| | From ST-elevation myocardial infarction to ST elevation with no myocardial infarction—review and overview of a new horizon of computerized electrocardiographic ischemia detection using high-fidelity implantable devicesReceived 2 June 2009 Abstract ST-segment elevation is the clinical hallmark of ST-elevation myocardial infarction; however pathophysiologically ST elevation occurs in association with acute coronary occlusion long before any myocardial necrosis occurs, for example. with no myocardial infarction (MI). The clinical utility of these laboratory observations has previously been limited; however, with the advent of permanently implantable high-fidelity electrocardiogram monitors, such utility constitutes a new horizon for high-risk patients. Rapidly progressive changes in the endocardial electrogram, with real-time alarms, could shift the timing, and hence the paradigm of care from interruption of MI to prevention of MI. Introduction: a 30-year overview of ST-elevation myocardial infarction diagnosis, therapy, and health care  For 3 decades, progressive insights into the pathophysiology of ST-elevation myocardial infarction (STEMI) have guided the development and application of therapeutics with a striking reduction of STEMI-related mortality. Early understanding that STEMI syndromes represented a progressive wave front of cell death over time [1] across the anatomic distribution of a coronary artery occluded by acute thrombosis [2] provided the mechanistic basis for concepts such as “interruption” of the STEMI with “salvage” of still viable myocardium in the infarct zone. Mortality benefit related to reperfusion of the infarct artery using both thrombolytic [3] and mechanical percutaneous coronary intervention (PCI) [4] has since become a global standard for STEMI care. With widespread adoption of this standard, attention has focused on almost every aspect of factors affecting the speed and quality with which reperfusion can be achieved. Comparisons of thrombolytic regimens [5], adjuncts to PCI [6], and infrastructure metrics defining sources and implications of time delays and strategies of regionalized transport [7] have all been reported. Across all of these efforts, the unifying theme of STEMI diagnosis and intervention is the emphasis on temporal criticality, driven by the STEMI pathophysiology of “time is muscle” [8]. From professional society guidelines to its most literal nomenclature, the diagnosis of STEMI is primarily determined by ST-segment elevation on the surface electrocardiogram (ECG). Unlike anginal symptoms, physical examination, or imaging of myocardial contractility, the uniquely specific anatomic correlation between pathological ST-segment elevation and a totally occluded coronary artery supplying viable myocardium [9] is the basis for the uniquely pivotal role of the ECG in triggering STEMI diagnosis and the time-based metrics of STEMI therapy. Recognition of the critical role of ECG diagnosis to care-based timelines and outcomes has driven both guidelines and research directions, from emergency department (ED) requirements for a diagnostic ECG to be acquired and interpreted by a doctor of medicine within 5 minutes in chest pain presentations to efforts to provide diagnostic ECG technology for prehospital field use 7, 10, 11. Moving diagnostic ECG technology “upstream” in ED evaluation or into the field setting has time-saving value to delivery of care. In patients with established infarction, models suggest that for every 30 minutes of delay reduction, 1-year mortality rates fall by approximately 7.5% [12]. In addition, however, research efforts associated with faster ECG diagnosis of STEMI have consistently reported a higher percentage of patients with diagnostic ST elevation but no measurable myocardial necrosis, or so-called aborted MI patients 10, 13. As a clinical syndrome defined by the surface ECG, it might be more appropriate to use nomenclature such as ST elevation with no MI, or STEnoMI. In this article, we will review and, hence, provide an overview of the basis and implications of STEnoMI. Revisiting the pathophysiology of ST-segment elevation: focal ischemia not infarction Although most ST elevation seen in clinical practice is in patients presenting with established MI, laboratory recordings from patients undergoing elective PCI have provided ample evidence that rapidly progressive ST elevation is an ECG hallmark of the profound and focal ischemia associated with abrupt interruption of coronary flow [14], not with infarction and cell death per se. In a cohort of elective patients with viable myocardium distal to coronary balloon inflations, the average time to 200 μV of new ST elevation over baseline levels was 22 seconds, with complete resolution of such ST elevation