Beyond Stroke Prevention in Atrial Fibrillation: Exploring Further Unmet Needs with Rivaroxaban.

With improved life expectancy and the aging population, the global burden of atrial fibrillation (AF) continues to increase, and with AF comes an estimated fivefold increased risk of ischaemic stroke. Prophylactic anticoagulant therapy is more effective in reducing the risk of ischaemic stroke in AF patients than acetylsalicylic acid or dual-antiplatelet therapy combining ASA with clopidogrel. Non-vitamin K antagonist oral anticoagulants are the standard of care for stroke prevention in patients with non-valvular AF. The optimal anticoagulant strategy to prevent thromboembolism in AF patients who are undergoing percutaneous coronary intervention and stenting, those who have undergone successful transcatheter aortic valve replacement and those with embolic stroke of undetermined source are areas of ongoing research. This article provides an update on three randomized controlled trials of rivaroxaban, a direct, oral factor Xa inhibitor, that are complete or are ongoing, in these unmet areas of stroke prevention: oPen-label, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in patients with Atrial Fibrillation who undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial; the New Approach riVaroxaban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial and the Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO) trial. The data from these studies are anticipated to help address continuing challenges for a range of patients at risk of stroke.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Randomized Trial of Primary PCI with or without RoutineManual Thrombectomy

During primary percutaneous coronary intervention (PCI), manual thrombectomymay reduce distal embolization and thus improve microvascular perfusion. Smalltrials have suggested that thrombectomy improves surrogate and clinical outcomes,but a larger trial has reported conflicting results.MethodsWe randomly assigned 10,732 patients with ST-segment elevation myocardial infarction(STEMI) undergoing primary PCI to a strategy of routine upfront manualthrombectomy versus PCI alone. The primary outcome was a composite of deathfrom cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, orNew York Heart Association (NYHA) class IV heart failure within 180 days. The keysafety outcome was stroke within 30 days.ResultsThe primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomygroup versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in thethrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.86). Therates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone;hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.34) and the primary outcome plusstent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio,1.00; 95% CI, 0.89 to 1.14; P = 0.95) were also similar. Stroke within 30 days occurredin 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%)in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P = 0.02).ConclusionsIn patients with STEMI who were undergoing primary PCI, routine manual thrombectomy,as compared with PCI alone, did not reduce the risk of cardiovasculardeath, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heartfailure within 180 days but was associated with an increased rate of stroke within30 days. (Funded by Medtronic and the Canadian Institutes of Health Research;TOTAL ClinicalTrials.gov number, NCT01149044.

Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits.

BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.

Temporal trends in the use of invasive cardiac procedures for non-ST segment elevation acute coronary syndromes according to initial risk stratification.

BACKGROUND: Current guidelines support an early invasive strategy in the management of high-risk non-ST elevation acute coronary syndromes (NSTE-ACS). Although studies in the 1990s suggested that highrisk patients received less aggressive treatment, there are limited data on the contemporary management patterns of NSTE-ACS in Canada. OBJECTIVE: To examine the in-hospital use of coronary angiography and revascularization in relation to risk among less selected patients with NSTE-ACS. METHODS: Data from the prospective, multicentre Global Registry of Acute Coronary Events (main GRACE and expanded GRACE2) were used. Between June 1999 and September 2007, 7131 patients from across Canada with a final diagnosis of NSTE-ACS were included the study. The study population was stratified into low-, intermediate- and high-risk groups, based on their calculated GRACE risk score (a validated predictor of in-hospital mortality) and according to time of enrollment. RESULTS: While rates of in-hospital death and reinfarction were significantly (P<0.001) greater in higher-risk patients, the in-hospital use of cardiac catheterization in low- (64.7%), intermediate- (60.3%) and highrisk (42.3%) patients showed an inverse relationship (P<0.001). This trend persisted despite the increase in the overall rates of cardiac catheterization over time (47.9% in 1999 to 2003 versus 51.6% in 2004 to 2005 versus 63.8% in 2006 to 2007; P<0.001). After adjusting for confounders, intermediate-risk (adjusted OR 0.80 [95% CI 0.70 to 0.92], P=0.002) and high-risk (adjusted OR 0.38 [95% CI 0.29 to 0.48], P<0.001) patients remained less likely to undergo in-hospital cardiac catheterization. CONCLUSION: Despite the temporal increase in the use of invasive cardiac procedures, they remain paradoxically targeted toward low-risk patients with NSTE-ACS in contemporary practice. This treatment-risk paradox needs to be further addressed to maximize the benefits of invasive therapies in Canada.

