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1.  A framework for assessing Health Economic Evaluation (HEE) quality appraisal instruments 
Background
Health economic evaluations support the health care decision-making process by providing information on costs and consequences of health interventions. The quality of such studies is assessed by health economic evaluation (HEE) quality appraisal instruments. At present, there is no instrument for measuring and improving the quality of such HEE quality appraisal instruments. Therefore, the objectives of this study are to establish a framework for assessing the quality of HEE quality appraisal instruments to support and improve their quality, and to apply this framework to those HEE quality appraisal instruments which have been subject to more scrutiny than others, in order to test the framework and to demonstrate the shortcomings of existing HEE quality appraisal instruments.
Methods
To develop the quality assessment framework for HEE quality appraisal instruments, the experiences of using appraisal tools for clinical guidelines are used. Based on a deductive iterative process, clinical guideline appraisal instruments identified through literature search are reviewed, consolidated, and adapted to produce the final quality assessment framework for HEE quality appraisal instruments.
Results
The final quality assessment framework for HEE quality appraisal instruments consists of 36 items organized within 7 dimensions, each of which captures a specific domain of quality. Applying the quality assessment framework to four existing HEE quality appraisal instruments, it is found that these four quality appraisal instruments are of variable quality.
Conclusions
The framework described in this study should be regarded as a starting point for appraising the quality of HEE quality appraisal instruments. This framework can be used by HEE quality appraisal instrument producers to support and improve the quality and acceptance of existing and future HEE quality appraisal instruments. By applying this framework, users of HEE quality appraisal instruments can become aware of methodological deficiencies inherent in existing HEE quality appraisal instruments. These shortcomings of existing HEE quality appraisal instruments are illustrated by the pilot test.
doi:10.1186/1472-6963-12-253
PMCID: PMC3507835  PMID: 22894708
2.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined:
the diagnostic accuracy of FDG PET for predicting functional recovery;
the impact of PET viability imaging on prognosis (mortality and other patient outcomes); and
the contribution of PET viability imaging to treatment decision making and subsequent patient outcomes.
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD)1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of PET for detecting myocardial viability?
What is the prognostic value of PET viability imaging (mortality and other clinical outcomes)?
What is the contribution of PET viability imaging to treatment decision making?
What is the safety of PET viability imaging?
Literature Search
A literature search was performed on July 17, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 to July 16, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2004. Reference lists of included studies were also examined for any additional relevant studies not already identified. The quality of the body of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
English language full-reports
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known CAD
PET imaging using FDG for the purpose of detecting viable myocardium
Criteria applying to diagnostic accuracy studies:
Assessment of functional recovery ≥3 months after revascularization
Raw data available to calculate sensitivity and specificity
Gold standard: prediction of global or regional functional recovery
Criteria applying to prognosis studies:
Mortality studies that compare revascularized patients with non-revascularized patients and patients with viable and non-viable myocardium
Exclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
PET perfusion imaging
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Animal or phantom studies
Studies focusing on the technical aspects of PET
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Duplicate publications
Criteria applying to diagnostic accuracy studies
Gold standard other than functional recovery (e.g., PET or cardiac MRI)
Assessment of functional recovery occurs before patients are revascularized
Outcomes of Interest
Diagnostic accuracy studies
Sensitivity and specificity
Positive and negative predictive values (PPV and NPV)
Positive and negative likelihood ratios
Diagnostic accuracy
Adverse events
Prognosis studies
Mortality rate
Functional status
Exercise capacity
Quality of Life
Influence on PET viability imaging on physician decision making
Statistical Methods
Pooled estimates of sensitivity and specificity were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced. The area under the sROC curve was estimated by numerical integration with a cubic spline (default option). Finally, pooled estimates of mortality rates were calculated using weighted means.
Quality of Evidence
The quality of evidence assigned to individual diagnostic studies was determined using the QUADAS tool, a list of 14 questions that address internal and external validity, bias, and generalizibility of diagnostic accuracy studies. Each question is scored as “yes”, “no”, or “unclear”. The quality of the body of evidence was then assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
A total of 40 studies met the inclusion criteria and were included in this review: one health technology assessment, two systematic reviews, 22 observational diagnostic accuracy studies, and 16 prognosis studies. The available PET viability imaging literature addresses two questions: 1) what is the diagnostic accuracy of PET imaging for the assessment; and 2) what is the prognostic value of PET viability imaging. The diagnostic accuracy studies use regional or global functional recovery as the reference standard to determine the sensitivity and specificity of the technology. While regional functional recovery was most commonly used in the studies, global functional recovery is more important clinically. Due to differences in reporting and thresholds, however, it was not possible to pool global functional recovery.
Functional recovery, however, is a surrogate reference standard for viability and consequently, the diagnostic accuracy results may underestimate the specificity of PET viability imaging. For example, regional functional recovery may take up to a year after revascularization depending on whether it is stunned or hibernating tissue, while many of the studies looked at regional functional recovery 3 to 6 months after revascularization. In addition, viable tissue may not recover function after revascularization due to graft patency or re-stenosis. Both issues may lead to false positives and underestimate specificity. Given these limitations, the prognostic value of PET viability imaging provides the most direct and clinically useful information. This body of literature provides evidence on the comparative effectiveness of revascularization and medical therapy in patients with viable myocardium and patients without viable myocardium. In addition, the literature compares the impact of PET-guided treatment decision making with SPECT-guided or standard care treatment decision making on survival and cardiac events (including cardiac mortality, MI, hospital stays, unintended revascularization, etc).
The main findings from the diagnostic accuracy and prognosis evidence are:
Based on the available very low quality evidence, PET is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 91.5% (95% CI, 88.2% – 94.9%) and 67.8% (95% CI, 55.8% – 79.7%), respectively.
Based the available very low quality of evidence, an indirect comparison of pooled estimates of sensitivity and specificity showed no statistically significant difference in the diagnostic accuracy of PET viability imaging for regional functional recovery using perfusion/metabolism mismatch with FDG PET plus either a PET or SPECT perfusion tracer compared with metabolism imaging with FDG PET alone.
FDG PET + PET perfusion metabolism mismatch: sensitivity, 89.9% (83.5% – 96.4%); specificity, 78.3% (66.3% – 90.2%);
FDG PET + SPECT perfusion metabolism mismatch: sensitivity, 87.2% (78.0% – 96.4%); specificity, 67.1% (48.3% – 85.9%);
FDG PET metabolism: sensitivity, 94.5% (91.0% – 98.0%); specificity, 66.8% (53.2% – 80.3%).
