Immunogenicity and protective efficacy of an anti-Streptococcus pyogenes vaccine candidate in multiple animal species

Streptococcus pyogenes, also known as Group A Streptococcus (GAS) has been associated with a range of diseases from the mild pharyngitis and pyoderma to more severe invasive infections such as streptococcal toxic shock. GAS also causes a number of non-suppurative post-infectious diseases such as rheumatic fever, rheumatic heart disease and glomerulonephritis. The large extent of GAS disease burden necessitates the need for a prophylactic vaccine that could target the diverse GAS emm types circulating globally. Anti-GAS vaccine strategies have focused primarily on the GAS M-protein, an extracellular virulence factor anchored to GAS cell wall. As opposed to the hypervariable N-terminal region, the C-terminal portion of the protein is highly conserved among different GAS emm types and is the focus of a leading GAS vaccine candidate, J8-DT/alum. The vaccine candidate J8-DT/alum was shown to be immunogenic in mice, rabbits and the non-human primates, hamadryas baboons. Similar responses to J8-DT/alum were observed after subcutaneous and intramuscular immunization with J8-DT/alum, in mice and in rabbits. Further assessment of parameters that may influence the immunogenicity of J8-DT demonstrated that the immune responses were identical in male and female mice and the use of alum as an adjuvant in the vaccine formulation significantly increased its immunogenicity, resulting in a long-lived serum IgG response. Contrary to the previous findings, the data in this thesis indicates that a primary immunization with J8-DT/alum (50ƒÊg) followed by a single boost is sufficient to generate a robust immune response in mice. As expected, the IgG response to J8- DT/alum was a Th2 type response consisting predominantly of the isotype IgG1 accompanied by lower levels of IgG2a. Intramuscular vaccination of rabbits with J8-DT/alum demonstrated that an increase in the dose of J8-DT/alum up to 500ƒÊg does not have an impact on the serum IgG titers achieved. Similar to the immune response in mice, immunization with J8-DT/alum in baboons also established that a 60ƒÊg dose compared to either 30ƒÊg or 120ƒÊg was sufficient to generate a robust immune response. Interestingly, mucosal infection of naive baboons with a M1 GAS strain did not induce a J8-specific serum IgG response. As J8-DT/alum mediated protection has been previously reported to be due to the J8- specific antibody formed, the efficacy of J8-DT antibodies was determined in vitro and in vivo. In vitro opsonization and in vivo passive transfer confirmed the protective potential of J8-DT antibodies. A reduction in the bacterial burden after challenge with a bioluminescent M49 GAS strain in mice that were passively administered J8-DT IgG established that protection due to J8-DT was mediated by antibodies. The GAS burden in infected mice was monitored using bioluminescent imaging in addition to traditional CFU assays. Bioluminescent GAS strains including the ‘rheumatogenic’ M1 GAS could not be generated due to limitations with transformation of GAS, however, a M49 GAS strain was utilized during BLI. The M49 serotype is traditionally a ‘nephritogenic’ serotype associated with post-streptococcal glomerulonephritis. Anti- J8-DT antibodies now have been shown to be protective against multiple GAS strains such as M49 and M1. This study evaluated the immunogenicity of J8-DT/alum in different species of experimental animals in preparation for phase I human clinical trials and provided the ground work for the development of a rapid non-invasive assay for evaluation of vaccine candidates.

The relationship between particulate air pollution and emergency hospital visits for hypertension in Beijing, China

BACKGROUND: A number of epidemiological studies have examined the adverse effect of air pollution on mortality and morbidity. Also, several studies have investigated the associations between air pollution and specific-cause diseases including arrhythmia, myocardial infarction, and heart failure. However, little is known about the relationship between air pollution and the onset of hypertension. OBJECTIVE: To explore the risk effect of particulate matter air pollution on the emergency hospital visits (EHVs) for hypertension in Beijing, China. METHODS: We gathered data on daily EHVs for hypertension, fine particulate matter less than 2.5 microm in aerodynamic diameter (PM(2.5)), particulate matter less than 10 microm in aerodynamic diameter (PM(10)), sulfur dioxide, and nitrogen dioxide in Beijing, China during 2007. A time-stratified case-crossover design with distributed lag model was used to evaluate associations between ambient air pollutants and hypertension. Daily mean temperature and relative humidity were controlled in all models. RESULTS: There were 1,491 EHVs for hypertension during the study period. In single pollutant models, an increase in 10 microg/m(3) in PM(2.5) and PM(10) was associated with EHVs for hypertension with odds ratios (overall effect of five days) of 1.084 (95% confidence interval (CI): 1.028, 1.139) and 1.060% (95% CI: 1.020, 1.101), respectively. CONCLUSION: Elevated levels of ambient particulate matters are associated with an increase in EHVs for hypertension in Beijing, China.

Embedding values through global education in social sciences pre-service teacher education : linking the head and heart

This chapter aims to situate values education as a core component of social science pre-service teacher education. In particular, it reflects on an experiment in embedding a values laden Global Education perspective in a fourth year social science curriculum method unit. This unit was designed and taught by the researcher on the assumption that beginning social science teachers need to be empowered with pedagogical skills and new dispositions to deal with value laden emerging global and regional concerns in their secondary school classrooms. Moreover, it was assumed that when pre-service teachers engage in dynamic and interactive learning experiences in their curriculum unit, they commence the process of ‘capacity building’ those skills which prepare them for their own lifelong professional learning. This approach to values education also aimed at providing pre-service teachers with opportunities to ‘create deep understandings of teaching and learning’ (Barnes, 1989, p. 17) by reflecting on the ways in which ‘pedagogy can be transformative’ (Lovat and Toomey, 2011 add page no from Chapter One). It was assumed that this tertiary experience would foster the sine qua non of teaching – a commitment to students and their learning. Central to fostering new ‘dispositions’ through this approach, was the belief in the power of pedagogy to make the difference in enhancing student participation and learning. In this sense, this experiment in values education in secondary social science pre-service teacher education aligns with the Troika metaphor for a paradigm change, articulated by Lovat and Toomey (2009) in Chapter One.

