The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response

Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants. In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge. The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.

Refined plastic hinge analysis of steel frame structures comprising non-compact sections : II : verification

Application of "advanced analysis" methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A refined plastic hinge method suitable for practical advanced analysis of steel frame structures comprising non-compact sections is presented in a companion paper. The method implicitly accounts for the effects of gradual cross-sectional yielding, longitudinal spread of plasticity, initial geometric imperfections, residual stresses, and local buckling. The accuracy and precision of the method for the analysis of steel frames comprising non-compact sections is established in this paper by comparison with a comprehensive range of analytical benchmark frame solutions. The refined plastic hinge method is shown to be more accurate and precise than the conventional individual member design methods based on elastic analysis and specification equations.

Postpartum care for Aboriginal and non-Aboriginal women with Gestational Diabetes Mellitus across urban, rural and remote locations : a protocol for a cohort linkage study

Background: Gestational diabetes mellitus (GDM) is increasing, along with obesity and type 2 diabetes (T2DM), with Aboriginal and Torres Strait Islander people* in Australia particularly affected. GDM causes serious complications in pregnancy, birth, and the longer term, for both women and their infants. Women diagnosed with GDM have an eightfold risk of developing T2DM after pregnancy, compared with women who have not had GDM. Indigenous women have an even higher risk, at a younger age, and progress more quickly from GDM to T2DM, compared to non-Indigenous women. If left undetected and untreated, T2DM can lead to heart disease, stroke, renal disease, kidney failure, amputations and blindness. A GDM diagnosis offers a ‘window of opportunity’ for diabetes health interventions and it is vital that acceptable and effective prevention, treatment, and post-pregnancy care are provided. Low rates of post-pregnancy screening for T2DM are reported among non-Aboriginal women in Australia and among Indigenous women in other countries, however data for Aboriginal women are scarce. Breastfeeding, a healthy diet, and exercise can also help to prevent T2DM, and together with T2DM screening are recommended elements of ‘post-pregnancy care’ for women with GDM, This paper describes methods for a data linkage study to investigate rates of post-pregnancy care among women with GDM. Methods/Design: This retrospective cohort includes all women who gave birth at Cairns Base Hospital in Far North Queensland, Australia, from 2004 to 2010, coded as having GDM in the Cairns Base Hospital Clinical Coding system. Data linkage is being conducted with the Queensland Perinatal Data Collection, and three laboratories. Hospital medical records are being reviewed to validate the accuracy of GDM case ascertainment, and gather information on breastfeeding and provision of dietary advice. Multiple logistic regression is being used to compare post-pregnancy care between Aboriginal and non-Aboriginal women, while adjusting for other factors may impact on post-pregnancy care. Survival analysis is being used to estimate the rates of progression from GDM to T2DM. Discussion: There are challenges to collecting post-pregnancy data for women with GDM. However, research is urgently needed to ensure adequate post-pregnancy care is provided for women with GDM in Australia.

Planning for sustainability of non motorised public transport in a developing city