Given these findings, further higher quality studies are required to determine the comparative effectiveness and clinical utility of metabolism and perfusion/metabolism mismatch viability imaging with PET.
Based on very low quality of evidence, patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy. Given the quality of evidence, however, this estimate of effect is uncertain so further higher quality studies in this area should be undertaken to determine the presence and magnitude of the effect.
While revascularization may reduce mortality in patients with viable myocardium, current moderate quality RCT evidence suggests that PET-guided treatment decisions do not result in statistically significant reductions in mortality compared with treatment decisions based on SPECT or standard care protocols. The PARR II trial by Beanlands et al. found a significant reduction in cardiac events (a composite outcome that includes cardiac deaths, MI, or hospital stay for cardiac cause) between the adherence to PET recommendations subgroup and the standard care group (hazard ratio, .62; 95% confidence intervals, 0.42 – 0.93; P = .019); however, this post-hoc sub-group analysis is hypothesis generating and higher quality studies are required to substantiate these findings.
The use of FDG PET plus SPECT to determine perfusion/metabolism mismatch to assess myocardial viability increases the radiation exposure compared with FDG PET imaging alone or FDG PET combined with PET perfusion imaging (total-body effective dose: FDG PET, 7 mSv; FDG PET plus PET perfusion tracer, 7.6 – 7.7 mSV; FDG PET plus SPECT perfusion tracer, 16 – 25 mSv). While the precise risk attributed to this increased exposure is unknown, there is increasing concern regarding lifetime multiple exposures to radiation-based imaging modalities, although the incremental lifetime risk for patients who are older or have a poor prognosis may not be as great as for healthy individuals.
PMCID: PMC3377573  PMID: 23074393
3.  Limitations of transoesophageal echocardiography in patients with focal cerebral ischaemic events. 
British Heart Journal  1992;67(4):297-303.
OBJECTIVE--To investigate the detection rate of cardiac sources of embolism by transoesophageal echocardiography in patients with focal cerebral ischaemic events and to relate the echocardiographic findings to other clinical findings. DESIGN--Prospective study with blinded analysis of the echocardiographic data and subsequent comparison with the other clinical findings. SETTING--Regional cardiothoracic unit based in a teaching hospital. PATIENTS--131 consecutive patients with focal ischaemic cerebral events (49 with a transient ischaemic attack, 77 with a cerebrovascular accident, and five with a retinal arterial embolus) referred for echocardiography. INTERVENTIONS--Full M mode, cross sectional, Doppler, and contrast echocardiography by both the precordial and transoesophageal techniques. RESULTS--Precordial echocardiography detected a cardiac abnormality in 72 patients. Transoesophageal echocardiography confirmed all the precordial findings (except left ventricular hypertrophy, which at present cannot be defined with this technique) and detected other abnormalities in a further 20 patients (18 with potential right-to-left shunts and two with valve vegetations). It also showed spontaneous contrast echoes in 27 of 28 patients with a large left atrium and showed atrial thrombus in three. Cardiac abnormalities were clinically detected in 53 patients, all of which were confirmed or documented by echocardiography. In the 78 patients with no clinically detectable cardiac abnormality six had mitral valve prolapse and one had a regional wall motion defect (identified by precordial echocardiography) and 17 had potential right-to-left shunts (11 of which were identified only by transoesophageal echocardiography). CONCLUSIONS--Transoesophageal echocardiography is more sensitive than precordial echocardiography in detecting potential sources of embolism in these patients. However, except for the detection of a potential right-to-left shunt, the yield in patients with no cardiac abnormality is low. Moreover, the abnormalities detected in those with previously detected cardiac disease merely confirm the clinical diagnosis. Patients with left atrial spontaneous contrast echoes may benefit from anticoagulation but this requires further study. Until more data are available on this feature and on the role of potential right-to-left shunts in this population, the contribution of echocardiography, precordial or transoesophageal, remains limited.
Images
PMCID: PMC1024836  PMID: 1389703
4.  Barcoding Human Physical Activity to Assess Chronic Pain Conditions 
PLoS ONE  2012;7(2):e32239.
Background
Modern theories define chronic pain as a multidimensional experience – the result of complex interplay between physiological and psychological factors with significant impact on patients' physical, emotional and social functioning. The development of reliable assessment tools capable of capturing the multidimensional impact of chronic pain has challenged the medical community for decades. A number of validated tools are currently used in clinical practice however they all rely on self-reporting and are therefore inherently subjective. In this study we show that a comprehensive analysis of physical activity (PA) under real life conditions may capture behavioral aspects that may reflect physical and emotional functioning.
Methodology
PA was monitored during five consecutive days in 60 chronic pain patients and 15 pain-free healthy subjects. To analyze the various aspects of pain-related activity behaviors we defined the concept of PA ‘barcoding’. The main idea was to combine different features of PA (type, intensity, duration) to define various PA states. The temporal sequence of different states was visualized as a ‘barcode’ which indicated that significant information about daily activity can be contained in the amount and variety of PA states, and in the temporal structure of sequence. This information was quantified using complementary measures such as structural complexity metrics (information and sample entropy, Lempel-Ziv complexity), time spent in PA states, and two composite scores, which integrate all measures. The reliability of these measures to characterize chronic pain conditions was assessed by comparing groups of subjects with clinically different pain intensity.
Conclusion
The defined measures of PA showed good discriminative features. The results suggest that significant information about pain-related functional limitations is captured by the structural complexity of PA barcodes, which decreases when the intensity of pain increases. We conclude that a comprehensive analysis of daily-life PA can provide an objective appraisal of the intensity of pain.
doi:10.1371/journal.pone.0032239
PMCID: PMC3285674  PMID: 22384191
5.  Magnetic Resonance Imaging (MRI) for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of noninvasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and cost-effectiveness of cardiovascular magnetic resonance imaging (cardiac MRI) for the assessment of myocardial viability. To evaluate the effectiveness of cardiac MRI viability imaging, the following outcomes were examined: the diagnostic accuracy in predicting functional recovery and the impact of cardiac MRI viability imaging on prognosis (mortality and other patient outcomes).
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) 1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or, in some cases, through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent, due to the formation of myocardial scar, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 µg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of cardiac MRI for detecting myocardial viability?
What is the impact of cardiac MRI viability imaging on prognosis (mortality and other clinical outcomes)?
