scientific confirmation of these benefits [11]. The unregulated, over-the-counter (OTC) product is available in doses ranging from 50 μg found in multivitamin
BackgroundRecent single‐center and retrospective studies suggest that acute myocardial infarction (AMI) could be immediately excluded without serial sampling in patients with initial high‐sensitivity cardiac troponin T (hs‐cTnT) levels below the limit of detection (LoD) of the assay and no electrocardiogram (ECG) ischemia. ObjectiveWe aimed to determine the external validity of those findings in a multicenter study at 12 sites in nine countries. MethodsTRAPID‐AMI was a prospective diagnostic cohort study including patients with suspected cardiac chest pain within 6 hours of peak symptoms. Blood drawn on arrival was centrally tested for hs‐cTnT (Roche; 99th percentile = 14 ng/L, LoD = 5 ng/L). All patients underwent serial troponin sampling over 4–14 hours. The primary outcome, prevalent AMI, was adjudicated based on sensitive troponin I (Siemens Ultra) levels. Major adverse cardiac events (MACE) including AMI, death, or rehospitalization for acute coronary syndrome with coronary revascularization were determined after 30 days. ResultsWe included 1,282 patients, of whom 213 (16.6%) had AMI and 231 (18.0%) developed MACE. Of 560 (43.7%) patients with initial hs‐cTnT levels below the LoD, four (0.7%) had AMI. In total, 471 (36.7%) patients had both initial hs‐cTnT levels below the LoD and no ECG ischemia. These patients had a 0.4% (n = 2) probability of AMI, giving 99.1% (95% confidence interval [CI] = 96.7% to 99.9%) sensitivity and 99.6% (95% CI = 98.5% to 100.0%) negative predictive value. The incidence of MACE in this group was 1.3% (95% CI = 0.5% to 2.8%). ConclusionsIn the absence of ECG ischemia, the detection of very low concentrations of hs‐cTnT at admission seems to allow rapid, safe exclusion of AMI in one‐third of patients without serial sampling. This could be used alongside careful clinical assessment to help reduce unnecessary hospital admissions.
Background— The TRAPID-AMI trial study (High-Sensitivity Troponin-T Assay for Rapid Rule-Out of Acute Myocardial Infarction) evaluated high-sensitivity cardiac troponin-T (hs-cTnT) in a 1-hour acute myocardial infarction (AMI) exclusion algorithm. Our study objective was to evaluate the prognostic utility of a modified HEART score (m-HS) within this trial. Methods and Results— Twelve centers evaluated 1282 patients in the emergency department for possible AMI from 2011 to 2013. Measurements of hs-cTnT (99th percentile, 14 ng/L) were performed at 0, 1, 2, and 4 to 14 hours. Evaluation for major adverse cardiac events (MACEs) occurred at 30 days (death or AMI). Low-risk patients had an m-HS≤3 and had either hs-cTnT<14 ng/L over serial testing or had AMI excluded by the 1-hour protocol. By the 1-hour protocol, 777 (60%) patients had an AMI excluded. Of those 777 patients, 515 (66.3%) patients had an m-HS≤3, with 1 (0.2%) patient having a MACE, and 262 (33.7%) patients had an m-HS≥4, with 6 (2.3%) patients having MACEs ( P =0.007). Over 4 to 14 hours, 661 patients had a hs-cTnT<14 ng/L. Of those 661 patients, 413 (62.5%) patients had an m-HS≤3, with 1 (0.2%) patient having a MACE, and 248 (37.5%) patients had an m-HS≥4, with 5 (2.0%) patients having MACEs ( P =0.03). Conclusions— Serial testing of hs-cTnT over 1 hour along with application of an m-HS identified a low-risk population that might be able to be directly discharged from the emergency department.