after reperfusion with balloon deflation (Fig. 1). With the advent of continuous digital high-fidelity 12-lead monitors to capture such PCI recordings [15], it became clear that not only were these patterns quite stable over time, but such ST-elevation “fingerprints” were quite identical whether the coronary occlusion mechanistically resulted from a balloon occlusion or from spontaneous thrombotic occlusion 16, 17, 18. Finally, before the development of stents for PCI, it was shown that a partial occlusion with some flow using a perfusion balloon would produce ST depression on the surface 12-lead ECG, whereas transient but complete occlusion of the identical coronary site in the same patient using a nonperfusion balloon would produce unequivocal diagnostic ST elevation (Fig. 2). Intense and focal potassium leak across cell membranes as adenosine triphosphatase-dependent sodium-potassium pumps fail during ischemia is widely considered to be one of the primary electronic sources of the focal ST-elevation vector. In human subjects, these changes and mechanical uncoupling of calcium-dependent contractile elements both occur within seconds of abrupt coronary occlusion and long in advance of irreversible cell death [19]. Even in the setting of established MI, ST elevation actually represents more the ongoing active ischemia in the area at risk, whereas QRS changes and Q waves more directly represent the progress of infarction and cell death 20, 21. Thus, although STEMI has become a defining ECG-based element quite useful in clinical practice where most patients present with established, ongoing MI, it must be recognized that the defining ECG feature itself, pathological ST elevation, signifies ischemia induced by an occluded coronary, but not cell death per se. The defining differences between STEMI and STEnoMI are timing, clinical application, and relevance to practice. Breaking the time barrier of established MI presentations: reaching beyond the anginal warning system Electrocardiographic changes within seconds of coronary occlusion can only be useful if the technology is in place to evaluate the key waveforms. Even advances such as prehospital electrocardiography are subject to the most profound barrier to earlier detection and treatment of acute STEMI: the limitations of human anginal warning system and individual responses to it. Of all the delay metrics associated with STEMI care, patient-related delays in symptom recognition and decisions to call for help constitute approximately 66% of the barrier to diagnosis and reperfusion therapy [22]. In 1994, the median time from onset of anginal symptoms to decisions to seek care was 2 hours [23], and this time delay remains unchanged 15 years later despite millions of dollars of public awareness and educational efforts by professional societies. Nonspecificity of symptoms, mildness of symptoms, denial, sex-related differences, and a long list of additional features all make it clear that although public education and awareness are important, more objective instrumentation technology will be required to break the 2-hour barrier from symptom onset to first presentation. One avenue for such technology is through the use of permanently implantable high-fidelity ECG monitors 24, 25, 26. This approach leverages decades of knowledge and experience with pacemaker/implantable cardioverter defibrillator (ICD) technologies, including materials, decision-making programming, battery life, lead technologies, and magnetic interface data import/export capabilities. For the purposes of STEnoMI detection, such devices have a long list of unique and critical potential advantages, including (1) constantly monitor ambulatory patients in any setting/location; (2) stable, fixed lead position(s); (3) independent of thoracic cage dimension, pulmonary, or other insulators; and (4) low impedance, very-high signal/noise quality endocardial electrogram (EGM) waveforms. Even more critically, the potential of such devices would be to advance detection capability and time frames previously limited to laboratory recordings out to ambulatory management environments, opening the window to presymptomatic identification of rapidly progressive ST-segment changes indicating acute coronary occlusion. Attached to real-time alert systems, the potential this technology opens is to shift the outpatient time frame of STEMI care from 2 hours after onset of coronary occlusion, presenting with established MI, to ST-elevation detection within 2 minutes of coronary occlusion, alerting before MI can become established, for example, alerting to detection of STEnoMI. Clinical implications of STEnoMI detection using implantable high-fidelity ECG monitoring The most obvious clinical implication of very early detection of