Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

Introducing standardized protocols for anthropological measurement of virtual subadult crania using computed tomography

Objectives This study introduces and assesses the precision of a standardized protocol for anthropometric measurement of the juvenile cranium using three-dimensional surface rendered models, for implementation in forensic investigation or paleodemographic research. Materials and methods A subset of multi-slice computed tomography (MSCT) DICOM datasets (n=10) of modern Australian subadults (birth—10 years) was accessed from the “Skeletal Biology and Forensic Anthropology Virtual Osteological Database” (n>1200), obtained from retrospective clinical scans taken at Brisbane children hospitals (2009–2013). The capabilities of Geomagic Design X™ form the basis of this study; introducing standardized protocols using triangle surface mesh models to (i) ascertain linear dimensions using reference plane networks and (ii) calculate the area of complex regions of interest on the cranium. Results The protocols described in this paper demonstrate high levels of repeatability between five observers of varying anatomical expertise and software experience. Intra- and inter-observer error was indiscernible with total technical error of measurement (TEM) values ≤0.56 mm, constituting <0.33% relative error (rTEM) for linear measurements; and a TEM value of ≤12.89 mm2, equating to <1.18% (rTEM) of the total area of the anterior fontanelle and contiguous sutures. Conclusions Exploiting the advances of MSCT in routine clinical assessment, this paper assesses the application of this virtual approach to acquire highly reproducible morphometric data in a non-invasive manner for human identification and population studies in growth and development. The protocols and precision testing presented are imperative for the advancement of “virtual anthropology” into routine Australian medico-legal death investigation.

Design, implementation and multisite evaluation of a system suitability protocol for the quantitative assessment of instrument performance in liquid chromatography-multiple reaction monitoring-MS (LC-MRM-MS)

Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM-MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LC-SID-MRM-MS platforms for routine use, with pass/fail criteria for system suitability performance measures defined as peak area coefficient of variation <0.15, peak width coefficient of variation <0.15, standard deviation of RT <0.15 min (9 s), and the RT drift <0.5min (30 s). The deleterious effect of a marginally performing LC-SID-MRM-MS system on the limit of quantification (LOQ) in targeted quantitative assays illustrates the use and need for a SSP to establish robust and reliable system performance. Use of a SSP helps to ensure that analyte quantification measurements can be replicated with good precision within and across multiple laboratories and should facilitate more widespread use of MRM-MS technology by the basic biomedical and clinical laboratory research communities.

The primary school as a logic machine

This paper makes a case for thinking about the primary school as a logic machine (apparatus) as a way of thinking about processes of in-school stratification. Firstly we discuss related literature on in-school stratification in primary schools, particularly as it relates to literacy learning. Secondly we explain how school reform can be thought about in terms of the idea of the machine or apparatus. In which case the processes of in-school stratification can be mapped as more than simply concerns about school organisation (such as students grouping) but also involve a politics of truth, played out in each school, that constitutes school culture and what counts as ‘good’ pedagogy. Thirdly, the chapter will focus specifically on research conducted into primary schools in the Northern Suburbs of Adelaide, one of the most educationally disadvantaged regions in Australia, as a case study of the relationship between in-school stratification and the reproduction of inequality. We will draw from more than 20 years of ethnographic work in primary school in the northern suburbs of Adelaide and provide a snapshot of a recent attempt to improve literacy achievement in a few Northern Suburbs public primary schools (SILA project). The SILA project, through diagnostic reviews, has provided a significant analysis of the challenges facing policy and practice in such challenging school contexts that also maps onto existing (inter)national research. These diagnostic reviews said ‘hard things’ that required attention by SILA schools and these included: · an over reliance on whole class, low level, routine tasks and hence a lack of challenge and rigour in the learning tasks offered to students ; · a focus on the 'code breaking' function of language at the expense of richer conceptualisations of literacy that might guide teachers’ understanding of challenging pedagogies ; · the need for substantial shifts in the culture of schools, especially unsettling deficit views of students and their communities ; · a need to provide a more ‘consistent’ approach to teaching literacy across the school; · a need to focus School Improvement Plans in order to implement a clear focus on literacy learning; and, · a need to sustain professional learning to produce new knowledge and practice . The paper will conclude with suggestions for further research and possible reform projects into the primary school as a logic machine.

Vectors and methods for hairpin RNA and artificial microRNA-mediated gene silencing in plants

In plant cells, DICER-LIKE4 processes perfectly double-stranded RNA (dsRNA) into short interfering (si) RNAs, and DICER-LIKE1 generates micro (mi) RNAs from primary miRNA transcripts (pri-miRNA) that form fold-back structures of imperfectly dsRNA. Both si and miRNAs direct the endogenous endonuclease, ARGONAUTE1 to cleave complementary target single-stranded RNAs and either small RNA (sRNA)-directed pathway can be harnessed to silence genes in plants. A routine way of inducing and directing RNA silencing by siRNAs is to express self-complementary single-stranded hairpin RNA (hpRNA), in which the duplexed region has the same sequence as part of the target gene's mRNA. Artificial miRNA (amiRNA)-mediated silencing uses an endogenous pri-miRNA, in which the original miRNA/miRNA* sequence has been replaced with a sequence complementary to the new target gene. In this chapter, we describe the plasmid vector systems routinely used by our research group for the generation of either hpRNA-derived siRNAs or amiRNAs.