How does cardiac MRI compare with cardiac PET imaging for the assessment of myocardial viability?
What is the contribution of cardiac MRI viability imaging to treatment decision making?
Is cardiac MRI cost-effective compared with other cardiac imaging modalities for the assessment of myocardial viability?
Literature Search
A literature search was performed on October 9, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 until October 9, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2005. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports
Published between January 1, 2005 and October 9, 2009
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known coronary artery disease (CAD)
Used contrast-enhanced MRI
Assessment of functional recovery ≥ 3 months after revascularization
Exclusion Criteria
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Studies where TP, TN, FP, FN cannot be determined
Outcomes of Interest
Sensitivity
Specificity
Positive predictive value (PPV)
Negative Predictive value (NPV)
Positive likelihood ratio
Negative likelihood ratio
Diagnostic accuracy
Mortality rate (for prognostic studies)
Adverse events
Summary of Findings
Based on the available very low quality evidence, MRI is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 84.5% (95% CI: 77.5% – 91.6%) and 71.0% (95% CI: 68.8% – 79.2%), respectively.
Subgroup analysis demonstrated a statistically significant difference in the sensitivity of MRI to assess myocardial viability for studies using ≤25% hyperenhancement as a viability threshold versus studies using ≤50% hyperenhancement as their viability threshold [78.7 (95% CI: 69.1% - 88.2%) and 96.2 (95% CI: 91.8 – 100.6); p=0.0044 respectively]. Marked differences in specificity were observed [73.6 (95% CI: 62.6% - 84.6%) and 47.2 (95% CI: 22.2 – 72.3); p=0.2384 respectively]; however, these findings were not statistically significant.
There were no statistically significant differences between the sensitivities or specificities for any other subgroups including mean preoperative LVEF, imaging method for function recovery assessment, and length of follow-up.
There was no evidence available to determine whether patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy.
PMCID: PMC3426228  PMID: 23074392
6.  Disorders characterised by pain: a methodological review of population surveys. 
OBJECTIVE--To review a series of conceptual and methodological problems encountered in surveys primarily devoted to pain disorders. CRITERIA FOR INCLUSION AND EXCLUSION OF ARTICLES--Published reports were systematically collected by electronic database searches (Medline), citations in existing publications, and through personal contacts. Relevant articles from clinical and epidemiological research on pain were included and special attention was given to epidemiological research on back pain. CONCLUSIONS--Surveys of pain disorders should be based on a multidimensional pain model that includes nociceptive input, pain perception, suffering, and pain behaviour as major components. Because of the limited applicability of diagnostic procedures or genuine "non-specificity" of pain states, or both, epidemiological surveys may result in a considerable proportion of cases without an identifiable pathophysiological basis. Staging and grading procedures for pain disorders (as distinguished from classification) may comprise various aspects of pain perception: regional distribution, pain intensity, temporal characteristics, sensory qualities, and dimensions of cognitive-emotional appraisal. Description of temporal development and chronification (staging) should refer to different components of the multidimensional pain model. Explicit a posteriori procedures for grading are preferable to implicit grading based on question wording. Evidence from several sources suggests that localistic concepts of pain may be misleading. Identification of complex pain syndromes should be one primary target for epidemiological pain surveys. Of the many factors that may impair the reliability and validity of data collected in pain surveys, recall biases seem to deserve special attention.
PMCID: PMC1060027  PMID: 7830005
7.  Integrated oncogeriatric approach: a systematic review of the literature using concept analysis 
BMJ Open  2012;2(6):e001483.
Objectives
The purpose of this study was to provide a more precise definition of an integrated oncogeriatric approach (IOGA) through concept analysis.
Data sources
The literature was reviewed from January 2005 to April 2011 integrating three broad terms: geriatric oncology, multidisciplinarity and integrated care delivery models.
Study eligibility criteria
Citation selection was based on: (1) elderly cancer patients as the study population; (2) disease management and (3) case studies, intervention studies, assessments, evaluations and studies. Inclusion and exclusion criteria were refined in the course of the literature search.
Interventions
Initiatives in geriatric oncology that relate to oncology services, social support services and primary care services for elderly cancer patients.
Participants
Elderly cancer patients aged 70 years old or more.
Study appraisal and synthesis methods
Rodgers’ concept analysis method was used for this study. The analysis was carried out according to thematic analysis based on the elements of the Chronic Care Model.
Results
The search identified 618 citations. After in-depth appraisal of 327 potential citations, 62 articles that met our inclusion criteria were included in the analysis. Three IOGA main attributes were identified, which constitute IOGA's core aspects: geriatric assessment (GA), comorbidity burden and treatment outcomes. The IOGA concept comprises two broad antecedents: coordinated healthcare delivery and primary supportive care services. Regarding the consequents of an integrated approach in geriatric oncology, the studies reviewed remain inconclusive.
Conclusions
Our study highlights the pioneering character of the multidimensional IOGA concept, for which the relationship between clinical and organisational attributes, on the one hand, and contextual antecedents, on the other, is not well understood. We have yet to ascertain IOGA's consequents.
Implications of key findings
There is clearly a need for a whole-system approach to change that will provide direction for multilevel (clinical, organisational, strategic) interventions to support interdisciplinary practice, education and research.
doi:10.1136/bmjopen-2012-001483
PMCID: PMC3533132  PMID: 23220777
Oncology; Geriatric Medicine
8.  Multi-centred mixed-methods PEPFAR HIV care & support public health evaluation: study protocol 
BMC Public Health  2010;10:584.
Background
A public health response is essential to meet the multidimensional needs of patients and families affected by HIV disease in sub-Saharan Africa. In order to appraise curret provision of HIV care and support in East Africa, and to provide evidence-based direction to future care programming, and Public Health Evaluation was commissioned by the PEPFAR programme of the US Government.
Methods/Design
This paper described the 2-Phase international mixed methods study protocol utilising longitudinal outcome measurement, surveys, patient and family qualitative interviews and focus groups, staff qualitative interviews, health economics and document analysis.
Aim 1) To describe the nature and scope of HIV care and support in two African countries, including the types of facilities available, clients seen, and availability of specific components of care [Study Phase 1]. Aim 2) To determine patient health outcomes over time and principle cost drivers [Study Phase 2].