Most large cities around the world are undergoing rapid transport sector development to cater for increased urbanization. Subsequently the issues of mobility, access equity, congestion, operational safety and above all environmental sustainability are becoming increasingly crucial in transport planning and policy making. The popular response in addressing these issues has been demand management, through improvement of motorised public transport (MPT) modes (bus, train, tram) and non-motorized transport (NMT) modes (walk, bicycle); improved fuel technology. Relatively little attention has however been given to another readily available and highly sustainable component of the urban transport system, non-motorized public transport (NMPT) such as the pedicab that operates on a commercial basis and serves as an NMT taxi; and has long standing history in many Asian cities; relatively stable in existence in Latin America; and reemerging and expanding in Europe, North America and Australia. Consensus at policy level on the apparent benefits, costs and management approach for NMPT integration has often been a major transport planning problem. Within this context, this research attempts to provide a more complete analysis of the current existence rationale and possible future, or otherwise, of NMPT as a regular public transport system. The analytical process is divided into three major stages. Stage 1 reviews the status and role condition of NMPT as regular public transport on a global scale- in developing cities and developed cities. The review establishes the strong ongoing and future potential role of NMPT in major developing cities. Stage 2 narrows down the status review to a case study city of a developing country in order to facilitate deeper role review and status analysis of the mode. Dhaka, capital city of Bangladesh, has been chosen due to its magnitude of NMPT presence. The review and analysis reveals the multisectoral and dominant role of NMPT in catering for the travel need of Dhaka transport users. The review also indicates ad-hoc, disintegrated policy planning in management of NMPT and the need for a planning framework to facilitate balanced integration between NMPT and MT in future. Stage 3 develops an integrated, multimodal planning framework (IMPF), based on a four-step planning process. This includes defining the purpose and scope of the planning exercise, determining current deficiencies and preferred characteristics for the proposed IMPF, selection of suitable techniques to address the deficiencies and needs of the transport network while laying out the IMPF and finally, development of a delivery plan for the IMPF based on a selected layout technique and integration approach. The output of the exercise is a planning instrument (decision tool) that can be used to assign a road hierarchy in order to allocate appropriate traffic to appropriate network type, particularly to facilitate the operational balance between MT and NMT. The instrument is based on a partial restriction approach of motorised transport (MT) and NMT, structured on the notion of functional hierarchy approach, and distributes/prioritises MT and NMT such that functional needs of the network category is best complemented. The planning instrument based on these processes and principles offers a six-level road hierarchy with a different composition of network-governing attributes and modal priority, for the current Dhaka transport network, in order to facilitate efficient integration of NMT with MT. A case study application of the instrument on a small transport network of Dhaka also demonstrates the utility, flexibility and adoptability of the instrument in logically allocating corridors with particular positions in the road hierarchy paradigm. Although the tool is useful in enabling balanced distribution of NMPT with MT at different network levels, further investigation is required with reference to detailed modal variations, scales and locations of a network to further generalise the framework application.

Distributed plasticity analysis of steel frame structures comprising non-compact sections

Application of 'advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A research project has been conducted with the aim of developing concentrated plasticity methods suitable for practical advanced analysis of steel frame structures comprising non-compact sections. A primary objective was to produce a comprehensive range of new distributed plasticity analytical benchmark solutions for verification of the concentrated plasticity methods. A distributed plasticity model was developed using shell finite elements to explicitly account for the effects of gradual yielding and spread of plasticity, initial geometric imperfections, residual stresses and local buckling deformations. The model was verified by comparison with large-scale steel frame test results and a variety of existing analytical benchmark solutions. This paper presents a description of the distributed plasticity model and details of the verification study.

Pseudo plastic zone analysis of steel frame structures comprising non-compact sections

Application of `advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A concentrated plasticity method suitable for practical advanced analysis of steel frame structures comprising non-compact sections is presented in this paper. The pseudo plastic zone method implicitly accounts for the effects of gradual cross-sectional yielding, longitudinal spread of plasticity, initial geometric imperfections, residual stresses, and local buckling. The accuracy and precision of the method for the analysis of steel frames comprising non-compact sections is established by comparison with a comprehensive range of analytical benchmark frame solutions. The pseudo plastic zone method is shown to be more accurate and precise than the conventional individual member design methods based on elastic analysis and specification equations.

Large-scale testing of steel frame structures comprising non-compact sections

Application of 'advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A research project has been conducted with the aim of developing concentrated plasticity methods suitable for practical advanced analysis of steel frame structures comprising non-compact sections. A series of large-scale tests were performed in order to provide experimental results for verification of the new analytical models. Each of the test frames comprised non-compact sections, and exhibited significant local buckling behaviour prior to failure. This paper presents details of the test program including the test specimens, set-up and instrumentation, procedure, and results.

A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/ cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer : a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1)

Background: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC. Patients and methods: Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m 2, carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m 2, ifosfamide 3 g/m 2 and cisplatin 50 mg/m 2 or mitomycin 6 mg/ m 2, vinblastine 6 mg/m 2 and cisplatin 50 mg/m 2, respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life. Results: The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change. Conclusions: The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained. © 2006 European Society for Medical Oncology.

