Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

The psychological and economic factors that influence energy consumption habits of low-income earners

Social marketers and governments have often targeted hard to reach or vulnerable groups (Gordon et al., 2006) such as young adults and low income earners. Past research has shown that low-income earners are often at risk of poor health outcomes and diminished lifestyle (Hampson et al., 2009; Scott et al., 2012). Young adults (aged 18 to 35) are in a transition phase of their life where lifestyle preferences are still being formed and are thus a useful target for long-term sustainable change. An area of focus for all levels of government is the use of energy with an aim to reduce consumption. There is little research to date that combines both of these groups and in particular in the context of household energy usage. Research into financially disadvantaged consumers is challenging the notion that that low income consumer purchasing and usage of products and services is based upon economic status (Sharma et al., 2012). Prior research shows higher income earners view items such as televisions and computers as necessities rather than non-essential (Karlsson et al., 2004). Consistent with this is growing evidence that low income earners purchase non-essential, energy intensive electronic appliances such as multiple big screen TV sets and additional refrigerators. With this in mind, there is a need for knowledge about how psychological and economic factors influence the energy consumption habits (e.g. appliances on standby power, leaving appliances turned on, running multiple devices at one time) of low income earners. Thus, our study sought to address the research question of: What are the factors that influence young adult low-income earners energy habits?

Sustainability Non-Price Incentives and Rewards: A Collaborative Procurement Perspective

Construction scholars suggest that procurement processes can be used as mechanisms to change construction industry practices. This paper discusses industry changes as a response to the calls for integration of sustainability ideals into construction practices. Because major infrastructure construction has been identified as a key producer of greenhouse gas emissions (GHGE), this study explores collaborative procurement models that have been used to facilitate mitigation of GHGE. The study focuses on the application of non-price incentives and rewards that work together as a binary mechanism. Data were collected using mixed-methods: government document content analysis was complemented with data collected through focus groups and individual interviews with both clients and contractors. This report includes examples of greening procurement agendas for three Australian road authorities relating to collaborative procurement project delivery models. Three collaborative procurement models, Alliance Consortium, Early Contractor Involvement and Public Private Partnerships provide evidence of construction projects that were completed early. It can also be argued that both clients and contractors are rewarded through collaborative project delivery. The incentive of early completion is rewarded with reduction of GHGE. This positive environmental outcome, based on a dual benefit and non-price sustainability criteria, suggests a step towards changed industry practices though the use of green procurement models.

Ross River virus disease activity associated with naturally occurring non-tidal flood events in Australia : A systematic review

Ross River virus (RRV) disease is the most common and widespread mosquito-borne disease in Australia, resulting in considerable health and economic cost to communities. While naturally occurring non-tidal flood events may enhance mosquito abundance, little is known about the impact of such events on RRV transmission. This paper critically reviews the existing evidence for an association between naturally occurring non-tidal flood events and RRV transmission. A systematic literature search was conducted on RRV transmission related to flooding and inundation from rain and riverine overflow. Overall, the evidence to support a positive association between flooding and RRV outbreaks is largely circumstantial, with the literature mostly reporting only coincidental occurrence between the two. However, for the Murray River, river flow and height (surrogates of flooding) were positively and significantly associated with RRV transmission. The association between non-tidal flooding and RRV transmission has not been studied comprehensively. More frequent flood events arising from climate change may result in increased outbreaks of RRV disease. Understanding the link between flood events and RRV transmission is necessary if resources for mosquito spraying and public health warnings are to be utilized more effectively and efficiently.