The study objectives are as follows. 1) To undertake a cross-sectional survey of service configuration and activity by sampling 10% of the facilities being funded by PEPFAR to provide HIV care and support in Kenya and Uganda (Phase 1) in order to describe care currently provided, including pharmacy drug reviews to determine availability and supply of essential drugs in HIV management. 2) To conduct patient focus group discussions at each of these (Phase 1) to determine care received. 3) To undertake a longitudinal prospective study of 1200 patients who are newly diagnosed with HIV or patients with HIV who present with a new problem attending PEPFAR care and support services. Data collection includes self-reported quality of life, core palliative outcomes and components of care received (Phase 2). 4) To conduct qualitative interviews with staff, patients and carers in order to explore and understand service issues and care provision in more depth (Phase 2). 5) To undertake document analysis to appraise the clinical care procedures at each facility (Phase 2). 6) To determine principle cost drivers including staff, overhead and laboratory costs (Phase 2).
Discussion
This novel mixed methods protocol will permit transparent presentation of subsequent dataset results publication, and offers a substantive model of protocol design to measure and integrate key activities and outcomes that underpin a public health approach to disease management in a low-income setting.
doi:10.1186/1471-2458-10-584
PMCID: PMC2955697  PMID: 20920241
9.  Enhanced morphological diagnosis in infective endocarditis by transoesophageal echocardiography. 
British Heart Journal  1990;63(2):109-113.
Thirty three consecutive patients with clinically suspected endocarditis were studied by both precordial cross sectional echocardiography and transoesophageal echocardiography. The diagnostic value of both techniques was assessed. The data were compared with findings at operation in 25 patients. In 21 patients with native valve endocarditis precordial echocardiography showed evidence of vegetations in six patients and suggested their presence in nine. Transoesophageal echocardiography identified vegetations in 18 patients. Complications were seen in four patients at precordial echocardiography and in nine patients at transoesophageal echocardiography. Precordial echocardiography did not show vegetations in any of the 12 patients with prosthetic valve endocarditis whereas transoesophageal echocardiography showed vegetations in four. Complications were seen in four patients at precordial echocardiography and in 10 at transoesophageal echocardiography. Echocardiographic findings were confirmed at operation in all 25 operated patients. In two patients both echocardiographic techniques had missed the perforation of the cusps of the aortic valve that was seen at operation, but this had no effect on patient management. Transoesophageal echocardiography is the best diagnostic approach when infective endocarditis is suspected in patients with either native or prosthetic valves.
Images
PMCID: PMC1024336  PMID: 2317403
10.  Assessment of myocardial perfusion and contractile function by inotropic stress Tc-99m sestamibi SPECT imaging and echocardiography for optimal detection of multivessel coronary artery disease 
Heart  1998;79(3):274-280.
Objective—To assess whether inotropic stress myocardial perfusion imaging, echocardiography, or a combination of the two could enhance the detection of multivessel disease, over and above clinical and exercise electrocardiographic data.
Design—100 consecutive patients investigated by exercise electrocardiography and diagnostic coronary arteriography underwent simultaneous inotropic stress Tc-99m sestamibi SPECT (MIBI) imaging and echocardiography. MIBI imaging and echocardiographic data were analysed using a 12 segment left ventricular model, and each segment was ascribed to a particular coronary artery territory. The presence of perfusion defects with MIBI imaging or of wall thickening abnormality with echocardiography in at least two coronary artery territories at peak stress was taken as diagnostic of multivessel disease. Arteriographic evidence of ⩾ 50% stenosis was considered significant.
Results—56 patients had multivessel disease. The sensitivity of the combination of MIBI imaging and echocardiography for detecting this was greater than either MIBI imaging or echocardiography alone (82%, 68%, and 68%, respectively; p = 0.005). Clinical and exercise electrocardiographic variables gave an R2 value of 18.2% for predicting multivessel disease. The addition of either MIBI imaging (R2 = 29.2%; p = 0.002) or echocardiography (R2 = 28.8%; p < 0.001) enhanced the detection of multivessel disease, and the inclusion of both had further incremental value (R2 = 34.8%; p = 0.003). Age (p = 0.03), MIBI imaging (p = 0.007), and echocardiography (p = 0.001) were independent predictors of multivessel disease.
Conclusions—The assessment of both myocardial perfusion and contractile function by simultaneous inotropic stress MIBI imaging and echocardiography optimises the non-invasive detection of multivessel disease.

 Keywords: multivessel disease;  inotropic stress;  SPECT imaging;  echocardiography
PMCID: PMC1728627  PMID: 9602662
11.  Additional diagnostic value of multiplane echocardiography over biplane imaging in assessment of mitral prosthetic valves. 
Heart  1996;75(6):609-613.
OBJECTIVE: To evaluate how often multiplane transoesophageal echocardiography yields new or complementary data in mitral prostheses in comparison with the exclusive use of biplane imaging. PATIENTS: 73 consecutive patients with mitral prostheses who underwent multiplane transoesophageal echocardiograpy between January 1993 and December 1994. METHODS: Biplane images (transverse and longitudinal planes) and multiplane images (transverse, longitudinal, and intermediate planes) were recorded on two separate videotapes. The data provided by multiplane transoesophageal echocardiography were evaluated as (a) new data (abnormalities missed by biplane imaging); (b) complementary data (better delineating lesions already visualised by biplane imaging); or (c) redundant data (data already provided by biplane imaging). RESULTS: Multiplane transoesophageal echocardiography revealed new abnormalities in seven patients (9.5%) (thrombi in three and paraprosthetic leaks in the remaining four) and complementary data in nine (12.3%). In patients with paraprosthetic regurgitation, the possibility of continuously visualising the sewing ring by means of sequential angulations allowed the circumferential extension of the leak to be measured. In seven patients with paravalvar regurgitation who underwent surgery, the extension of the leak as measured by the multiplane approach closely corresponded with the surgical data. CONCLUSIONS: In comparison with the exclusive use of biplane imaging, the multiplane approach added new or complementary data in a significant proportion of patients with mitral prostheses. The ability to obtain the sequential adjacent planes allowed a more reliable appraisal of the extension of the leak and other abnormalities.
Images
PMCID: PMC484386  PMID: 8697166
12.  A practical approach to goal-directed echocardiography in the critical care setting 
Critical Care  2014;18(6):681.