Evaluation of attitudes and perceptions of key clinical stakeholders regarding out-of-hospital diagnosis and treatment of ST elevation myocardial infarction patients using a region-wide survey.

INTRODUCTION: In ST elevation myocardial infarction (STEMI), prehospital management (PHM) may improve clinical outcomes through a reduction in reperfusion delay. The purpose of this study was to evaluate perceptions among healthcare stakeholder groups relating to the barriers and facilitators of implementing a PHM programme. METHODS: A 25-question cross-sectional survey, using a four-point Likert scale assessing barriers and facilitators of PHM, was distributed to paramedics, cardiologists, emergency physicians and emergency nurses within the Edmonton region, where prehospital STEMI treatment is established. The proportion of responses on each question was compared and differences between groups were determined using chi(2) and Fisher's exact tests. RESULTS: 57% (355/619) of subjects responded: 69% paramedics, 50% cardiologists, 54% emergency physicians and 45% emergency nurses. A majority believed PHM reduced treatment delays in both rural (96-100%) and urban (86-96%) areas, while decreasing patient mortality (paramedics 97%, cardiologists 74%, emergency physicians 85%, emergency nurses 88%). Regarding the capability of paramedics to deliver PHM, paramedics 25%, cardiologists 33%, emergency physicians 67%, and emergency nurses 47% stated that urban paramedics are better equipped and trained than rural paramedics. Although 81% of paramedics supported the possibility of PHM delivery without physician overview, 0% of cardiologists, 98% of emergency physicians and 95% emergency nurses agreed. A majority (71-88%) favoured mandatory signed informed consent. CONCLUSIONS: While stakeholders agreed on the benefits of PHM, perceptual differences existed on paramedics' ability to deliver PHM without physician overview. Addressing real and perceived barriers through communication and educational programmes may enhance PHM within this healthcare region and facilitate the implementation of PHM programmes.

Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: a prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain.

PURPOSE: To investigate whether apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues in neuropsychiatric systemic lupus erythematosus (NPSLE) patients differ from those of healthy controls. MATERIAL AND METHODS: Eight NPSLE patients (aged 23-55 years, mean 42.9 years) and 20 healthy age-matched controls (aged 22-59 years, mean 44.4 years) underwent conventional brain magnetic resonance (MR) and diffusion tensor imaging (DTI). The ADC, FA, principal eigenvalue (lambda parallel), and the corresponding average perpendicular eigenvalue (lambda perpendicular) (=(lambda2+lambda3)/2) were measured in selected regions of normal appearing gray and white matter brain parenchyma. For statistical evaluation of differences between the two groups, a Student's t-test was used. The P value for statistical significance was set to P=0.0025 after Bonferroni correction for multiple measurements. RESULTS: Significantly increased ADC values were demonstrated in normal-appearing areas in the insular cortex (P<0.001), thalamus (P<0.001), and the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients. Significantly decreased FA values were demonstrated in normal-appearing thalamus (P<0.001), corpus callosum (P=0.002), and in the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients compared to healthy controls. The lambda perpendicular was significantly higher in several of these regions in NPSLE patients compared to healthy controls. CONCLUSION: Our study demonstrates alterations in normal-appearing gray and white matter brain parenchyma of patients with NPSLE by means of abnormal ADC, FA, and eigenvalues. These alterations may be based on loss of tissue integrity in part due to demyelination. It is possible that DTI in the future could assist in the diagnosis of NPSLE and possibly help to further elucidate the pathogenesis of NPSLE.

Time to treatment and the impact of a physician on prehospital management of acute ST elevation myocardial infarction: insights from the ASSENT-3 PLUS trial.