Community wide interventions for increasing physical activity

Background Multi-strategic community wide interventions for physical activity are increasingly popular but their ability to achieve population level improvements is unknown. Objectives To evaluate the effects of community wide, multi-strategic interventions upon population levels of physical activity. Search methods We searched the Cochrane Public Health Group Segment of the Cochrane Register of Studies,The Cochrane Library, MEDLINE, MEDLINE in Process, EMBASE, CINAHL, LILACS, PsycINFO, ASSIA, the British Nursing Index, Chinese CNKI databases, EPPI Centre (DoPHER, TRoPHI), ERIC, HMIC, Sociological Abstracts, SPORTDiscus, Transport Database and Web of Science (Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index). We also scanned websites of the EU Platform on Diet, Physical Activity and Health; Health-Evidence.org; the International Union for Health Promotion and Education; the NIHR Coordinating Centre for Health Technology (NCCHTA); the US Centre for Disease Control and Prevention (CDC) and NICE and SIGN guidelines. Reference lists of all relevant systematic reviews, guidelines and primary studies were searched and we contacted experts in the field. The searches were updated to 16 January 2014, unrestricted by language or publication status. Selection criteria Cluster randomised controlled trials, randomised controlled trials, quasi-experimental designs which used a control population for comparison, interrupted time-series studies, and prospective controlled cohort studies were included. Only studies with a minimum six-month follow up from the start of the intervention to measurement of outcomes were included. Community wide interventions had to comprise at least two broad strategies aimed at physical activity for the whole population. Studies which randomised individuals from the same community were excluded. Data collection and analysis At least two review authors independently extracted the data and assessed the risk of bias. Each study was assessed for the setting, the number of included components and their intensity. The primary outcome measures were grouped according to whether they were dichotomous (per cent physically active, per cent physically active during leisure time, and per cent physically inactive) or continuous (leisure time physical activity time (time spent)), walking (time spent), energy expenditure (as metabolic equivalents or METS)). For dichotomous measures we calculated the unadjusted and adjusted risk difference, and the unadjusted and adjusted relative risk. For continuous measures we calculated percentage change from baseline, unadjusted and adjusted. Main results After the selection process had been completed, 33 studies were included. A total of 267 communities were included in the review (populations between 500 and 1.9 million). Of the included studies, 25 were set in high income countries and eight were in low income countries. The interventions varied by the number of strategies included and their intensity. Almost all of the interventions included a component of building partnerships with local governments or non-governmental organisations (NGOs) (29 studies). None of the studies provided results by socio-economic disadvantage or other markers of equity. However, of those included studies undertaken in high income countries, 14 studies were described as being provided to deprived, disadvantaged or low socio-economic communities. Nineteen studies were identified as having a high risk of bias, 10 studies were unclear, and four studies had a low risk of bias. Selection bias was a major concern with these studies, with only five studies using randomisation to allocate communities. Four studies were judged as being at low risk of selection bias although 19 studies were considered to have an unclear risk of bias. Twelve studies had a high risk of detection bias, 13 an unclear risk and four a low risk of bias. Generally, the better designed studies showed no improvement in the primary outcome measure of physical activity at a population level. All four of the newly included, and judged to be at low risk of bias, studies (conducted in Japan, United Kingdom and USA) used randomisation to allocate the intervention to the communities. Three studies used a cluster randomised design and one study used a stepped wedge design. The approach to measuring the primary outcome of physical activity was better in these four studies than in many of the earlier studies. One study obtained objective population representative measurements of physical activity by accelerometers, while the remaining three low-risk studies used validated self-reported measures. The study using accelerometry, conducted in low income, high crime communities of USA, emphasised social marketing, partnership with police and environmental improvements. No change in