Urgent cardiac ultrasound examination in the critical care setting is clinically useful. Application of goal-directed echocardiography in this setting is quite distinct from typical exploratory diagnostic comprehensive echocardiography, because the urgent critical care setting mandates a goal-directed approach. Goal-directed echocardiography most frequently aims to rapidly identify and differentiate the cause(s) of hemodynamic instability and/or the cause(s) of acute respiratory failure. Accordingly, this paper highlights 1) indications, 2) an easily memorized differential diagnostic framework for goal-directed echocardiography, 3) clinical questions that must be asked and answered, 4) practical issues to allow optimal image capture, 5) primary echocardiographic views, 6) key issues addressed in each view, and 7) interpretation of findings within the differential diagnostic framework. The most frequent indications for goal-directed echocardiography include 1) the spectrum of hemodynamic instability, shock, and pulseless electrical activity arrest and 2) acute respiratory failure. The differential diagnostic categories for hemodynamic instability can be remembered using the mnemonic ‘SHOCK’ (for Septic, Hypovolemic, Obstructive, Cardiogenic, and (K) combinations/other kinds of shock). RESP-F (for exacerbation of chronic Respiratory disease, pulmonary Embolism, ST changes associated with cardiac or pericardial disease, Pneumonia, and heart Failure) can be used for acute respiratory failure. The goals of goal-directed echocardiography in the unstable patient are: assessing global ventricular systolic function, identifying marked right ventricular and left ventricular enlargement, assessing intravascular volume, and the presence of a pericardial effusion. In an urgent or emergent setting, it is recommended to go directly to the best view, which is frequently the subcostal or apical view. The five views are the subcostal four-chamber view, subcostal inferior vena cava view, parasternal long axis view, parasternal short axis view, and the apical four chamber view. Always interpret goal-directed echocardiographic findings in the context of clinically available hemodynamic information. When goal-directed echocardiography is insufficient or when additional abnormalities are appreciated, order a comprehensive echocardiogram. Goal-directed echocardiography and comprehensive echocardiography are not to be used in conflict with each other.
doi:10.1186/s13054-014-0681-z
PMCID: PMC4331439  PMID: 25672460
13.  ‘Honeycomb appearance’ on three-dimensional transthoracic echocardiography as the landmark of left ventricular non-compaction: two case reports 
Introduction
Left ventricular non-compaction is a rare congenital heart disease, and is most commonly diagnosed via two-dimensional echocardiography according to echocardiographic criteria. Recently, transthoracic three-dimensional echocardiography has become available in the clinical setting.
Case presentation
We present two isolated cases of left ventricular non-compaction from Japan (in an 84-year-old woman and 47-year-old man) that were confirmed by two-dimensional echocardiography, contrast-enhanced two-dimensional echocardiography, three-dimensional echocardiography and cardiac magnetic resonance imaging. In both cases, three-dimensional echocardiography successfully demonstrated the trabecular meshwork of the left ventricle, referred to as a ‘honeycomb appearance’.
Conclusions
Three-dimensional echocardiography has the advantage of visualizing an en-face view of the trabecular meshwork, which is not possible with two-dimensional echocardiography. We further emphasize the clinical utility of three-dimensional echocardiography, which is not limited to just the observation of the trabeculations and inter-trabecular recesses, but can also visualize the trabecular meshwork with a ‘honeycomb appearance’.
doi:10.1186/1752-1947-7-142
PMCID: PMC3673848  PMID: 23718567
Left ventricular non-compaction; Magnetic resonance imaging; Three-dimensional echocardiography
14.  Multiplane Transesophageal Echocardiography for Multiclinical Dilemmas 
Acta Informatica Medica  2011;19(3):138-141.
Introduction
Transesophageal echocardiography was introduced 4 decades ago. Its use have had very limited clinical indication. Now it has become very useful clinical tool. Indications for its use are almost as indications for transthoracic echocardiography, especially to assess deeper cardiovascular structures. Transesophageal echocardiography is semi-invasive examination with small number of complications.
Aim of the study
To determine usefulness of transesophageal echocardiography in various cardiac conditions based in our experience. Also to encourage use of transesophageal echocardiography as reliable examination.
Methods
All of the patients signed a Term of Free Informed Consent, approved from Ethics Committee. We enrolled 425 patients who have done TEE in last 5 years (2006-2010) by authors. Medical history and Clinical evaluation was carefully performed by expert cardiologists. Procedures were performed in two different centers using machines, PHILIPS iE33 and Siemens accuson CV 70, with equipment attached to a multi frequency 2.5 to 3.5 MHz for TTE and 7.0 MHz for TEE multiplane transducer. TEE were performed and images were obtained according to the standard recommandations.
Results
The results were analyzed by a standard method of descriptive statistics using Pivot Table of Excel Office 2007. Results. We have analyzed 425 transesophageal echocardiography . The examination of the thoracic aorta in severe hypertension patients was conducted in 96 cases; atrial fibrillation in 118; aortic dissection 49 cases, aortic stenosis was evaluated in 28 cases; finding of source of emboli 36 cases; suspicion for aneurysm of the thoracic aorta in 14 cases, 11 cases with suspected endocarditis; the type of intervention for mitral valve was evaluated in 28 cases. Interatrial septum abnormalities 37 cases; and miscellaneous 18 cases. No minor or mayor complications happened.
Conlusion
Transesophageal echocardiography can elucidate many dubious serious conditions immediately after it is performed. So, we think that transesophageal echocardiography is very useful tool in everyday clinical use, almost without complications if it is done correctly.
doi:10.5455/aim.2011.19.138-141
PMCID: PMC3570941  PMID: 23408794
transesophageal echocardiography; transthoracic echocardiography; echocardiography.
15.  Comparison of echocardiographic measurements of left ventricular volumes to full volume magnetic resonance imaging in normal and diseased rats 
Background
Clinical two-dimensional (2D) and clinical three-dimensional (3D) echocardiography are validated against Cardiac Magnetic Resonance imaging (CMR), the gold standard for left ventricle (LV) volumes. In rodents, there is no widely accepted echocardiographic measure of whole LV volumes, and CMR measurements vary between studies. We compared LV volumes by 2D-echocardiography (hemisphere-cylinder (HC) model) to HC and full-volume (FV) CMR in normal and diseased rats to measure the impact of geometric models and imaging modalities.
Methods
Rats (n=27) underwent ascending aortic banding, myocardial infarction induction by either permanent left anterior descending artery (LAD) ligation or ischemia-reperfusion, and sham thoracotomy. Subsequently, we measured end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) using a HC-2D-echocardiography model combining parasternal short-axis and long-axis measurements and compared these to HC and FV-CMR.
