Iron oxide particles for atheroma imaging

The selection of patients for vascular interventions has been solely based on luminal stenosis and symptomatology. However, histological data from both the coronary and carotid vasculature suggest that other plaque features such as inflammation may be more important in predicting future thromboembolic events. Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans. It has reached the stage of development to have been recently used in an interventional drug study to not only assess inflammatory progression but also select patients at high risk. This article reviews the basic science behind the use of USPIO contrast agents in atheroma MR imaging, experimental work in animals, and how this has led to the emergence of this promising targeted imaging platform for assessment of high risk carotid atherosclerosis in humans.

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).

Combined PET-FDG and USPIO-enhanced MR imaging in patients with symptomatic moderate carotid artery stenosis

Introduction: PET-FDG and USPIO-enhanced MRI are increasingly being used in depicting carotid atheroma inflammation - a risk factor for the high risk plaque. Their combined use has not been previously reported. Report: Two patients presenting with stroke and identified with 50% carotid stenosis on duplex ultrasonography, underwent PET FDG and USPIO-enhanced MR imaging. Results were concordant and complementary suggesting that both techniques reflect similar metabolic processes. Discussion: The selection of patients for carotid revascularisation has largely been based on the severity of luminal stenosis alone. The two imaging modalities, which identify inflammatory activity, may be potential surrogate risk markers in the selection of patients eligible for carotid surgery, if plaque inflammation can be correlated with risk of developing clinical symptoms.

Correlation of carotid atheromatous plaque inflammation using USPIO-enhanced MR imaging with degree of luminal Stenosis

BACKGROUND AND PURPOSE Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The study explores the relationship between the degree of Magnetic Resonance (MR)"defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles and the severity of luminal stenosis in asymptomatic carotid plaques. METHODS Seventy-one patients with an asymptomatic carotid stenosis of ĝ‰¥40% underwent multi-sequence USPIO-enhanced MR imaging. Stenosis severity was measured according to the NASCET and ECST methods. RESULTS No demonstrable relationship between inflammation as measured by USPIO-enhanced signal change and the degree of luminal stenosis was found. CONCLUSIONS Inflammation and stenosis are likely to be independent risk factors, although this needs to be further validated.

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: An ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study

Introduction: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). Methods: 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. Results: The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p < 0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p < 0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p = 0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p < 0.001). Conclusions: These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.

Correlation of carotid atheromatous plaque inflammation with biomechanical stress: Utility of USPIO enhanced MR imaging and finite element analysis

Objective: The aim of this study was to explore whether there is a relationship between the degree of MR-defined inflammation using ultra small super-paramagnetic iron oxide (USPIO) particles, and biomechanical stress using finite element analysis (FEA) techniques, in carotid atheromatous plaques. Methods and Results: 18 patients with angiographically proven carotid stenoses underwent multi-sequence MR imaging before and 36 h after USPIO infusion. T2 * weighted images were manually segmented into quadrants and the signal change in each quadrant normalised to adjacent muscle was calculated after USPIO administration. Plaque geometry was obtained from the rest of the multi-sequence dataset and used within a FEA model to predict maximal stress concentration within each slice. Subsequently, a new statistical model was developed to explicitly investigate the form of the relationship between biomechanical stress and signal change. The Spearman's rank correlation coefficient for USPIO enhanced signal change and maximal biomechanical stress was -0.60 (p = 0.009). Conclusions: There is an association between biomechanical stress and USPIO enhanced MR-defined inflammation within carotid atheroma, both known risk factors for plaque vulnerability. This underlines the complex interaction between physiological processes and biomechanical mechanisms in the development of carotid atheroma. However, this is preliminary data that will need validation in a larger cohort of patients.

Non-invasive MR imaging of inflammation in a patient with both asymptomatic carotid atheroma and an abdominal aortic aneurysm: A case report

Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. USPIO-enhanced MRI imaging is a promising non-i nvasive method to identify high-risk atheromatous plaque inflammation in vivo in humans, in which areas of focal signal loss on MR images have been shown to correspond to the location of activated macrophages, typically at the shoulder regions of the plaque. This is the first report in humans describing simultaneous USPIO uptake within atheroma in two different arterial territories and again emphasises that atherosclerosis is a truly systemic disease. With further work, USPIO-enhanced MR imaging may be useful in identifying inflamed vulnerable atheromatous plaques in vivo, so refining patient selection for intervention and allowing appropriate early aggressive pharmacotherapy to prevent plaque rupture.

Photo-​induced proton coupled electron transfer from a benzophenone 'antenna' to an isoindoline nitroxide

The current study reports the synthesis and properties of a novel isoindoline nitroxide contg. a benzophenone chromophore fused into the carbon framework. When exposed to UV light, rather than undergoing traditional benzophenone photochem. pathways, the presence of the nitroxide enables an energy transfer process whereby the nitroxide enters an excited state which induces an efficient hydrogen atom transfer from unactivated alkanes.

Corporate fraud culture: Re-examining the corporate governance and performance relation

We analyse the corporate governance and performance relation, when conditioning on corporate fraud, for fraud firms during 2000 – 2007. Fraud firms are identified as either self- reported fraud events, or subject to regulatory investigation. We use the inverse Mills ratio procedure to account for firms' (unobservable) fraud culture in the dynamic system GMM model of the performance- governance relation. We find that corporate governance is an endogenously determined characteristic that has no causal impact on firm performance when conditioning on fraud. Fraud is a significant regulatory event but its overall economic impact at the firm level is highly variable.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Taking an evaluative stance to decision-making about professional development options in early childhood education and care

This article builds on our ongoing work in conceptualising an ‘evaluative stance’ framework to assist in understanding how leaders in the field of early childhood education and care (ECEC) make decisions about the selection of professional development options for themselves and their staff. It introduces the notion that evaluative mindsets can be considered in terms of attitudes towards decision-making that are based on personal epistemologies. Drawing on data from semi-structured interviews, it explores the mindsets of six experienced leaders in two long-established ECEC organisations in Australia with respect to their decision-making about professional development. The article concludes with a consideration of the potential utility of the framework and the coding template used in this exploratory study.