the seven-day average daily minutes of moderate to vigorous physical activity was observed during the two years of operation. Some program level effect was observed with more people walking in the intervention community, however this result was not evident in the whole community. Similarly, the two studies conducted in the United Kingdom (one in rural villages and the other in urban London; both using communication, partnership and environmental strategies) found no improvement in the mean levels of energy expenditure per person per week, measured from one to four years from baseline. None of the three low risk studies reporting a dichotomous outcome of physical activity found improvements associated with the intervention. Overall, there was a noticeable absence of reporting of benefit in physical activity for community wide interventions in the included studies. However, as a group, the interventions undertaken in China appeared to have the greatest possibility of success with high participation rates reported. Reporting bias was evident with two studies failing to report physical activity measured at follow up. No adverse events were reported.The data pertaining to cost and sustainability of the interventions were limited and varied. Authors' conclusions Although numerous studies have been undertaken, there is a noticeable inconsistency of the findings in the available studies and this is confounded by serious methodological issues within the included studies. The body of evidence in this review does not support the hypothesis that the multi-component community wide interventions studied effectively increased physical activity for the population, although some studies with environmental components observed more people walking. Plain language summary Community wide interventions for increasing physical activity Not having enough physical activity leads to poorer health. Regular physical activity can reduce the risk of chronic disease and improve one's health and wellbeing. The lack of physical activity is a common and in some cases a growing health problem. To address this, 33 studies have used improvement activities directed at communities, using more than one approach in a single program. When we first looked at the available research in 2011 we observed that there was a lack of good studies which could show whether this approach was beneficial or not. Some studies claimed that community wide programs improved physical activities and other studies did not. In this update we found four new studies that were of good quality; however none of these four studies increased physical activity levels for the population. Some studies reported program level effects such as observing more people walking, however the population level of physical activity had not increased. This review found that community wide interventions are very difficult to undertake, and it appears that they usually fail to provide a measurable benefit in physical activity for a population. It is apparent that many of the interventions failed to reach a substantial portion of the community, and we speculate that some single strategies included in the combination may lack individual effectiveness. Laički sažetak Intervencije u zajednici za povećanje tjelesne aktivnosti Nedostatna tjelesna aktivnost povezana je s lošijim zdravljem.Redovita tjelesna aktivnost može umanjiti rizik od kroničnih bolesti te poboljšati zdravlje i kvalitetu života pojedinca.Manjak tjelesne aktivnosti čest je problem, a učestalost tog problema se povećava.Cochrane sustavni pregled je analizirao 33 studije koje su istražile programe za povećanje tjelesne aktivnosti u zajednici, u kojima se koristilo više od jednog pristupa.Kad su prvi put pregledani dokazi iz istraživanja koja su bila dostupna 2011. godine, utvrđeno je da nema dovoljno dobrih studija koje bi mogle pokazati je li takav pristup koristan ili ne.Primjerice, neke studije tvrde da programi za povećanje tjelesne aktivnosti u zajednici poboljšavaju tjelesnu aktivnost pojedinaca u zajednici, a druge studije tvrde suprotno.U ovom obnovljenom sustavnom pregledu pronađene su 4 nove studije koje su bile visoke kvalitete, ail nijedna od tih studija nije pokazala da je istraživana intervencija dovela do povećanja tjelesne aktivnosti u zajednici.Neke su studije opisale učinak na način da je opisano da je uočeno da više ljudi u zajednici hoda, međutim, ukupna razina tjelesne aktivnosti u promatranoj populaciji nije se povećala.Ovaj sustavni pregled je utvrdio da je intervencije za povećanje tjelesne aktivnosti u zajednici teško provesti i čini se da one obično ne uspijevaju u svojoj namjeri da na mjerljiv način povećaju tjelesnu aktivnost u populaciji.Čini se da mnoge intervencije nisu uspjele doseći veći broj stanovnika u zajednici pa se može smatrati da neke od strategija uključene u analizirane kombinacije nisu zasebno učinkovite.

