Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: Rationale and design of the Sonolysis study

Contains fulltext : 70525.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND -: Experimental studies have shown that ultrasound contrast agents enhance the effectiveness of thrombolytic agents in the presence of ultrasound in vitro and in vivo. Recently, we have launched a clinical pilot study, called "Sonolysis", to study this effect in patients with ST-elevation myocardial infarction based on proximal lesions of the infarct-related artery. METHODS/DESIGN -: In our multicenter, randomized, placebo controlled clinical trial we will include patients between 18 and 80 years of age with their first ST-elevation myocardial infarction based on a proximal lesion of the infarct-related artery. After receiving a single bolus alteplase 50 mg IV (Actilyse(R) Boehringer Ingelheim GmbH), a loading dose of aspirin 500 mg, and heparin 5000 IU in the ambulance according to the prehospital thrombolysis protocol, patients, following oral informed consent, are randomized to undergo 15 minutes of pulsatile ultrasound with intravenous administration of ultrasound contrast agent or placebo without ultrasound. Afterwards coronary angiography and, if indicated, percutaneous coronary intervention will take place. A total of 60 patients will be enrolled in approximately 1 year.The primary endpoints are based on the coronary angiogram and consist of TIMI flow, corrected TIMI frame count, and myocardial blush grade. Follow-up includes 12-lead ECG, 2D-echocardiography, cardiac MRI, and enzyme markers to obtain our secondary endpoints, including the infarct size, wall motion abnormalities, and the global left ventricular function. DISCUSSION -: The Sonolysis study is the first multicenter, randomized, placebo controlled clinical trial investigating the therapeutic application of ultrasound and microbubbles in acute ST-elevation myocardial infarction patients. A positive finding may stimulate further research and technical innovations to implement the treatment in the ambulance and maybe obtain even more patency at an earlier stage. TRIAL REGISTRATION -: Trialregister NTR161

Association of childhood trauma with cognitive function in healthy adults: a pilot study

BACKGROUND: Animal and human studies suggest that stress experienced early in life has detrimental consequences on brain development, including brain regions involved in cognitive function. Cognitive changes are cardinal features of depression and posttraumatic stress disorder. Early-life trauma is a major risk factor for these disorders. Only few studies have measured the long-term consequences of childhood trauma on cognitive function in healthy adults. METHODS: In this pilot study, we investigated the relationship between childhood trauma exposure and cognitive function in 47 healthy adults, who were identified as part of a larger study from the general population in Wichita, KS. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Wide-Range-Achievement-Test (WRAT-3) to examine cognitive function and individual achievement. Type and severity of childhood trauma was assessed by the Childhood Trauma Questionnaire (CTQ). Data were analyzed using multiple linear regression on CANTAB measures with primary predictors (CTQ scales) and potential confounders (age, sex, education, income). RESULTS: Specific CTQ scales were significantly associated with measures of cognitive function. Emotional abuse was associated with impaired spatial working memory performance. Physical neglect correlated with impaired spatial working memory and pattern recognition memory. Sexual abuse and physical neglect were negatively associated with WRAT-3 scores. However, the association did not reach the significance level of p < 0.01. CONCLUSIONS: Our results suggest that physical neglect and emotional abuse might be associated with memory deficits in adulthood, which in turn might pose a risk factor for the development of psychopathology

Robust Biomarkers: Methodologically Tracking Causal Processes in Alzheimer’s Measurement

In biomedical measurement, biomarkers are used to achieve reliable prediction of, and useful causal information about patient outcomes while minimizing complexity of measurement, resources, and invasiveness. A biomarker is an assayable metric that discloses the status of a biological process of interest, be it normative, pathophysiological, or in response to intervention. The greatest utility from biomarkers comes from their ability to help clinicians (and researchers) make and evaluate clinical decisions. In this paper we discuss a specific methodological use of clinical biomarkers in pharmacological measurement: Some biomarkers, called ‘surrogate markers’, are used to substitute for a clinically meaningful endpoint corresponding to events and their penultimate risk factors. We confront the reliability of clinical biomarkers that are used to gather information about clinically meaningful endpoints. Our aim is to present a systematic methodology for assessing the reliability of multiple surrogate markers (and biomarkers in general). To do this we draw upon the robustness analysis literature in the philosophy of science and the empirical use of clinical biomarkers. After introducing robustness analysis we present two problems with biomarkers in relation to reliability. Next, we propose an intervention-based robustness methodology for organizing the reliability of biomarkers in general. We propose three relevant conditions for a robust methodology for biomarkers: (R1) Intervention-based demonstration of partial independence of modes: In biomarkers partial independence can be demonstrated through exogenous interventions that modify a process some number of “steps” removed from each of the markers. (R2) Comparison of diverging and converging results across biomarkers: By systematically comparing partially-independent biomarkers we can track under what conditions markers fail to converge in results, and under which conditions they successfully converge. (R3) Information within the context of theory: Through a systematic cross-comparison of the markers we can make causal conclusions as well as eliminate competing theories. We apply our robust methodology to currently developing Alzheimer’s research to show its usefulness for making causal conclusions