OBJECTIVES: To assess the impact of variation in prehospital care across distinct health care environments in ASSENT (assessment of the safety and efficacy of a new thrombolytic) -3 PLUS, a large (n = 1639) contemporary multicentred international trial of prehospital fibrinolysis. Specifically, the objectives were to assess predictors of time to treatment, whether components of time to treatment vary across countries, and the impact of physician presence before hospitalisation on time to treatment, adherence to protocol, and clinical events. METHODS: Patient characteristics associated with early treatment (< or = 2 hours), comparison of international variation in time to treatment, and components of delay were assessed. Trial specific patient data were linked with site specific survey responses. RESULTS: Younger age, slower heart rate, lower systolic blood pressure, and prior percutaneous coronary intervention were associated with early treatment. Country of origin accounted for the largest proportion of variation in time. Intercountry heterogeneity was shown in components of elapsed time to treatment. Physicians in the prehospital setting enrolled 63.8% of patients. The presence of a physician was associated with greater adherence to protocol mandated treatments and procedures but with delay in time to treatment (120 v 108 minutes, p < 0.001). CONCLUSION: Country of enrollment accounted for the largest proportion of variation in time to treatment and intercountry heterogeneity modulated components of delay. The effectiveness and safety of prehospital fibrinolysis was not influenced by the presence of a physician. These data, acquired in diverse health care environments, provide new understanding into the components of prehospital treatment delay and the opportunities to further reduce time to fibrinolysis for patients with ST elevation myocardial infarction.

Biochemical changes as a result of prolonged strenuous exercise.

OBJECTIVE: To briefly review biochemical changes that may result from prolonged strenuous exercise and to relate these changes to health risk. METHODS: Medline and Sports Discus databases were searched for relevant articles. Additional articles were found using cross referencing and the authors' knowledge of the subject area. RESULTS: Prolonged strenuous exercise may result in a series of biochemical changes that are of concern from a health point of view. Generally, these changes are benign, but some, especially hyponatraemia, are potentially life threatening occurrences. CONCLUSION: Doctors and athletes should be aware of the potentially adverse biochemical changes, especially hyponatraemia, that may result from prolonged strenuous exercise.

Cranial nerve clock. Part II: functional MR imaging of brain activation during a declarative memory task.

RATIONALE AND OBJECTIVES: The authors performed this study to assess brain activation during encoding and successful recall with a declarative memory paradigm that has previously been demonstrated to be effective for teaching students about the cranial nerves. MATERIALS AND METHODS: Twenty-four students underwent functional magnetic resonance (MR) imaging during encoding and recall of the name, number, and function of the 12 cranial nerves. The students viewed mnemonic graphic and text slides related to individual nerves, as well as their respective control slides. For the recall paradigm, students were prompted with the numbers 1-12 (test condition) intermixed with the number 14 (control condition). Subjects were tested about their knowledge of cranial nerves outside the MR unit before and after functional MR imaging. RESULTS: Students learned about the cranial nerves while undergoing functional MR imaging (mean post- vs preparadigm score, 8.1 +/- 3.4 [of a possible 12] vs 0.75 +/- 0.94, bilateral prefrontal cortex, left greater than right; P < 2.0 x 10(-12)) and maintained this knowledge at I week. The encoding and recall paradigms elicited distributed networks of brain activation. Encoding revealed statistically significant activation in the bilateral prefrontal cortex, left greater than right [corrected]; bilateral occipital and parietal associative cortices, parahippocampus region, fusiform gyri, and cerebellum. Successful recall activated the left much more than the right prefrontal, parietal associative, and anterior cingulate cortices; bilateral precuneus and cerebellum; and right more than the left posterior cingulate. CONCLUSION: A predictable pattern of brain activation at functional MR imaging accompanies the encoding and successful recall of the cranial nerves with this declarative memory paradigm.

Effects of half ironman competition on the development of late potentials.

OBJECTIVES: The primary purpose was to evaluate the prevalence of late potentials (LPs) in triathletes before and after a half ironman triathlon. The secondary purpose was to examine whether LPs are the electrocardiographic expression of a greater myocardial mass. METHODS: Nine asymptomatic male triathletes (mean age +/- SD, 32 +/- 5 yr) were examined using signal-averaged ECG (SAECG) 48-72 h before (PRE), immediately after (POST), and 24-48 h after the completion (RECOVERY) of a half ironman triathlon. Late potentials were considered to be present if two of the following SAECG anomalies were observed: 1) a prolonged filtered QRS (/QRS) complex (> or = 114 ms), 2) a lengthened low amplitude signal (LAS) duration (>38 ms), and/or 3) a low root mean square (RMS) voltage of the last 40 ms of the fQRS (<20 microV). Left ventricular dimensions were determined at PRE using M-mode echocardiography. RESULTS: There were no significant differences between PRE, POST, and RECOVERY in the fQRS duration, the LAS duration, or the RMS voltage. Two athletes displayed a single SAECG abnormality during PRE and two SAECG anomalies (i.e., LPs) during POST. Late potentials remained in one of the two athletes during RECOVERY. A moderate relationship existed between fQRS and left ventricular mass (r = 0.67, P < 0.05). CONCLUSIONS: Ultra-endurance training and/or events do not lead to LPs in the majority of triathletes who do not possess ventricular arrhythmias. However, a small subset of triathletes do display SAECG anomalies, which are augmented by an ultra-endurance event and may persist even after recovery from the event. Left ventricular mass does not affect overall SAECG parameters.