coronary occlusion is in the shift in paradigm from myocardial salvage and interruption of established MI to the prevention of measurable myocellular damage. Although currently it is more intuition than data, because such studies previously could never be done, such a paradigm shift would seem likely to yield improved outcomes even relative to the best of current STEMI care. Another potential implication is illustrated in Fig. 3. It should be remembered that “time is muscle” models such as De Luca and others [12] have developed are all built around patients enrolled in STEMI studies. Such models do not include the average 250 000 patients per year who die before hospital arrival—a cohort of enormous clinical relevance, but who are not included in STEMI studies at all. With a real-time shift from an average of 2 hours to 2 minutes from the onset of coronary occlusion, patients who otherwise experience catastrophic clinical courses or lethal dysrhythmias may receive presymptomatic warning in a time frame of life-saving proportion. In Fig. 3, ST elevation from coronary occlusion triggers the device's programmed alert 60 minutes before ventricular fibrillation. In a clinical circumstance, such an alarm could awaken an asymptomatic patient from sleep, or alert a patient about to take more Maalox for “heartburn,” and signal them to call 911, shifting events so that the patient is very likely to be under clinical care and near a defibrillator, rather than dying at home. In addition to real-time alarms potentially providing life-saving shifts in the timing and access to care, archiving of EGM waveforms from such very early events are likely to provide unique insights into the incidence and mechanisms of lethal ischemic arrhythmias. For instance, in the porcine recording in Fig. 3, it is noteworthy that fibrillation is immediately preceded by marked ST-segment recovery, suggesting that this was a reperfusion arrhythmia. The shift from a median of 2 hours into established infarction to 2 minutes into a coronary occlusion has other potentially profound implications for therapy. For instance, in the earliest phases of plaque rupture leading to thrombotic coronary occlusion, thrombus is predominantly composed of activated platelets, or “white” thrombus. As time goes by, the formation of a progressively organized thrombin-mediated protein structure emerges, ultimately requiring either thrombolytic agents or mechanical recanalization with PCI for reperfusion. The shift from 2 hours to 2 minutes from plaque rupture and coronary occlusion thus may include the substrate of the occlusion itself—at 2 minutes, it is conceivable that medical therapies such as aspirin, thienopyridines, or other platelet inhibitors might be sufficient to interrupt the clinical syndrome, without the need for urgent PCI or thrombolytics at all. Challenges to implantable high-fidelity ECG monitors and STEnoMI detection As significant as are the public health and clinical ramifications of STEnoMI detection, so are there an important array of key challenges that must be addressed if this unique diagnostic opportunity is to realize its potential. Such challenges may be considered from 3 perspectives: technical, clinical, and regulatory. Technical challenges for implantable ischemia monitors Signal fidelity Permanently implantable pacemaker/ICD platforms characteristically record very biased, high-frequency signals that are adequate for rhythm assessment, but which produce significant artifact in the low-frequency ST-segment component of an intracardiac EGM waveform. Sampling rates in many implantables are also significantly below what would be considered standard for a diagnostic surface ECG. Strategies for rectifying the fidelity of the ECG signal, either as it is recorded or through postprocessing in the user's interface, are critical for implantable devices to move into ischemia monitoring applications. Lead location, number, and configuration The absence of signal noise or insulation of the ECG signal by lungs or thorax in recording an EGM is advantageous; however, there are few data correlating any single bipolar EGM waveform morphology to what clinicians would recognize on the surface ECG as an inferior, anterior, lateral, or posterior ST-elevation pattern. Furthermore, because ischemia and, in particular, ST-elevation vectors are well known to be focal on the surface ECG, to what degree location of EGM lead position in the right ventricle and to what degree more local or more widespread bipoles (lead tip to coil vs lead tip to can; right shoulder can to tip vs left shoulder can to tip, etc) or providing more than a single bipolar lead will affect the diagnostic sensitivity or specificity of ST-event detection programming in these devices are still in early