Enterprise system investments for competitive advantage: An empirical study of Swiss SMEs

Previous research identifies various reasons companies invest in information technology (IT), often as a means to generate value. To add to the discussion of IT value generation, this study investigates investments in enterprise software systems that support business processes. Managers of more than 500 Swiss small and medium-sized enterprises (SMEs) responded to a survey regarding the levels of their IT investment in enterprise software systems and the perceived utility of those investments. The authors use logistic and ordinary least squares regression to examine whether IT investments in two business processes affect SMEs' performance and competitive advantage. Using cluster analysis, they also develop a firm typology with four distinct groups that differ in their investments in enterprise software systems. These findings offer key implications for both research and managerial practice.

Cluster randomised-control trial for an Australian child protection education program: Study protocol for the Learn to be safe with Emmy and friends™

Background Child maltreatment has severe short-and long-term consequences for children’s health, development, and wellbeing. Despite the provision of child protection education programs in many countries, few have been rigorously evaluated to determine their effectiveness. We describe the design of a multi-site gold standard evaluation of an Australian school-based child protection education program. The intervention has been developed by a not-for-profit agency and comprises 5 1-h sessions delivered to first grade students (aged 5–6 years) in their regular classrooms. It incorporates common attributes of effective programs identified in the literature, and aligns with the Australian education curriculum. Methods/Design A three-site cluster randomised controlled trial (RCT) of Learn to be safe with Emmy and friends™ will be conducted with children in approximately 72 first grade classrooms in 24 Queensland primary (elementary) schools from three state regions, over a period of 2 years. Entire schools will be randomised, using a computer generated list of random numbers, to intervention and wait-list control conditions, to prevent contamination effects across students and classes. Data will be collected at baseline (pre-assessment), immediately after the intervention (post-assessment), and at 6-, 12-, and 18-months (follow-up assessments). Outcome assessors will be blinded to group membership. Primary outcomes assessed are children’s knowledge of program concepts; intentions to use program knowledge, skills, and help-seeking strategies; actual use of program material in a simulated situation; and anxiety arising from program participation. Secondary outcomes include a parent discussion monitor, parent observations of their children’s use of program materials, satisfaction with the program, and parental stress. A process evaluation will be conducted concurrently to assess program performance. Discussion This RCT addresses shortcomings in previous studies and methodologically extends research in this area by randomising at school-level to prevent cross-learning between conditions; providing longer-term outcome assessment than any previous study; examining the degree to which parents/guardians discuss intervention content with children at home; assessing potential moderating/mediating effects of family and child demographic variables; testing an in-vivo measure to assess children’s ability to discriminate safe/unsafe situations and disclose to trusted adults; and testing enhancements to existing measures to establish greater internal consistency.

How childcare providers interpret "reasonable suspicion" of child abuse

- Background Childcare providers are often “first responders” for suspected child abuse, and how they understand the concept of “reasonable suspicion” will influence their decisions regarding which warning signs warrant reporting. - Objective The purpose of this study was to investigate how childcare providers interpret the threshold for reporting suspected abuse, and to consider the implications of these findings for professional training and development. - Method A convenience sample of 355 childcare providers completed the Reasonable Suspicion of Child Abuse survey to quantify what likelihood of child abuse constitutes “reasonable suspicion.” Responses were examined for internal consistency, evidence of a group standard, and associations with professional and personal demographics. - Results On a Rank Order Scale, responses for what constitutes “reasonable suspicion” ranged from requiring that abuse be “the” most likely cause (8 %) of an injury, to the second most likely (9 %), third (18 %), fourth (18 %), to even the seventh (8 %) or eighth (5 %) most likely cause of an injury. On a numerical probability scale, 21 % of respondents indicated that “abuse” would need to be ≥83 % likely before reasonable suspicion existed; 40 % stated that a likelihood between 53–82 % was needed; 27 % identified the necessary likelihood between 33–52 %; and 12 % set a threshold between 1–32 %. - Conclusions The present finding that no consensus exists for interpreting “reasonable suspicion” suggests that a broadly accepted interpretive framework is needed in order to help prepare childcare providers to know when to report suspected abuse.

Capacity building of early career researchers through cross-institutional mentoring

Most early career researchers in the first five years following doctoral qualification are faced with research challenges and opportunities, which necessitate the ability to navigate and overcome barriers, and to identify and benefit from possibilities. In this chapter, the authors outline an intentional mentoring initiative aimed at building the capacity of early career researchers within the Excellence in Research in Early Years Education Collaborative Research Network (CRN) in Australia. The initiative involved partnering early career researchers with experienced researchers and the inclusion of an early career representative on the network planning committee. The chapter discusses the many benefits for the mentee arising from the initiative including increased publication, momentum and confidence, as well as exposure to new methodologies, theoretical frameworks, and productive collaborative partnerships. It is hoped, however, that the findings will be of relevance to similar and diverse (funded/unfunded) research programs and collaborative networks wherever mentoring is applied as a capacity building strategy to assist researchers.