Non-market use and non-use values for preserving ecosystem services over time : a choice experiment application to coral reef ecosystems in New Caledonia

Non-use values (i.e. economic values assigned by individuals to ecosystem goods and services unrelated to current or future uses) provide one of the most compelling incentives for the preservation of ecosystems and biodiversity. Assessing the non-use values of non-users is relatively straightforward using stated preference methods, but the standard approaches for estimating non-use values of users (stated decomposition) have substantial shortcomings which undermine the robustness of their results. In this paper, we propose a pragmatic interpretation of non-use values to derive estimates that capture their main dimensions, based on the identification of a willingness to pay for ecosystem protection beyond one's expected life. We empirically test our approach using a choice experiment conducted on coral reef ecosystem protection in two coastal areas in New Caledonia with different institutional, cultural, environmental and socio-economic contexts. We compute individual willingness to pay estimates, and derive individual non-use value estimates using our interpretation. We find that, a minima, estimates of non-use values may comprise between 25 and 40% of the mean willingness to pay for ecosystem preservation, less than has been found in most studies.

Financing the project : economic incentives promoting sustainable property development

This chapter is focussed on the various financial instruments and incentives that have been implemented in a range of countries to encourage sustainable developments in all property sectors. It is an area that has undergone substantial change globally since 2008. Sustainable property development has been impacted by the Global Financial Crisis, particularly with regards to the availability of private sector funding and the requirements of funders who now have a more cautious approach to risk. Sustainability, and sometimes a lack of it, is increasingly viewed as a risk in some markets; it is also seen as an area in which governments, through creation of markets and through the use of fiscal instruments can seek to speed up the pace at which the economics of sustainable development makes good business sense. However, it is not just governments that provide the incentive for sustainability- or the dis-incentive for non-sustainable behaviours.

Empirical evaluation of the travel time reliability indicators: A case study for Brisbane corridor under recurrent and non-recurrent conditions

This research quantifies traffic congestion and travel time reliability with case study on a major arterial road in Brisbane. The focus is on the analysis of impact of incidents (e.g., road accidents) on travel time reliability. Real traffic (Bluetooth) and incident records from Coronation Drive, Brisbane are utilized for the study. The findings include significant impact of incidents on traffic congestion and travel time reliability. The knowledge gained is useful in various applications such as traveler information systems, and cost-benefit analysis of various strategies to reduce the traffic incidents and its' impacts.

Public private partnership infrastructure delivery: Benefits and costs for society

This research provides additional knowledge on the benefits and costs to society, in particular of road transport procured through Public-Private Partnership (PPP) arrangements. Currently, the public sector comparator (PSC) and cost-benefit analysis (CBA) used to evaluate and measure the benefits and costs of PPP are limited in their capacity to predict and forecast long-term events. PPP is attractive to governments due to the non-upfront payment, perceived value for money, and risk allocation and transfer to the private investor. However, public sector remains the guarantor, and under-writer of the private investor's loan from financial institutions and other voluntary risks which are unlimited to future compensatory claims. The new knowledge from this research is the introduction of a framework capable of evaluating, and measuring the associated PPP benefits, as well as the costs, effects, and impacts to society which are protracted and sporadic by nature.

Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer

Background The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. Methods NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Results Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Conclusions Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.

Infrastructure, investment and development evaluation: A Complex Stakeholder Perception Mapping approach for improving local and regional economic development outcomes

Partial evaluation of infrastructure investments have resulted in expensive mistakes, unsatisfactory outcomes and increased uncertainties for too many stakeholders, communities and economies in both developing and developed nations. "Complex Stakeholder Perception Mapping" (CSPM), is a novel approach that can address existing limitations by inclusively framing, capturing and mapping the spectrum of insights and perceptions using extended Geographic Information Systems. Maps generated in CSPM offer presentations of flexibly combined, complex perceptions of stakeholders on multiple aspects of development. CSPM extends the applications of GIS software in non-spatial mapping and of Multi-Criteria Analysis with a multidimensional evaluation platform and augments decision science capabilities in addressing complexities. Application of CSPM can improve local and regional economic gains from infrastructure projects and aid any multi-objective and multi-stakeholder decision situations.