stage (Fig. 4). Along these lines, whether additional leads or options for additional bipoles in monitoring add significant information for STEnoMI detection is currently unknown. Ischemia event triggers and thresholds Although it is expectable that abrupt coronary occlusion would generate EGM changes that are as diagnostic as is ST elevation on the surface ECG, specifically what those changes are remain to be defined. As a corollary, the optimal combination of ST-deviation measurement and measurement point, waveform morphology (depression vs. elevation) and rate of change over time that should trigger an implanted device to alarm in real time, versus changes that are simply rate related is also an area of active exploration. Whether ST-segment measurement alone provides sufficient information, or whether additional features of the QRS complex or T-wave changes are helpful, needs to be studied. Implantable platforms Currently, 2 platforms for implantable high-fidelity ECG devices for ischemia monitoring have been described: a stand-alone device [24] and an ICD/pacemaker platform with ECG monitoring capability. In ICD/pacemaker platforms, the ST-segment program is essentially just a diagnostic software feature imbedded in a therapeutic device, with a relatively nominal effect on overall battery life. For stand-alone devices, the hardware, software, and implantation procedure are all exclusive to ischemia monitoring and diagnostic device performance, with no therapeutic capability per se. Clinical challenges for implantable ischemia monitors Patient selection Stand-alone permanently implanted ECG monitors for real-time detection of STEnoMI are most likely to be appropriate only for patients at very high risk of suffering abrupt coronary occlusion. Exactly what criteria best define patients who would benefit from such a device remain to be explored. Adding high-fidelity ST-segment capability to ICD/pacemaker platforms, on the other hand, can be considered in almost any patient who has a clinical indication for a pacemaker or ICD who also has coronary artery disease. Natural history of STEnoMI The actual frequency of plaque rupture or transient coronary occlusion in a high-risk population is unknown. Thus, although the conceptual appeal of moving detection of coronary occlusion from an average of 2 hours to a median of 2 minutes is appealing, it is unknown what percentage of such events would actually progress to sustained occlusion and MI. Careful observations from early clinical using implantable devices to monitor sudden, progressive ST-segment deviation are likely to be quite informative. Regulatory challenges for implantable ischemia monitors Indication(s) for use Implantable devices with ECG monitoring and high-fidelity EGM capture could theoretically be developed for a wide range of clinical applications as regulatory claims. As an add-on software feature to a clinically indicated pacemaker or ICD, it is conceivable that the indication could be a simple “tool claim” such as “high-fidelity EGM monitoring.” As a stand-alone, permanently implantable diagnostic device, a clinical (“very early detection of STEnoMI”) or even therapeutic claim (“for reduction and prevention of MI”) could be considered. Defining a population of use As described above, the population of use is most likely to be driven by the implementation platform. For a stand-alone ischemia monitor, patients at high risk for STEMI and, thus, for STEnoMI would need to be defined. As a software feature for pacemaker/ICD platforms, the population might simply be defined as patients with clinical indications for pacemaker/ICD who also have coronary artery disease. Use of alarms The use of real-time alarms for high-risk events in diagnostic medical devices is an important area of device regulation. False alarms or false-positive triggers that may cause distress to asymptomatic people and cause them to needlessly engage emergency health care services underlie concerns with regard to appropriate specificity for such triggering. Conversely, there are concerns that patients with device implants might develop false reassurance. For instance, if a patient with an implantable high-fidelity ECG monitor experienced chest pains from a pulmonary embolus, would they potentially ignore their symptoms because they assume that if they were having a real problem, their device would be alarming? User interface What, how, and where information is communicated to bedside clinical caretakers all represent novel areas to be developed for implantable STEnoMI or ischemia monitors. What waveforms, digital measurements or trend graphics, parameters of ST-deviation, ST-vector, time, heart rate, conduction, or other features are incorporated in user interfaces will require development