An unusual case of ST elevation in a 39-year-old man.

A 39-year-old man presented to a university hospital emergency department with anginal chest pain, ventricular tachycardia and ST elevation in the anterolateral leads (V3 to V6, I and aVL). Due to discrepancies in the history and physical examination, thrombolysis was withheld until a past electrocardiogram could be obtained, which was unchanged. Subsequent investigations revealed no evidence of myocardial necrosis, and the patient was diagnosed with hypertrophic cardiomyopathy. This is the first reported case of hypertrophic cardiomyopathy with ST elevation as the predominant electrocardiographic abnormality. In patients with discrepancies in the clinical presentation, it is essential to obtain past elecrocardiograms to ensure appropriate utility of thrombolysis.

Distribution and dynamics of laser-polarized (129)Xe magnetization in vivo.

The first magnetic resonance imaging studies of laser-polarized (129)Xe, dissolved in the blood and tissue of the lungs and the heart of Sprague-Dawley rats, are described. (129)Xe resonances at 0, 192, 199, and 210 ppm were observed and assigned to xenon in gas, fat, tissue, and blood, respectively. One-dimensional chemical-shift imaging (CSI) reveals xenon magnetization in the brain, kidney, and lungs. Coronal and axial two-dimensional CSI show (129)Xe dissolved in blood and tissue in the thorax. Images of the blood resonance show xenon in the lungs and the heart ventricle. Images of the tissue resonance reveal xenon in lung parenchyma and myocardium. The (129)Xe spectrum from a voxel located in the heart ventricle shows a single blood resonance. Time-resolved spectroscopy shows that the dynamics of the blood resonance match the dynamics of the gas resonance and demonstrates efficient diffusion of xenon gas to the lung parenchyma and then to pulmonary blood. These observations demonstrate the utility of laser-polarized (129)Xe to detect exchange across the gas-blood barrier in the lungs and perfusion into myocardial tissue. Applications to measurement of lung function, kidney perfusion, myocardial perfusion, and regional cerebral blood flow are discussed. Magn Reson Med 42:1137-1145, 1999.

Brain MRI with laser-polarized 129Xe.

The feasibility of brain MRI with laser-polarized 129Xe in a small animal model is demonstrated. Naturally abundant 129Xe is polarized and introduced into the lungs of Sprague-Dawley rats. Polarized xenon gas dissolves in the blood and is transported to the brain where it accumulates in brain tissue. Spectroscopic studies reveal a single, dominant, tissue-phase NMR resonance in the head at 194.5 ppm relative to the gas phase resonance. Images of 129Xe in the rat head were obtained with 98-microliter voxels by 2D chemical shift imaging and show that xenon is localized to the brain. This work establishes that nuclear polarization produced in the gas phases survives transport to the brain where it may be imaged. Increases in polarization and delivered volume of 129Xe will allow clinical measurements of regional cerebral blood flow.

Newer designs of aphakic spectacle eyeglasses.

This paper discusses the four available types of plastic aphakic spectacle lenses, which include (1) nonaspheric nonlineticular, (2)hardly aspheric lenticular and moderately aspheric lenticular, (3) mildly aspheric nonlenticular, and (4) highly aspheric nonlenticular in much larger eye size but adjusted closer to the eye to produce an enlarged visual field and suppress the "jack-in-the-box" phenomenon. Absolute size of the refracted peripheral visual fields through these types will be compared for the stationary eye in primary fixation. These visual fields were performed on the Amark projection perimeter. Helpful hints will be presented on how to determine if the patient has obtained the types of lenses prescribed and how to best prescribe each of these lenses.