Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Divergent outcomes following transcytosis of IgG targeting intracellular and extracellular chlamydial antigens

Antibodies can play a protective but non-essential role in natural chlamydial infections dependent on antigen specificity and antibody isotype. IgG is the dominant antibody in both male and female reproductive tract mucosal secretions, and is bi-directionally trafficked across epithelia by the neonatal Fc receptor (FcRn). Using physiologically relevant pH-polarized epididymal epithelia grown on Transwells®, IgG specifically targeting an extracellular chlamydial antigen; the Major Outer Membrane Protein (MOMP), enhanced uptake and translocation of infection at pH 6-6.5 but not at neutral pH. This was dependent on FcRn expression. Conversely, FcRn-mediated transport of IgG targeting the intracellular chlamydial inclusion membrane protein A (IncA), induced aberrant inclusion morphology, recruited autophagic proteins independent of lysosomes, and significantly reduced infection. Challenge of female mice with MOMP-specific IgG-opsonized C. muridarum delayed infection clearance but exacerbated oviduct occlusion. In male mice, MOMP-IgG elicited by immunization afforded no protection against testicular chlamydial infection, whereas; the transcytosis of IncA-IgG significantly reduced testicular chlamydial burden. Together these data show that the protective and pathological effects of IgG are dependent on FcRn-mediated transport as well as the specificity of IgG for intracellular or extracellular antigens.

Linking dynamic-capability portfolios and innovation outcomes

The objective of this paper is to explore the relationship between dynamic capabilities and different types of online innovations. Building on qualitative data from the publishing industry, our analysis revealed that companies that had relatively strong dynamic capabilities in all three areas (sensing, seizing and reconfiguration) seem to produce innovations that combine their existing capabilities on either the market or the technology dimension with new capabilities on the other dimension thus resulting in niche creation and revolutionary type innovations. Correspondingly, companies with a weaker or more one-sided set of dynamic capabilities seem to produce more radical innovations requiring both new market and technological capabilities. The study therefore provides an empirical contribution to the emerging work on dynamic capabilities through its in-depth investigation of the capabilities of the four case firms, and by mapping the patterns between the firm's portfolio of dynamic capabilities and innovation outcomes.

A randomized controlled trial of self-management programme improves health-related outcomes of older people with heart failure

Aims This paper is a report on the effectiveness of a self-management programme based on the self-efficacy construct, in older people with heart failure. Background Heart failure is a major health problem worldwide, with high mortality and morbidity, making it a leading cause of hospitalization. Heart failure is associated with a complex set of symptoms that arise from problems in fluid and sodium retention. Hence, managing salt and fluid intake is important and can be enhanced by improving patients' self-efficacy in changing their behaviour. Design Randomized controlled trial. Methods Heart failure patients attending cardiac clinics in northern Taiwan from October 2006–May 2007 were randomly assigned to two groups: control (n = 46) and intervention (n = 47). The intervention group received a 12-week self-management programme that emphasized self-monitoring of salt/fluid intake and heart failure-related symptoms. Data were collected at baseline as well as 4 and 12 weeks later. Data analysis to test the hypotheses used repeated-measures anova models. Results Participants who received the intervention programme had significantly better self-efficacy for salt and fluid control, self-management behaviour and their heart failure-related symptoms were significantly lower than participants in the control group. However, the two groups did not differ significantly in health service use. Conclusion The self-management programme improved self-efficacy for salt and fluid control, self-management behaviours, and decreased heart failure-related symptoms in older Taiwanese outpatients with heart failure. Nursing interventions to improve health-related outcomes for patients with heart failure should emphasize self-efficacy in the self-management of their disease.

Engraftment outcomes after HPC co-culture with mesenchymal stromal cells and osteoblasts

Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage− Sca-1+ c-kit+ (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice.

A preliminary study into the environmental and economic consequences of a sugar factory depithing operation

Bagasse stockpile operations have the potential to lead to adverse environmental and social impacts. Dust releases can cause occupational health and safety concerns for factory workers and dust emissions impact on the surrounding community. Preliminary modelling showed that bagasse depithing would likely reduce the environmental risks, particularly dust emissions, associated with large-scale bagasse stockpiling operations. Dust emission properties were measured and used for dispersion modelling with favourable outcomes. Modelling showed a 70% reduction in peak ground level concentrations of PM10 dust (particles with an aerodynamic diameter less than 10 μm) from operations on depithed bagasse stockpiles compared to similar operations on stockpiles of whole bagasse. However, the costs of a depithing operation at a sugar factory were estimated to be approximately $2.1 million in capital expenditure to process 100 000 t/y of bagasse and operating costs were 200 000 p.a. The total capital cost for a 10 000 t/y operation was approximately $1.6 million. The cost of depithing based on a discounted cash flow analysis was $5.50 per tonne of bagasse for the 100 000 t/y scenario. This may make depithing prohibitively expensive in many situations if installed exclusively as a dust control measure.

Successful outcomes in vocational education and training courses and mathematics: how pedagogy and expectations influence achievement

This paper reports on a four year Australian Research Council funded Linkage Project titled Skilling Indigenous Queensland, conducted in regional areas of Queensland, Australia from 2009 to 2013. The project sought to investigate Vocational Education and Training (VET) and teaching, Indigenous learners’ needs, employer culture and expectations and community culture and expectations to identify best practice in numeracy teaching for Indigenous VET learners. Specifically it focused on ways to enhance the teaching and learning of courses and the associated mathematics in such courses to benefit learners and increase their future opportunities of employment. To date thirty - nine teachers/trainers/teacher aides and two hundred and thirty - one students consented to participate in the project. Nine VET courses offered in schools and Technical and Further Education Institutes (TAFE) were nominated to be the focus on the study. This paper focuses on student questionnaire responses and interview responses from teachers/trainers one high school principal and five students as a result of these processes, the findings indicated that VET course teachers work hard to adopt contextualising strategies to their teaching; however this process is not always straight forward because of the perceptions of how mathematics has been taught and learned by trainers and teachers. Further teachers, trainers and students have high expectations of one another with the view to successful outcomes from the courses.