to optimize integration of such information into chest pain evaluation and critical care management. How information is transmitted from the implanted device to a bedside user interface—through telemetry, magnetic coupling, or other options—may differentiate certain real-time from other more retrospective EGM collections for patient care. And finally, where implantable device user interfaces are applied—in prehospital, ED, catherization laboratory, or critical care unit settings—also has relevance to optimal interface design. End point definition Permanently implantable STEnoMI monitoring may identify events that do not fit ready constructs for clinical event definition. For instance, suppose a monitor triggers a real-time alarm in an asymptomatic patient, and the patient calls 911. Emergency medical technicians arrive within 4 minutes, and administer an extra dose of aspirin. On arrival in the ED 8 minutes later, the patient is asymptomatic, and both surface ECG and cardiac enzymes are normal. What defines whether this scenario is an MI prevented and perhaps a life saved, or is it just a false-positive device alarm? STEnoMI monitoring is so novel that it is most likely that in early studies, cohort definitions will be as critical as any individual patient profiles to understand device safety and performance. Summary Permanently implantable, computer-assisted, high-fidelity ECG monitor technology with real-time alarms has the potential to alert even asymptomatic patients within minutes of abrupt coronary occlusion, for example, when they are experiencing STEnoMI ischemia rather than MI. Potential ramifications of this time-frame shift from a current average of first medical care after 2 hours of chest pain with established infarction to within 2 minutes of the onset of coronary occlusion include identification of patients who otherwise would die before reaching hospital, elucidation of mechanisms of fatal ischemic arrhythmias, and potential clinical response to more simple antiplatelet therapies without the need for thrombolytics or emergency PCI to sustain reperfusion. On the other hand, as with any new “breakthrough” medical device technology, many technical, clinical, and regulatory specifics need to be addressed to understand the optimal signal alarm triggers, patient population who could benefit, and integration of such unique EGM waveforms and measures into complex clinical management scenarios, such as prehospital response, EDs, and intensive care units. References 1. 1Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial ischemic cell death. Lab Invest. 1979;40:633. MEDLINE 2. 2DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897. MEDLINE |
CrossRef
3. 3The GUSTO Angiographic Investigators . The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615;. MEDLINE |
CrossRef
4. 4Dangas G, Aymong ED, Mehran R, et al. CADILLAC Investigators. Predictors of and outcomes of early thrombosis following balloon angioplasty versus primary stenting in acute myocardial infarction and usefulness of abciximab (the CADILLAC trial). Am J Cardiol. 2004;94:983. Abstract | Full Text |
Full-Text PDF (106 KB)
|
CrossRef
5. 5Topol EJ, Ohman EM, Armstrong PW, et al. Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III Trial. Circulation. 2000;102:1761. 6. 6Stone GW, Webb J, Cox DA, et al. Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial. JAMA. 2005;293:1063.
CrossRef
7. 7Andersen HR, Nielsen TT, Rasmussen K, et al. DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003;349:733.
CrossRef
8. 8Gibson CM. Time is myocardium and time is outcomes (editorial). Circulation. 2001;104:2632. 9. 9Krucoff MW, Veldkamp RF, Kanani PM, et al. The impact of autoperfusion on quantitative electrocardiographic parameters of ischemia severity, extent, and “burden” during salvage of elective coronary angioplasty. J Invasive Cardiol. 1994 Sep;6:234. MEDLINE 10. 10Weaver WD, Cerqueira M, Hallstrom AP, et al. Prehospital-initiated vs hospital-initiated thrombolytic therapy. The Myocardial Infarction Triage and Intervention Trial. JAMA. 1993;270:1211. MEDLINE 11. 11Adams GL, Campbell PT, Adams JM, et al. Effectiveness of prehospital wireless transmission of electrocardiograms to a cardiologist via hand-held device for patients with acute myocardial infarction (from the Timely Intervention in Myocardial Emergency, NorthEast Experience [TIME-NE]). Am J Cardiol. 2006;98:1160. Abstract | Full Text |
Full-Text PDF (627 KB)
|
CrossRef
12. 12De Luca G, Suryapranata H, Zijlstra F, et al. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol. 2003;42:991. Abstract | Full Text |
Full-Text PDF (198 KB)
|
CrossRef
13. 13Verheugt FW, Gersh BJ, Armstrong PW. Aborted myocardial infarction: new target for reperfusion therapy. Eur Heart J. 2006;27:901.