Lifestyle factors associated concurrently and prospectively with co-morbid cardiovascular disease in a population-based cohort of colorectal cancer survivors

Aims To assess self-reported lifetime prevalence of cardiovascular disease (CVD) among colorectal cancer survivors, and examine the cross-sectional and prospective associations of lifestyle factors with co-morbid CVD. Methods Colorectal cancer survivors were recruited (n = 1966). Data were collected at approximately 5, 12, 24 and 36 months post-diagnosis. Cross-sectional findings included six CVD categories (hypercholesterolaemia, hypertension, diabetes, heart failure, kidney disease and ischaemic heart disease (IHD)) at 5 months post-diagnosis. Longitudinal outcomes included the probability of developing (de novo) co-morbid CVD by 36 months post-diagnosis. Lifestyle factors included body mass index, physical activity, television (TV) viewing, alcohol consumption and smoking. Results Co-morbid CVD prevalence at 5 months post-diagnosis was 59%, and 16% of participants with no known CVD at the baseline reported de novo CVD by 36 months. Obesity at the baseline predicted de novo hypertension (odds ratio [OR] = 2.20, 95% confidence intervals [CI] = 1.09, 4.45) and de novo diabetes (OR = 6.55, 95% CI = 2.19, 19.53). Participants watching >4 h of TV/d at the baseline (compared with <2 h/d) were more likely to develop ischaemic heart disease by 36 months (OR = 5.51, 95% CI = 1.86, 16.34). Conclusion Overweight colorectal cancer survivors were more likely to suffer from co-morbid CVD. Interventions focusing on weight management and other modifiable lifestyle factors may reduce functional decline and improve survival.

Differences in Treatment and Management of Indigenous and Non-Indigenous Patients Presenting with Chest Pain: Results of the Heart Protection Partnership (HPP) Study

BACKGROUND: Indigenous patients with acute coronary syndromes represent a high-risk group. There are however few contemporary datasets addressing differences in the presentation and management of Indigenous and non-Indigenous patients with chest pain. METHODS: The Heart Protection Project, is a multicentre retrospective audit of consecutive medical records from patients presenting with chest pain. Patients were identified as Indigenous or non-Indigenous, and time to presentation and cardiac investigations as well as rates of cardiac investigations and procedures were compared between the two groups. RESULTS: Of the 2380 patients included, 199 (8.4%) identified as Indigenous, and 2174 (91.6%) as non-Indigenous. Indigenous patients were younger, had higher rates hyperlipidaemia, diabetes, smoking, known coronary artery disease and a lower rate of prior PCI; and were significantly less likely to have private health insurance, be admitted to an interventional facility or to have a cardiologist as primary physician. Following adjustment for difference in baseline characteristics, Indigenous patients had comparable rates of cardiac investigations and delay times to presentation and investigations. CONCLUSIONS: Although the Indigenous population was identified as a high-risk group, in this analysis of selected Australian hospitals there were no significant differences in treatment or management of Indigenous patients in comparison to non-Indigenous.

Which components of heart failure programs are effective? A meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of heart failure management in 9,560 patients (Abridged Cochrane Review)

Aims--Telemonitoring (TM) and structured telephone support (STS) have the potential to deliver specialised management to more patients with chronic heart failure (CHF), but their efficacy is still to be proven. Objectives To review randomised controlled trials (RCTs) of TM or STS on all- cause mortality and all-cause and CHF-related hospitalisations in patients with CHF, as a non-invasive remote model of specialised disease-management intervention.--Methods and Results--Data sources:We searched 15 electronic databases and hand-searched bibliographies of relevant studies, systematic reviews, and meeting abstracts. Two reviewers independently extracted all data. Study eligibility and participants: We included any randomised controlled trials (RCT) comparing TM or STS to usual care of patients with CHF. Studies that included intensified management with additional home or clinic visits were excluded. Synthesis: Primary outcomes (mortality and hospitalisations) were analysed; secondary outcomes (cost, length of stay, quality of life) were tabulated.--Results: Thirty RCTs of STS and TM were identified (25 peer-reviewed publications (n=8,323) and five abstracts (n=1,482)). Of the 25 peer-reviewed studies, 11 evaluated TM (2,710 participants), 16 evaluated STS (5,613 participants) and two tested both interventions. TM reduced all-cause mortality (risk ratio (RR 0•66 [95% CI 0•54-0•81], p<0•0001) and STS showed similar trends (RR 0•88 [95% CI 0•76-1•01], p=0•08). Both TM (RR 0•79 [95% CI 0•67-0•94], p=0•008) and STS (RR 0•77 [95% CI 0•68-0•87], p<0•0001) reduced CHF-related hospitalisations. Both interventions improved quality of life, reduced costs, and were acceptable to patients. Improvements in prescribing, patient-knowledge and self-care, and functional class were observed.--Conclusion: TM and STS both appear effective interventions to improve outcomes in patients with CHF.