Fashion system Shanghai : the advent of a new gatekeeper

The term fashion system describes inter-relationships between production and consumption illustrating how the production of fashion is a collective activity. For instance, Yuniya Kawamura notes systems for the production of fashion differ around the globe and are subject to constant change, and Jennifer Craik draws attention to an ‘array of competing and intermeshing systems cutting across western and non-western cultures. In China, Shanghai’s nascent fashion system seeks to emulate the Eurocentric system of Fashion Weeks and industry support groups. It promises emergent designers a platform for global competition, yet there are tensions from within. Interaction with a fashion system inevitably means becoming validated or legitimised. Legitimisation in turn depends upon gatekeepers who make aesthetic judgments about the status, quality and cultural value of a designers work. Notwithstanding the proliferation of fashion media, in Shanghai a new gatekeeper has arrived, seeking to filter authenticity from artifice, offering truth in a fashion market saturated with fakery and the hollowness of foreign consumptive practice, and providing a place of sanctuary for Chinese fashion design. Thus this paper discusses how new agencies are allowing designers in Shanghai greater control over their brand image while creating novel opportunities for promotion and sales. It explores why designers choose this new model and provides new knowledge of the curation of fashion by these gatekeepers.

How do Chinese fashion designers become global fashion leaders? A new perspective on legitimisation in China’s fashion system

The term fashion system describes inter-relationships between production and consumption, illustrating how the production of fashion is a collective activity. For instance, Yuniya Kawamura (2011) notes systems for the production of fashion differ around the globe and are subject to constant change, and Jennifer Craik (1994, 6) draws attention to an ‘array of competing and intermeshing systems cutting across western and non-western cultures. In China, Shanghai’s nascent fashion system seeks to emulate the Eurocentric system of Fashion Weeks and industry support groups. It promises designers a platform for global competition, yet there are tensions from within. Interaction with a fashion system inevitably means becoming validated or legitimised. Legitimisation in turn depends upon gatekeepers who make aesthetic judgments about the status, quality, and cultural value of a designers work (Becker 2008). My paper offers a new perspective on legitimisation that is drawn mainly from my PhD research. I argue that some Chinese fashion designers are on the path to becoming global fashion designers because they have embraced a global aesthetic that resonates with the human condition, rather than the manufactured authenticity of a Eurocentric fashion system that perpetuates endless consumption. In this way, they are able to ‘self-legitimise’. I contend these designers are ‘designers for humans’, because they are able to look beyond the mythology of fashion brands, and the Eurocentric fashion system, where they explore the tensions of man and culture in their practice. Furthermore, their design ethos pursues beauty, truth and harmony in the Chinese philosophical sense, as well as incorporating financial return in a process that is still enacted through a fashion system. Accordingly, cultural tradition, heritage and modernity, while still valuable, have less impact on their practice.

A biological staging model for operable non-small cell lung cancer

Background Currently the best prognostic index for operable non-small cell lung cancer (NSCLC) is the TNM staging system. Molecular biology holds the promise of predicting outcome for the individual patient and identifying novel therapeutic targets. Angiogenesis, matrix metalloproteinases (MMP)-2 and -9, and the erb/HER type I tyrosine kinase receptors are all implicated in the pathogenesis of NSCLC. Methods A retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days postoperative survival with a minimum follow up of 2 years was undertaken. Immunohistochemical analysis was performed on paraffin embedded sections for the microvessel marker CD34, MMP-2 and MMP-9, EGFR, and c-erbB-2 to evaluate the relationships between and impact on survival of these molecular markers. Results Tumour cell MMP-9 (HR 1.91 (1.23-2.97)), a high microvessel count (HR 1.97 (1.28-3.03)), and stage (stage II HR 1.44 (0.87-2.40), stage IIIa HR 2.21 (1.31-3.74)) were independent prognostic factors. Patients with a high microvessel count and tumour cell MMP-9 expression had a worse outcome than cases with only one (HR 1.68 (1.04-2.73)) or neither (HR 4.43 (2.29-8.57)) of these markers. EGFR expression correlated with tumour cell MMP-9 expression (p<0.001). Immunoreactivity for both of these factors within the same tumour was associated with a poor prognosis (HR 2.22 (1.45-3.41)). Conclusion Angiogenesis, EGFR, and MMP-9 expression provide prognostic information independent of TNM stage, allowing a more accurate outcome prediction for the individual patient. The development of novel anti-angiogenic agents, EGFR targeted therapies, and MMP inhibitors suggests that target specific adjuvant treatments may become a therapeutic option in patients with resected NSCLC.