Evolving a design driven ‘hybrid’ research approach to inform and advance sustainable outcomes in the built environment sector

A significant reduction in global greenhouse gas (GHG) emissions is a priority, and the preservation of existing building stock presents a significant opportunity to reduce the carbon footprint of our built environment. Within this ‘wicked’ problem context, and moving beyond the ad hoc and incremental performance improvements that have been made to date, collaborative and multidisciplinary efforts are required to find rapid and transformational solutions. Design has emerged as a strategic and redirective practice, and lessons can therefore be learned about transformation and potentially applied in the built environment. The purpose of this paper is to discuss a pragmatic and novel research approach for undertaking such applied design driven research. This paper begins with a discussion of key contributions from design science (rational) and action research (reflective) philosophies in creating an emerging methodological ‘hybrid design approach’. This research approach is then discussed in relation to its application to specific research exploring the processes, methods and lessons from design in heritage building retrofit projects. Drawing on both industry and academic knowledge to ensure relevance and rigour, it is anticipated that the hybrid design approach will be useful for others tackling such complex wicked problems that require context-specific solutions.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Improving construction management : an investigation into the influences of effective stakeholder involvement on project quality outcomes

This research has developed a framework to improve the effectiveness and efficiency of stakeholder involvement during the early planning stages of residential construction projects, in order to improve many of the quality issues that occur during the construction phases of such projects. A mixed methods approach (survey, interviews and case studies) was employed to collect the required data. It is expected that with development, this framework can bring some significant benefits to future construction projects in terms of reducing rework and wastage, improving timely delivery and avoiding disputes. The research is also anticipated to produce three high impact journal articles.

Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults

BACKGROUND Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Interventions for asthma therapies have been traditionally based on symptoms and spirometry. OBJECTIVES To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was on 31 October 2006. SELECTION CRITERIA All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS Results of searches were reviewed against pre-determined criteria for inclusion. Three sets of reviewers selected relevant studies.Two review authors independently assessed trial quality extracted data. Authors were contacted for further information but none were received. Data was analysed as "treatment received" and sensitivity analyses performed. MAIN RESULTS Three adult studies were included; these studies were clinically and methodologically heterogenous (use of medications, cut off for percentage of sputum eosinophils and definition of asthma exacerbation). There were no eligible paediatric studies. Of 246 participants randomised, 221 completed the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms; pooled odds ratio (OR) was 0.49 (95% CI 0.28 to 0.87); number needed to treat to benefit (NNTB) was 6 (95% CI 4 to 32).There were also differences between groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids but the reduction in hospitalisations was not statistically significant. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was similar in both groups and no adverse events were reported. However sputum induction was not always possible. AUTHORS' CONCLUSIONS Tailored asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. This review supports the use of sputum eosinophils to tailor asthma therapy for adults with frequent exacerbations and severe asthma. Further studies need to be undertaken to strengthen these results and no conclusion can be drawn for children with asthma.

Self-regulation from birth to age seven : associations with maternal mental health, parenting, and social, emotional and behavioural outcomes for children

Self-regulation refers to our individual capacities to regulate our behaviours, emotions, and thoughts, with these skills developing rapidly across early childhood. This thesis examined sleep, emotional, and cognitive regulation development, and related parental influences, for children participating in the Longitudinal Study of Australian Children. Important longitudinal associations among children's self-regulation, maternal mental health, parenting, and later behaviour problems for children were also investigated. A unique contribution of this research was a prevalence estimate of early childhood self-regulation problems in Australian children that was documented for the first time.

Comparing different approach and avoidance models of learning and personality in the prediction of work, university, and leadership outcomes

Jackson (2005) developed a hybrid model of personality and learning, known as the learning styles profiler (LSP) which was designed to span biological, socio-cognitive, and experiential research foci of personality and learning research. The hybrid model argues that functional and dysfunctional learning outcomes can be best understood in terms of how cognitions and experiences control, discipline, and re-express the biologically based scale of sensation-seeking. In two studies with part-time workers undertaking tertiary education (N equals 137 and 58), established models of approach and avoidance from each of the three different research foci were compared with Jackson's hybrid model in their predictiveness of leadership, work, and university outcomes using self-report and supervisor ratings. Results showed that the hybrid model was generally optimal and, as hypothesized, that goal orientation was a mediator of sensation-seeking on outcomes (work performance, university performance, leader behaviours, and counterproductive work behaviour). Our studies suggest that the hybrid model has considerable promise as a predictor of work and educational outcomes as well as dysfunctional outcomes.

The effects of transformational leadership behaviors on follower outcomes : an identity-based analysis

The aim of this study was to explore two of the mechanisms by which transformational leaders have a positive influence on followers. It examined the mediating role of follower’s leader and group identification on the associations among different transformational leader behaviours and follower job satisfaction and supervisor-rated job performance. One hundred and seventy-nine healthcare employees and 44 supervisors participated in the study. The results from multilevel structural equation modelling provided results that partially supported the predicted model. Identification with the leader significantly mediated the positive associations between supportive leadership, intellectual stimulation, personal recognition, in the prediction of job satisfaction and job performance. Leader identification also mediated the relationship between supportive leadership, intellectual stimulation, personal recognition, and group identification. However, group identification did not mediate the associations between vision leadership and inspirational communication, in the prediction of job satisfaction and job performance. The results highlight the role of individualized forms of leadership and leader identification in enhancing follower outcomes.