Results
Diseased groups showed LV dilatation and dysfunction. HC-echocardiography and FV-CMR measures of EDV, ESV and EF were correlated. On Bland-Altman plots, EDV were concordant between both methods while HC-echocardiography underestimated ESV, resulting in a modest overestimation of EF versus FV-CMR. Other 2D-echocardiographic geometric models offered less concordance with FV-CMR than HC. HC-CMR overestimates LV volumes versus FV-CMR, while HC-echocardiography underestimates HC-CMR volumes. Echocardiography underestimates corresponding LV dimensions by CMR, particularly short-axis.
Conclusions
Concordant measures of LV volume and function were obtained using: (1) a relatively simple HC model of the LV inclusive of two orthogonal 2D-echocardiographic planes, and (2) FV-CMR in normal and diseased rats. The HC model appears to compensate the underestimation of LV dimensions by echocardiography.
doi:10.1016/j.echo.2013.04.016
PMCID: PMC3725209  PMID: 23706342
Echocardiography; magnetic resonance imaging; rat; animal ultrasound; animal models of disease
16.  Stress Echocardiography for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas"> www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of the analysis is to determine the diagnostic accuracy of stress echocardiography (ECHO) in the diagnosis of patients with suspected coronary artery disease (CAD) compared to coronary angiography (CA).
Stress Echocardiography
Stress ECHO is a non-invasive technology that images the heart using ultrasound. It is one of the most commonly employed imaging techniques for investigating a variety of cardiac abnormalities in both community and hospital settings. A complete ECHO exam includes M-mode, 2-dimensional (2-D) images and Doppler imaging.
In order to diagnosis CAD and assess whether myocardial ischemia is present, images obtained at rest are compared to those obtained during or immediately after stress. The most commonly used agents used to induce stress are exercise and pharmacological agents such as dobutamine and dipyridamole. The hallmark of stress-induced myocardial ischemia is worsening of wall motion abnormalities or the development of new wall motion abnormalities. A major challenge for stress ECHO is that the interpretation of wall motion contractility and function is subjective. This leads to inter-observer variability and reduced reproducibility. Further, it is estimated that approximately 30% of patients have sub-optimal stress ECHO exams. To overcome this limitation, contrast agents for LV opacification have been developed.
Although stress ECHO is a relatively easy to use technology that poses only a low risk of adverse events compared to other imaging technologies, it may potentially be overused and/or misused in CAD diagnosis. Several recent advances have been made focusing on quantitative methods for assessment, improved image quality and enhanced portability, however, evidence on the effectiveness and clinical utility of these enhancements is limited.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of stress ECHO for the diagnosis of patients with suspected CAD compared to the reference standard of CA?
What is the clinical utility1 of stress ECHO?
Literature Search
A literature search was performed on August 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until August 21, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search.
Inclusion Criteria
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, retrospective analyses
Minimum sample size of 20 enrolled patients
Comparison to CA (reference standard)
Definition of CAD specified as either ≥50%, ≥70% or ≥75% coronary artery stenosis on CA
Reporting accuracy data on individual patients (rather than accuracy data stratified by segments of the heart)
English
Human
Exclusion Criteria
Duplicate studies
Non-systematic reviews, case reports
Grey literature (e.g., conference abstracts)
Insufficient data for independent calculation of sensitivity and specificity
Use of ECHO for purposes other than diagnosis of CAD (e.g., arrhythmia, valvular disease, mitral stenosis, pre-operative risk of MI)
Transesophageal ECHO since its primary use is for non-CAD indications such as endocarditis, intracardiac thrombi, valvular disorders
Only resting ECHO performed
Outcomes of Interest
Accuracy outcomes (sensitivity, specificity, positive predictive value, negative predictive value)
Costs
Summary of Findings
Given the vast amount of published literature on stress ECHO, it was decided to focus on the studies contained in the comprehensive 2007 review by Heijenbrok-Kal et al. (1) as a basis for the MAS evidence-based analysis. In applying our inclusion and exclusion criteria, 105 observational studies containing information on 13,035 patients were included. Six studies examined stress ECHO with adenosine, 26 with dipyridamole and 77 with dobutamine, the latter being the most commonly used pharmacological stress ECHO agent in Ontario. A further 18 studies employed exercise as the stressor.2 The prevalence of CAD ranged from 19% to 94% with a mean estimated prevalence of 70%. Based on the results of these studies the following conclusions were made:
Based on the available evidence, stress ECHO is a useful imaging modality for the diagnosis of CAD in patients with suspected disease. The overall pooled sensitivity is 0.80 (95% CI: 0.77 – 0.82) and the pooled specificity is 0.84 (95% CI: 0.82 – 0.87) using CA as the reference standard. The AUC derived from the sROC curve is 0.895 and the DOR is 20.64.
For pharmacological stress, the pooled sensitivity is 0.79 (95% CI: 0.71 – 0.87) and the pooled specificity is 0.85 (95% CI: 0.83 – 0.88). When exercise is employed as the stress agent, the pooled sensitivity is 0.81 (95% CI: 0.76– 0.86) and the pooled specificity is 0.79 (95% CI: 0.71 – 0.87). Although pharmacological stress and exercise stress would be indicated for different patient populations based on ability to exercise there were no significant differences in sensitivity and specificity.
Based on clinical experts, diagnostic accuracy on stress ECHO depends on the patient population, the expertise of the interpreter and the quality of the image.
PMCID: PMC3377563  PMID: 23074412
17.  Assessing Patient Attitudes to Computerized Screening in Primary Care: Psychometric Properties of the Computerized Lifestyle Assessment Scale 
Background
Computer-based health-risk assessments are electronic surveys which can be completed by patients privately, for example during their waiting time in a clinic, generating a risk report for the clinician and a recommendation sheet for the patient at the point of care. Despite increasing popularity of such computer-based health-risk assessments, patient attitudes toward such tools are rarely evaluated by reliable and valid scales. The lack of psychometric appraisal of appropriate scales is an obstacle to advancing the field.
Objective
This study evaluated the psychometric properties of a 14-item Computerized Lifestyle Assessment Scale (CLAS).
Methods
Out of 212 female patients receiving the study information at a family practice clinic, 202 completed a paper questionnaire, for a response rate of 97.6%. After 2 weeks, 52 patients completed the scale a second time.
