Modulating RNA structure and catalysis: lessons from small cleaving ribozymes

RNA is a key molecule in life, and comprehending its structure/function relationships is a crucial step towards a more complete understanding of molecular biology. Even though most of the information required for their correct folding is contained in their primary sequences, we are as yet unable to accurately predict both the folding pathways and active tertiary structures of RNA species. Ribozymes are interesting molecules to study when addressing these questions because any modifications in their structures are often reflected in their catalytic properties. The recent progress in the study of the structures, the folding pathways and the modulation of the small ribozymes derived from natural, self-cleaving, RNA motifs have significantly contributed to today’s knowledge in the field

Incremental value of heart-type fatty acid-binding protein in suspected acute myocardial infarction early after symptom onset.

BACKGROUND The early diagnosis of acute myocardial infarction (AMI) very soon after symptom onset remains a major clinical challenge, even when using high-sensitivity cardiac troponin (hs-cTnT). METHODS AND RESULTS We investigated the incremental value of heart-type fatty acid-binding protein (hFABP) in a pre-specified subgroup analysis of patients presenting with suspected AMI within 1 h of symptom onset to the emergency department (ED) in a multicentre study. HFABP was measured in a blinded fashion. Two independent cardiologists using all available clinical information, including hs-cTnT, adjudicated the final diagnosis. Overall, 1411 patients were enrolled, of whom 105 patients presented within 1 h of symptom onset. Of these, 34 patients (32.4%) had AMI. The diagnostic accuracy as quantified by the area under the receiver-operating characteristics curve (AUC) of hFABP was high (0.84 (95% CI 0.74-0.94)). However, the additional use of hFABP only marginally increased the diagnostic accuracy of hs-cTnT (AUC 0.88 (95% CI 0.81-0.94) for hs-cTnT alone to 0.90 (95% CI 0.83-0.98) for the combination; p=ns). After the exclusion of 18 AMI patients with ST-segment elevation, similar results were obtained. Among the 16 AMI patients without ST-segment elevation, six had normal hs-cTnT at presentation. Of these, hFABP was elevated in two (33.3%) patients. CONCLUSIONS hFABP does not seem to significantly improve the early diagnostic accuracy of hs-cTnT in the important subgroup of patients with suspected AMI presenting to the ED very early after symptom onset

Residential demand management and distribution grid impact assessment

Demand Response in the residential sector has the potential to help future energy systems to balance variable power generation with electric demand. Harnessing its flexibility is however a challenge. We study in this article a day-ahead planning optimization and a stochastic appliance scheduling procedure that could serve different objectives. The aim of the study is twofold. In a first step, we develop a bottom-up consumption model and a flexibility model in which users set preferences on the flexibility that each load is capable to deliver. The model both accounts for the active and reactive part of the power exchanged with the grid. In a second step, the impact of control decisions on the distribution grid is assessed. It is shown that voltage imbalance factor is likely to exhibit larger extreme values when demand response is used to fulfill external objective, especially in feeders where clients are single phase connected

Diagnostic and prognostic value of autoantibodies anti-apolipoprotein A-1 and anti-phosphorylcholine in acute non-ST elevation myocardial infarction

Autoantibodies have been shown to play a critical role in predicting major adverse cardiovascular events in atherosclerotic patients. We aimed to assess the diagnostic accuracy of autoantibodies to apolipoprotein A-1 (anti-apoA-1 IgG) and to phosphorylcholine (anti-PC IgM) for non-ST segment elevation acute myocardial infarction (NSTEMI) and to explore their potential prognostic value

Clinical impact of the 2010-2012 low-end shift of high-sensitivity cardiac troponin T

The clinical implications of the 2010-2012 low-end shift of high-sensitivity cardiac troponin T (hs-cTnT) regarding possible misdiagnosis of acute myocardial infarction are largely unknown.We aimed to quantify the impact of the 2010-2012 low-end shift and adjustment issue in 857 patients presenting to the emergency department with suspected acute myocardial infarction by comparing measurements performed with affected 2010-2012 lots with recalculated 2010-2012 values using a linear regression formula (provided by the manufacturer) and the corrected assay (re-measured in 2013). The final diagnosis was adjudicated by two independent cardiologists using all information including coronary angiography, echocardiography and serial hs-cTnT levels (with the corrected 2013 assay).Acute myocardial infarction was the adjudicated diagnosis in 195 patients (22.7%). Median hs-TnT values were 8.5 ng/l for affected lots, 11.1 ng/l with recalculated and 10 ng/l with the corrected assay (

Optimizing early rule-out strategies for acute myocardial infarction: utility of 1-hour copeptin