Invading edge vs. inner (edvin) patterns of vascularization : an interplay between angiogenic and vascular survival factors defines the clinical behaviour of non-small cell lung cancer

Neo-angiogenesis during neoplastic growth involves endothelial mitogenic and migration stimuli produced by cancer or tumour stromal cells. Although this active angiogenesis takes place in the tumour periphery, the process of vessel growth and survival in inner areas and its clinical role remain largely unexplored. The present study compared the microvessel score (MS) as well as the single endothelial cell score (ECS) in the invading edge and in inner areas of non-small cell lung carcinomas (NSCLCs). Three different patterns of vascular growth were distinguished: the edvin (edge vs. inner) type 1, where a low MS was observed in both peripheral and inner tumour areas; the edvin type 2, where a high MS was noted in the invading front but a low MS in inner areas; and the edvin type 3, where both peripheral and inner tumour areas had a high MS. The ECS was high in the invading edge in edvin type 2 and 3 cases and was sharply decreased in both types in inner areas, suggesting that endothelial cell migration is unlikely to contribute to the angiogenic process in areas away from the tumour front. Expression of the vascular endothelial growth factor (VEGF) and of thymidine phosphorylase (TP) was associated with a high MS in the invading edge. VEGF was associated with a high MS in inner areas (edvin 3), while TP expression was associated with edvin type 2, showing that VEGF (and not TP) contributes to the preservation of the inner vasculature. Both edvin type 2 and 3 cases showed an increased incidence of node metastasis, but edvin type 3 cases had a poorer prognosis, even in the N1-stage group. The present study suggests that tumour factors regulating angiogenesis and vascular survival are not identical. A possible method is reported to quantify these two parameters by comparing the MS in the invading edge and inner areas (edvin types). This observation may contribute to the evaluation of the effectiveness of different therapeutic approaches, namely vascular targeting vs. anti-angiogenesis. Copyright (C) 2000 John Wiley and Sons, Ltd.

On parallel hybrid-electric propulsion system for unmanned aerial vehicles

This paper presents a review of existing and current developments and the analysis of Hybrid-Electric Propulsion Systems (HEPS) for small fixed-wing Unmanned Aerial Vehicles (UAVs). Efficient energy utilisation on an UAV is essential to its functioning, often to achieve the operational goals of range, endurance and other specific mission requirements. Due to the limitations of the space available and the mass budget on the UAV, it is often a delicate balance between the onboard energy available (i.e. fuel) and achieving the operational goals. One technology with potential in this area is with the use of HEPS. In this paper, information on the state-of-art technology in this field of research is provided. A description and simulation of a parallel HEPS for a small fixed-wing UAV by incorporating an Ideal Operating Line (IOL) control strategy is described. Simulation models of the components in a HEPS were designed in the MATLAB Simulink environment. An IOL analysis of an UAV piston engine was used to determine the most efficient points of operation for this engine. The results show that an UAV equipped with this HEPS configuration is capable of achieving a fuel saving of 6.5%, compared to the engine-only configuration.

SRL 172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer : phase III results

Background: This open-label, randomised phase III study was designed to further investigate the clinical activity and safety of SRL172 (killed Mycobacterium vaccae suspension) with chemotherapy in the treatment of non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomised to receive platinum-based chemotherapy, consisting of up to six cycles of MVP (mitomycin, vinblastine and cisplatin or carboplatin) with (210 patients) or without (209 patients) monthly SRL172. Results: There was no statistical difference between the two groups in overall survival (primary efficacy end point) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65). However, a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%), than in the chemotherapy alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group. Patients in the chemotherapy alone group had greater deterioration in their Global Health Status score (-14.3) than patients in the chemotherapy plus SRL172 group (-6.6) (P = 0.02). Conclusion: In this non-placebo controlled trial, SRL172 when added to standard cancer chemotherapy significantly improved patient quality of life without affecting overall survival times. © 2004 European Society for Medical Oncology.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.