Results
Principal component analysis revealed that CLAS is a multidimensional scale consisting of four subscales (factors): (1) Benefits: patient-perceived benefits toward the quality of medical consultation and means of achieving them, (2) Privacy-Barrier: concerns about information privacy, (3) Interaction-Barrier: concerns about potential interference in their interaction with the physician, and (4) Interest: patient interest in computer-assisted health assessments. Each subscale had good internal consistency reliability ranging from .50 (2-item scale) to .85 (6-item scale). The study also provided evidence of scale stability over time with intraclass correlation coefficients of .91, .82, .86, and .67 for the four subscales, respectively. Construct validity was supported by concurrent hypotheses testing.
Conclusions
The CLAS is a promising approach for evaluating patients’ attitudes toward computer-based health-risk assessments.
doi:10.2196/jmir.955
PMCID: PMC2483923  PMID: 18440918
Computers; scale; psychometric; screening; risk assessment; family practice
18.  Distinct Brain Systems Mediate the Effects of Nociceptive Input and Self-Regulation on Pain 
PLoS Biology  2015;13(1):e1002036.
Two distinct parallel neural systems independently contribute to our overall experience of pain – separately modulated by noxious input and by cognitive self-regulation.
Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.
Author Summary
Does cognitive self-regulation influence pain experience by affecting the primary representations of painful (nociceptive) stimuli in the brain? Or does it regulate reported pain via a neural pathway that is distinct from the one that mediates nociceptive pain? The present study demonstrates that nociceptive and cognitive manipulations of pain influence two distinct, separable neural systems, which operate together to construct the pain experience. The neurologic pain signature (NPS) mediates the effects of noxious input, whereas a fronto-striatal pathway connecting nucleus accumbens and ventromedial prefrontal cortex mediates the effects of cognitive self-regulation of pain. These findings help move the field beyond the “one system” view of pain as a primarily nociceptive process, and provide a foundation for new approaches to multidimensional pain assessment and treatment.
doi:10.1371/journal.pbio.1002036
PMCID: PMC4285399  PMID: 25562688
19.  History of echocardiography in the Netherlands: 30 years of education and clinical applications 
Netherlands Heart Journal  2008;16(1):16-20.
The development of ultrasound has created great opportunities for diagnostic cardiac imaging. For more than 30 years, echocardiography has been the most important and cost-effective diagnostic imaging modality in clinical cardiology. Many developments originated in the Netherlands, including the very first practical real-time crosssectional imaging of the moving heart with a linear array. Milestones include the first portable echo apparatus, early versions of echo catheters and transoesophageal echocardiography probes as well as many clinical ‘firsts’ with reference to the more than 100 Dutch dissertations related to echocardiography. The future of echocardiography promises to be as productive and exciting as it has been in the previous three decades, including threedimensional echocardiography, myocardial perfusion echocardiography, tissue Doppler imaging and speckle tracking. New potential therapeutic applications are upcoming. In this article, the advances of echocardiography in the Netherlands are described, in the past and during 30 years of education, as was recently presented by three Dutch pioneers during the ‘Echomiddagen 2006-2007’ organised by the CVOI. (Neth Heart J 2008;16:16-20.18317539)
PMCID: PMC2246311  PMID: 18317539
history; cardiac ultrasound; echocardiography; Doppler; Buys Ballot
20.  Development and Validation of a New Multidimensional Measure of Inspiration: Associations with Risk for Bipolar Disorder 
PLoS ONE  2014;9(3):e91669.
Background
Individuals at risk for, and diagnosed with, bipolar disorder (BD) appear to have heightened levels of creativity. Although inspiration is creativity, the ways in which individuals appraise and respond emotionally to inspiration in BD remain unexplored.
Method
The present study reports on a new measure of inspiration (External and Internal Sources of Inspiration Scale - EISI). The reliability and validity of EISI were explored along with associations between EISI and BD risk.
Results
Among a cross-national student sample (N = 708) 5 inspiration factors were derived from EISI (self, other, achievement, prosocial and external inspiration). Reliability, concurrent validity and convergent/divergent validity were good. Total EISI and all subscales were associated with increased positive rumination, and total EISI and the achievement EISI subscale were associated with impulsivity. Total EISI, self and prosocial EISI subscales were independently associated with BD risk and current mania symptoms.
Conclusion
This new measure of inspiration is multidimensional, reliable and valid. Findings suggest that self and prosocial focused inspiration are particularly associated with risk for BD after controlling for current manic symptoms. Future studies in clinical populations may illuminate the relationships between inspiration and creativity in BD.
doi:10.1371/journal.pone.0091669
PMCID: PMC3966762  PMID: 24670894
21.  Development and evaluation of a cancer-related fatigue patient education program: protocol of a randomized controlled trial 
BMC Nursing  2008;7:12.
Background
Cancer-related fatigue (CRF) and its impact on patients' quality of life has been an increasing subject of research. However, in Germany there is a lack of evidence-based interventions consistent with the multidimensional character of fatigue. The objective of this study is to develop and evaluate a self-management program for disease-free cancer patients to cope with CRF.
Methods
Based on evidence extracted from a literature review, a curriculum for the self-management program was elaborated. The curriculum was reviewed and validated by an interdisciplinary expert group and the training-modules will be pretested with a small number of participants and discussed in terms of feasibility and acceptance.
To determine the efficacy of the program a randomised controlled trial will be carried out: 300 patients will be recruited from oncological practices in Bremen, Germany, and will be allocated to intervention or control group. The intervention group participates in the program, whereas the control group receives standard care and the opportunity to take part in the program after the end of the follow-up (waiting control group). Primary outcome measure is the level of fatigue, secondary outcome measures are quality of life, depression, anxiety, self-efficacy and physical activity. Data will be collected before randomisation, after intervention, and after a follow-up of 6 months.
Discussion
Because there are no comparable self-management programs for cancer survivors with fatigue, the development of the curriculum has been complex; therefore, the critical appraisal by the experts was an important step to validate the program and their contributions have been integrated into the curriculum. The experts appreciated the program as filling a gap in outpatient cancer care.
If the results of the evaluation prove to be satisfactory, the outpatient care of cancer patients can be broadened and supplemented.
Trial Registration
ClinicalTrials NCT00552552
doi:10.1186/1472-6955-7-12
PMCID: PMC2491613  PMID: 18651943
22.  Computer supported collaborative learning in a clerkship: an exploratory study on the relation of discussion activity and revision of critical appraisal papers 
BMC Medical Education  2012;12:79.