Combined testing of high-sensitivity cardiac troponin T (hs-cTnT) and copeptin at presentation provides a very high-although still imperfect-negative predictive value (NPV) for the early rule-out of acute myocardial infarction (AMI). We hypothesized that a second copeptin measurement at 1 h might further increase the NPV.In a prospective diagnostic multicenter study, we measured hs-cTnT and copeptin concentrations at presentation and at 1 h in 1439 unselected patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists blinded to copeptin concentrations. We investigated the incremental value of 1-h copeptin in the rule-out setting (0-h hs-cTnT negative and 0-h copeptin negative) and the intermediate-risk setting (0-h hs-cTnT negative and 0-h copeptin positive).The adjudicated diagnosis was AMI in 267 patients (18.6%). For measurements obtained at presentation, the NPV in the rule-out setting was 98.6% (95% CI, 97.4%-99.3%). Whereas 1-h copeptin did not increase the NPV significantly, 1-h hs-cTnT did, to 99.6% (95% CI, 98.7%-99.9%, P = 0.008). Similarly, in the intermediate-risk setting (NPV 92.8%, 95% CI, 88.7%-95.8%), 1-h copeptin did not significantly increase the NPV (P = 0.751), but 1-h hs-cTnT did, to 98.6 (95% CI, 96%-99.7%, P < 0.001).One-hour copeptin increased neither the safety of the rule-out process nor the NPV in the intermediate-risk setting. In contrast, the incremental value of 1-h hs-cTnT was substantial in both settings. ClinicalTrials.gov/NCT00470587

Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction.

AIMS: High-sensitivity cardiac troponin (hs-cTn) assays provide higher diagnostic accuracy for acute myocardial infarction (AMI) when compared with conventional assays, but may result in increased use of unnecessary coronary angiographies due to their increased detection of cardiomyocyte injury in conditions other than AMI. METHODS AND RESULTS: We evaluated the impact of the clinical introduction of high-sensitivity cardiac troponin T (hs-cTnT) on the use of coronary angiography, stress testing, and time to discharge in 2544 patients presenting with symptoms suggestive of AMI to the emergency department (ED) within a multicentre study either before (1455 patients) or after (1089 patients) hs-cTnT introduction. Acute myocardial infarction was more often the clinical discharge diagnosis after hs-cTnT introduction (10 vs. 14%, P < 0.001), while unstable angina less often the clinical discharge diagnosis (14 vs. 9%, P = 0.007). The rate of coronary angiography was similar before and after the introduction of hs-cTnT (23 vs. 23%, P = 0.092), as was the percentage of coronary angiographies showing no stenosis (11 vs. 7%, P = 0.361). In contrast, the use of stress testing was substantially reduced from 29 to 19% (P < 0.001). In outpatients, median time to discharge from the ED decreased by 79 min (P < 0.001). Mean total costs decreased by 20% in outpatients after the introduction of hs-cTnT (P = 0.002). CONCLUSION: The clinical introduction of hs-cTn does not lead to an increased or inappropriate use of coronary angiography. Introduction of hs-cTn is associated with an improved rule-out process and thereby reduces the need for stress testing and time to discharge.R.T. reports speaker honoraria from B.R.A.H.M.S. and Roche. T.R. reports grants from Swiss National Science Foundation (PASMP3-136995) as well as personal fees from Swiss Heart Foundation and from Goldschmidt-Jacobson Foundation. C.M. reports research grants from the Swiss National Science Foundation, the European Union, the KTI, and the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, 8sense, Abbott, ALERE, Astra Zeneca, Beckman Coulter, Biomerieux, Brahms, Critical Diagnostics,Nanosphere, Roche, Siemens, Singulex, and the University Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Astra Zeneca, BG medicine, Biomerieux, BMS, Brahms, Cardiorentis, Daiichi Sankyo, Novartis, Radiometer, Roche, Sanofi, Siemens, and Singulex

Incremental value of copeptin to highly sensitive cardiac Troponin I for rapid rule-out of myocardial infarction

The incremental value of copeptin, a novel marker of endogenous stress, for rapid rule-out of non-ST-elevation myocardial infarction (NSTEMI) is unclear when sensitive or even high-sensitivity cardiac troponin cTn (hs-cTn) assays are used.In an international multicenter study we evaluated 1929 consecutive patients with symptoms suggestive of acute myocardial infarction (AMI). Measurements of copeptin, three sensitive and three hs-cTn assays were performed at presentation in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists using all clinical information including coronary angiography and levels of hs-cTnT. The incremental value in the diagnosis of NSTEMI was quantified using four outcome measures: area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), sensitivity and negative predictive value (NPV). Early presenters (< 4h since chest pain onset) were a pre-defined subgroup.NSTEMI was the adjudicated final diagnosis in 358 (18.6%) patients. As compared to the use of cTn alone, copeptin significantly increased AUC for two (33%) and IDI (between 0.010 and 0.041 (all p < 0.01)), sensitivity and NPV for all six cTn assays (100%); NPV to 96-99% when the 99 th percentile of the respective cTnI assay was combined with a copeptin level of 9 pmol/l (all p < 0.01). The incremental value in early presenters was similar to that of the overall cohort.When used for rapid rule-out of NSTEM in combination with sensitive or hs-cTnI assays, copeptin provides a numerically small, but statistically and likely also clinically significant incremental value