Tone detection thresholds for a 10-kHz tone in NMRI mice were determined in psychoacoustic experiments using both a constant-stimuli procedure and a two-down/one-up adaptive-tracking procedure in the same subjects and applying identical threshold criteria (70.7% response probability). Constant-stimuli thresholds were on average 24 dB lower than adaptive-tracking thresholds, and there was a trend indicating that constant-stimuli thresholds were less variable than adaptive-tracking thresholds. Furthermore, in the constant-stimuli procedure the number of trials constituting the psychometric function could be reduced from 100 to 50 trials without a large loss of accuracy of threshold determination. In the constant-stimuli procedure, the threshold value was affected by the threshold criteria. The lowest and least variable constant-stimuli thresholds were obtained by applying signal detection theory and a criterion of d' = 1. Thus, the constant-stimuli procedure in combination with signal detection theory appears to be better suited than the adaptive-tracking procedure to determine auditory sensory thresholds.
ObjectivePatients with suspected acute myocardial infarction (AMI) in the setting of left bundle branch block (LBBB) present an important diagnostic and therapeutic challenge to the clinician.MethodsWe prospectively evaluated the incidence of AMI and diagnostic performance of specific ECG and high-sensitivity cardiac troponin (hs-cTn) criteria in patients presenting with chest discomfort to 26 emergency departments in three international, prospective, diagnostic studies. The final diagnosis of AMI was centrally adjudicated by two independent cardiologists according to the universal definition of myocardial infarction.ResultsAmong 8830 patients, LBBB was present in 247 (2.8%). AMI was the final diagnosis in 30% of patients with LBBB, with similar incidence in those with known LBBB versus those with presumably new LBBB (29% vs 35%, p=0.42). ECG criteria had low sensitivity (1%–12%) but high specificity (95%–100%) for AMI. The diagnostic accuracy as quantified by the receiver operating characteristics (ROC) curve of hs-cTnT and hs-cTnI concentrations at presentation (area under the ROC curve (AUC) 0.91, 95% CI 0.85 to 0.96 and AUC 0.89, 95% CI 0.83 to 0.95), as well as that of their 0/1-hour and 0/2-hour changes, was very high. A diagnostic algorithm combining ECG criteria with hs-cTnT/I concentrations and their absolute changes at 1 hour or 2 hours derived in cohort 1 (45 of 45(100%) patients with AMI correctly identified) showed high efficacy and accuracy when externally validated in cohorts 2 and 3 (28 of 29 patients, 97%).ConclusionMost patients presenting with suspected AMI and LBBB will be found to have diagnoses other than AMI. Combining ECG criteria with hs-cTnT/I testing at 0/1 hour or 0/2 hours allows early and accurate diagnosis of AMI in LBBB.Trial registration numberAPACE: NCT00470587; ADAPT: ACTRN12611001069943; TRAPID-AMI: RD001107;Results.
The TRAPID-AMI (High Sensitivity Cardiac Troponin T assay for rapid Rule-out of Acute Myocardial Infarction) study evaluated a rapid “rule-out” acute myocardial infarction (AMI). We evaluated what symptoms were associated with AMI as part of a substudy of TRAPID-AMI. There were 1282 patients evaluated from 12 centers in Europe, the United States of America, and Australia from 2011 to 2013. Multiple symptom variables were prospectively obtained and evaluated for association with the final diagnosis of AMI. Multivariate logistic regression analysis was done, and odds ratios (OR) were calculated. There were 213/1282 (17%) AMIs. Four independent predictors for the diagnosis of AMI were identified: radiation to right arm or shoulder [OR = 3.0; confidence interval (CI): 1.8–5.0], chest pressure (OR = 2.5; CI: 1.3–4.6), worsened by physical activity (OR = 1.7; CI: 1.2–2.5), and radiation to left arm or shoulder (OR = 1.7; CI: 1.1–2.4). In the entire group, 131 (10%) had radiation to right arm or shoulder, 897 (70%) had chest pressure, 385 (30%) worsened with physical activity, and 448 (35%) had radiation to left arm or shoulder. Duration of symptoms was not predictive of AMI. There were no symptoms predictive of non-AMI. Relationship between AMI size and symptoms was also studied. For 213 AMI patients, cardiac troponins I values were divided into 4 quartiles. Symptoms including pulling chest pain, supramammillary right location, and right arm/shoulder radiation were significantly more likely to occur in patients with larger AMIs. In a large multicenter trial, only 4 symptoms were associated with the diagnosis of AMI, and no symptoms that were associated with a non-AMI diagnosis.
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