Background
Medical students in clerkship are continuously confronted with real and relevant patient problems. To support clinical problem solving skills, students perform a Critical Appraisal of a Topic (CAT) task, often resulting in a paper. Because such a paper may contain errors, students could profit from discussion with peers, leading to paper revision. Active peer discussion by a Computer Supported Collaborative Learning (CSCL) environment show positive medical students perceptions on subjective knowledge improvement. High students’ activity during discussions in a CSCL environment demonstrated higher task-focussed discussion reflecting higher levels of knowledge construction. However, it remains unclear whether high discussion activity influences students’ decisions revise their CAT paper. The aim of this research is to examine whether students who revise their critical appraisal papers after discussion in a CSCL environment show more task-focussed activity and discuss more intensively on critical appraisal topics than students who do not revise their papers.
Methods
Forty-seven medical students, stratified in subgroups, participated in a structured asynchronous online discussion of individual written CAT papers on self-selected clinical problems. The discussion was structured by three critical appraisal topics. After the discussion, the students could revise their paper. For analysis purposes, all students’ postings were blinded and analysed by the investigator, unaware of students characteristics and whether or not the paper was revised. Postings were counted and analysed by an independent rater, Postings were assigned into outside activity, non-task-focussed activity or task-focussed activity. Additionally, postings were assigned to one of the three critical appraisal topics. Analysis results were compared by revised and unrevised papers.
Results
Twenty-four papers (51.6%) were revised after the online discussion. The discussions of the revised papers showed significantly higher numbers of postings, more task-focussed activities, and more postings about the two critical appraisal topics: “appraisal of the selected article(s)”, and “relevant conclusion regarding the clinical problem”.
Conclusion
A CSCL environment can support medical students in the execution and critical appraisal of authentic tasks in the clinical workplace. Revision of CAT papers appears to be related to discussions activity, more specifically reflecting high task-focussed activity of critical appraisal topics.
doi:10.1186/1472-6920-12-79
PMCID: PMC3507639  PMID: 22906218
23.  Head to head comparison of 2D vs real time 3D dipyridamole stress echocardiography 
Real-time three-dimensional (RT-3D) echocardiography has entered the clinical practice but true incremental value over standard two-dimensional echocardiography (2D) remains uncertain when applied to stress echo. The aim of the present study is to establish the additional value of RT-3D stress echo over standard 2D stress echocardiography. We evaluated 23 consecutive patients (age = 65 ± 10 years, 16 men) referred for dipyridamole stress echocardiography with Sonos 7500 (Philips Medical Systems, Palo, Alto, CA) equipped with a phased – array 1.6–2.5 MHz probe with second harmonic capability for 2D imaging and a 2–4 MHz matrix-phased array transducer producing 60 × 70 volumetric pyramidal data containing the entire left ventricle for RT-3D imaging. In all patients, images were digitally stored in 2D and 3D for baseline and peak stress with a delay between acquisitions of less than 60 seconds. Wall motion analysis was interpreted on-line for 2D and off-line for RT-3D by joint reading of two expert stress ecocardiographist. Segmental image quality was scored from 1 = excellent to 5 = uninterpretable. Interpretable images were obtained in all patients. Acquisition time for 2D images was 67 ± 21 sec vs 40 ± 22 sec for RT-3D (p = 0.5). Wall motion analysis time was 2.8 ± 0.5 min for 2D and 13 ± 7 min for 3D (p = 0.0001). Segmental image quality score was 1.4 ± 0.5 for 2D and 2.6 ± 0.7 for 3D (p = 0.0001). Positive test results was found in 5/23 patients. 2D and RT-3D were in agreement in 3 out of these 5 positive exams. Overall stress result (positive vs negative) concordance was 91% (Kappa = 0.80) between 2D and RT-3D. During dipyridamole stress echocardiography RT-3D imaging is highly feasible and shows a high concordance rate with standard 2D stress echo. 2D images take longer time to acquire and RT-3D is more time-consuming to analyze. At present, there is no clear clinical advantage justifying routine RT-3D stress echocardiography use.
doi:10.1186/1476-7120-6-31
PMCID: PMC2474587  PMID: 18570640
24.  Echocardiography or auscultation? How to evaluate systolic murmurs. 
Canadian Family Physician  2003;49:163-167.
OBJECTIVE: To compare cardiac physical examination with echocardiography for evaluating systolic murmurs. QUALITY OF EVIDENCE: Three databases were searched for studies comparing echocardiography and auscultation as to sensitivity and diagnostic accuracy: MEDLINE (Ovid Online), EMBASE, and Current Contexts. The quality of reported data is lowered by subjective interpretation of results of both cardiac physical examination and echocardiography, especially Doppler colour flow imaging. MAIN MESSAGE: In adults, functional systolic murmurs can usually be distinguished from organic murmurs. Pathologic murmurs frequently have one or more associated clinical abnormalities. If a clinician determines a murmur is benign, results of echocardiography are very likely to be normal, especially in young and middle-aged adults. According to current guidelines, echocardiography should not be ordered for "innocent" systolic murmurs in patients who are asymptomatic and have otherwise normal findings on examination. If patients with functional systolic murmurs could be identified and not routinely referred for echocardiography, great cost savings could be realized. CONCLUSION: Echocardiography is not required for all patients with systolic murmurs and should not replace cardiac physical examination.
PMCID: PMC2214179  PMID: 12619738
25.  A Primer on the Methods and Applications for Contrast Echocardiography in Clinical Imaging 
Contrast echocardiography is broadly described as a variety of techniques whereby the blood pool on cardiac ultrasound is enhanced with encapsulated gas-filled microbubbles or other acoustically active nano- or microparticles. The development of this technology has occurred primarily in response to the need improve current diagnostic applications of echocardiography such as the need to better define left ventricular cavity volumes, regional wall motion, or the presence or absence of masses and thrombi. A secondary reason for the development of contrast echocardiography has been to expand the capabilities of echocardiography. These new applications include myocardial perfusion imaging for detection of ischemia and viability, perfusion imaging of masses/tumors, and molecular imaging. The ability to fill all of these current and future clinical roles has been predicated on the ability to produce robust contrast signal which, in turn, has relied on technical innovation with regards to the microbubble contrast agents and the ultrasound imaging paradigms. In this review, we will discuss the basics of contrast echocardiography including the composition of microbubble contrast agents, the unique imaging methods used to optimize contrast signal-to-noise ratio, and the clinical applications of contrast echocardiography that have made a clinical impact.
doi:10.4250/jcu.2014.22.3.101
PMCID: PMC4192406  PMID: 25309685
Microbubbles; Left ventricular opacification; Myocardial contrast echocardiography

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