CrossRef
14. 14Krucoff MW, Pope JE, Bottner RK, Renzi RH, Wagner GS, Kent KM. Computer-assisted ST-segment monitoring: experience during and after brief coronary occlusion. J Electrocardiol. 1987;20(Suppl):15. 15. 15Krucoff MW, Wagner NB, Pope JE, et al. The portable programmable microprocessor-driven real-time 12-lead electrocardiographic monitor: a preliminary report of a new device for the noninvasive detection of successful reperfusion or silent coronary reocclusion. Am J Cardiol. 1990;65:143. MEDLINE |
CrossRef
16. 16Krucoff MW, Parente AR, Bottner RK, et al. Stability of multilead ST-segment “fingerprints” over time after percutaneous transluminal coronary angioplasty and its usefulness in detecting reocclusion. Am J Cardiol. 1988;61:1232. MEDLINE |
CrossRef
17. 17Bush HS, Ferguson JJ, Angelini P, Willerson JT. Twelve-lead electrocardiographic evaluation of ischemia during percutaneous transluminal coronary angioplasty and its correlation with acute reocclusion.. Am Heart J. 1991;121(6 Pt 1):1591. MEDLINE |
CrossRef
18. 18Krucoff MW, Croll MA, Pope JE, et al. Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with multiple simultaneous early angiographic observations. Am J Cardiol. 1993;71:145. MEDLINE |
CrossRef
19. 19Chierchia S, Lazzari M, Freedman SB, et al. Impairment of myocardial perfusion and function during painless myocardial ischemia. J Am Coll Cardiol. 1983;1:924. Abstract |
Full-Text PDF (824 KB)
|
CrossRef
20. 20Aldrich HR, Wagner NB, Boswick J, et al. Use of initial ST-segment deviation for prediction of final electrocardiographic size of acute myocardial infarction. Am J Cardiol. 1988;61:749. MEDLINE |
CrossRef
21. 21Clemmensen P, Grande P, Aldrich HR, Wagner GS. Evaluation of formulas for estimating the final size of acute myocardial infarcts from quantitative ST-segment elevation on the initial standard 12-lead ECG. J Electrocardiol. 1991;24:77. MEDLINE |
CrossRef
22. 22Dracup K, Alonzo AA, Atkins JM, et al. The physician's role in minimizing prehospital delay in patients at high risk for acute myocardial infarction: recommendations from the National Heart Attack Alert Program. Working Group on Educational Strategies to Prevent Prehospital Delay in Patients at High Risk for Acute Myocardial Infarction. Ann Intern Med. 1997;126:645. MEDLINE 23. 23Gibler WB, Armstrong PW, Ohman EM, et al. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) Investigators. Persistence of delays in presentation and treatment for patients with acute myocardial infarction: The GUSTO-I and GUSTO-III experience. Ann Emerg Med. 2002;39:123. Abstract | Full Text |
Full-Text PDF (122 KB)
|
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24. 24Theres H, Stadler RW, Stylos L, et al. Comparison of electrocardiogram and intrathoracic electrogram signals for detection of ischemic ST segment changes during normal sinus and ventricular paced rhythms. J Cardiovasc Electrophysiol. 2002;13:990. MEDLINE 25. 25Fischell TA, Fischell DR, Fischell RE, et al. Potential of an intracardiac electrogram for the rapid detection of coronary artery occlusion. Cardiovasc Revasc Med. 2005;6:14. Abstract | Full Text |
Full-Text PDF (287 KB)
|
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26. 26Fischell TA, Fischell DR, Fischell RE, Virmani R, DeVries JJ, Krucoff MW. Real-time detection and alerting for acute ST-segment elevation myocardial ischemia using an implantable, high-fidelity, intracardiac electrogram monitoring system with long-range telemetry in an ambulatory porcine model. J Am Coll Cardiol. 2006;48:2306. Abstract | Full Text |
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Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA  Duke University Medical Center, Duke Clinical Research Institute, 508 Fulton Street (111A), Durham, NC 27705, USA.
PII: S0022-0736(09)00257-X doi:10.1016/j.jelectrocard.2009.06.015 © 2009 Elsevier Inc. All rights reserved. | |
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