The alchemy of junk: patent law and non-coding DNA

This article considers the recent international controversy over the patents held by a Melbourne firm, Genetic Technologies Limited (GTG), in respect of non-coding DNA and genomic mapping. It explores the ramifications of the GTG dispute in terms of licensing, litigation, and policy reform, and—as a result of this dispute—the perceived conflict between law and science. GTG has embarked upon an ambitious licensing program with twenty seven commercial licensees and five research licensees. Most significantly, GTG has obtained an exclusive licence from Myriad Genetics to use and exploit its medical diagnostics in Australia, New Zealand, and the Asia-Pacific region. In the US, GTG brought a legal action for patent infringement against the Applera Corporation and its subsidiaries. In response, Applera counterclaimed that the patents of GTG were invalid because they failed to comply with the requirements of US patent law, such as novelty, inventive step, and written specifications. In New Zealand, the Auckland District Health Board brought legal action in the High Court, seeking a declaration that the patents of GTG were invalid, and that, in any case, the Board has not infringed them. The New Zealand Ministry of Health and the Ministry of Economic Development have reported to Cabinet on the issues relating to the patenting of genetic material. Similarly, the Australian Law Reform Commission (ALRC) has also engaged in an inquiry into gene patents and human health; and the Advisory Council on Intellectual Property (ACIP) has considered whether there should be a new defence in respect of experimental use and research.

Global business services: Increasing specialization and integration of the world economy as drivers of economic growth

Purpose The purpose of this paper is to explore the contribution of global business services to improved productivity and economic growth of the world economy, which has gone largely unnoticed in service research. Design/methodology/approach The authors draw on macroeconomic data and industry reports, and link them to the non-ownership-concept in service research and theories of the firm. Findings Business services explain a large share of the growth of the global service economy. The fast growth of business services coincides with shifts from domestic production towards global outsourcing of services. A new wave of global business services are traded across borders and have emerged as important drivers of growth in the world’s service sector. Research limitations/implications This paper advances the understanding of non-ownership services in an increasingly global and specialized post-industrial economy. The paper makes a conceptual contribution supported by descriptive data, but without empirical testing. Originality/value The authors integrate the non-ownership concept and three related economic theories of the firm to explain the role of global business services in driving business performance and the international transformation of service economies.

Priority threat management of non-native plants to maintain ecosystem integrity across heterogeneous landscapes

Invasive non-native plants have negatively impacted on biodiversity and ecosystem functions world-wide. Because of the large number of species, their wide distributions and varying degrees of impact, we need a more effective method for prioritizing control strategies for cost-effective investment across heterogeneous landscapes. Here, we develop a prioritization framework that synthesizes scientific data, elicits knowledge from experts and stakeholders to identify control strategies, and appraises the cost-effectiveness of strategies. Our objective was to identify the most cost-effective strategies for reducing the total area dominated by high-impact non-native plants in the Lake Eyre Basin (LEB). We use a case study of the ˜120 million ha Lake Eyre Basin that comprises some of the most distinctive Australian landscapes, including Uluru-Kata Tjuta National Park. More than 240 non-native plant species are recorded in the Lake Eyre Basin, with many predicted to spread, but there are insufficient resources to control all species. Lake Eyre Basin experts identified 12 strategies to control, contain or eradicate non-native species over the next 50 years. The total cost of the proposed Lake Eyre Basin strategies was estimated at AU$1·7 billion, an average of AU$34 million annually. Implementation of these strategies is estimated to reduce non-native plant dominance by 17 million ha – there would be a 32% reduction in the likely area dominated by non-native plants within 50 years if these strategies were implemented. The three most cost-effective strategies were controlling Parkinsonia aculeata, Ziziphus mauritiana and Prosopis spp. These three strategies combined were estimated to cost only 0·01% of total cost of all the strategies, but would provide 20% of the total benefits. Over 50 years, cost-effective spending of AU$2·3 million could eradicate all non-native plant species from the only threatened ecological community within the Lake Eyre Basin, the Great Artesian Basin discharge springs. Synthesis and applications. Our framework, based on a case study of the ˜120 million ha Lake Eyre Basin in Australia, provides a rationale for financially efficient investment in non-native plant management and reveals combinations of strategies that are optimal for different budgets. It also highlights knowledge gaps and incidental findings that could improve effective management of non-native plants, for example addressing the reliability of species distribution data and prevalence of information sharing across states and regions.

Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: Results of a randomised placebo-controlled trial (ABILITY-1)

Purpose: To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Methods: Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index. Results: Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases. Conclusions: In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.