Age-related trends in urinary excretion of bisphenol A in Australian children and adults : evidence from a pooled sample study using samples of convenience

Bisphenol A (BPA or 4,4’-(propane-2,2-diyl)diphenol) is a chemical intermediate in the production of polycarbonate and epoxy resins, and used in a wide range of applications. BPA has attracted significant attention in the past decade due to its frequency of detection in human populations worldwide, demonstrated animal toxicity and potential impact on human health, particularly during critical periods of development. The aim of this study was to perform a preliminary assessment of age-related trends in urinary concentration and to estimate daily excretion of BPA in Australian children (aged (>0 – <5 years) and adults (≥15 – <75 years). This was achieved using 79 samples pooled by age and gender, created from 868 individual samples of convenience collected as part of routine, community-based pathology testing. Total BPA was analyzed using online-SPE-LC-MS/MS and detected in all samples with a range of 0.65 – 265 ng/ml. No significant differences were observed between males and females. A urine flow model was constructed from published values and used to provide an estimate of daily excretion per unit bodyweight for each pooled sample. The daily excretion estimates ranged from 26.2 – 18200 ng/kg-d for children; and 20.1 – 165 ng/kg-d for adults. Urinary concentrations and estimated excretion rates were inversely associated with age, and estimated daily excretion rates in infants and young children were significantly higher than in adults (geometric mean: 107 and 47.0 ng/kg-d, respectively). Higher excretion of BPA in children may be explained by their higher food consumption relative to body weight compared to adults and adolescents, and may also reflect alternative exposure pathways and sources. Keywords: bisphenol A, biomonitoring, children, urine flow, Australia

Learning processes in creative service teams : towards a dynamic systems theory

The fastest-growing segment of jobs in the creative sector are in those firms that provide creative services to other sectors (Hearn, Goldsmith, Bridgstock, Rodgers 2014, this volume; Cunningham 2014, this volume). There are also a large number of Creative Services (Architecture and Design, Advertising and Marketing, Software and Digital Content occupations) workers embedded in organizations in other industry sectors (Cunningham and Higgs 2009). Ben Goldsmith (2014, this volume) shows, for example, that the Financial Services sector is the largest employer of digital creative talent in Australia. But why should this be? We argue it is because ‘knowledge-based intangibles are increasingly the source of value creation and hence of sustainable competitive advantage (Mudambi 2008, 186). This value creation occurs primarily at the research and development (R and D) and the marketing ends of the supply chain. Both of these areas require strong creative capabilities in order to design for, and to persuade, consumers. It is no surprise that Jess Rodgers (2014, this volume), in a study of Australia’s Manufacturing sector, found designers and advertising and marketing occupations to be the most numerous creative occupations. Greg Hearn and Ruth Bridgstock (2013, forthcoming) suggest ‘the creative heart of the creative economy […] is the social and organisational routines that manage the generation of cultural novelty, both tacit and codified, internal and external, and [cultural novelty’s] combination with other knowledges […] produce and capture value’. 2 Moreover, the main “social and organisational routine” is usually a team (for example, Grabher 2002; 2004).

Second-order inelastic analysis of composite framed structures based on the refined plastic hinge method

Composite steel-concrete structures experience non-linear effects which arise from both instability-related geometric non-linearity and from material non-linearity in all of their component members. Because of this, conventional design procedures cannot capture the true behaviour of a composite frame throughout its full loading range, and so a procedure to account for those non-linearities is much needed. This paper therefore presents a numerical procedure capable of addressing geometric and material non-linearities at the strength limit state based on the refined plastic hinge method. Different material non-linearity for different composite structural components such as T-beams, concrete-filled tubular (CFT) and steel-encased reinforced concrete (SRC) sections can be treated using a routine numerical procedure for their section properties in this plastic hinge approach. Simple and conservative initial and full yield surfaces for general composite sections are proposed in this paper. The refined plastic hinge approach models springs at the ends of the element which are activated when the surface defining the interaction of bending and axial force at first yield is reached; a transition from the first yield interaction surface to the fully plastic interaction surface is postulated based on a proposed refined spring stiffness, which formulates the load-displacement relation for material non-linearity under the interaction of bending and axial actions. This produces a benign method for a beam-column composite element under general loading cases. Another main feature of this paper is that, for members containing a point of contraflexure, its location is determined with a simple application of the method herein and a node is then located at this position to reproduce the real flexural behaviour and associated material non-linearity of the member. Recourse is made to an updated Lagrangian formulation to consider geometric non-linear behaviour and to develop a non-linear solution strategy. The formulation with the refined plastic hinge approach is efficacious and robust, and so a full frame analysis incorporating geometric and material non-linearity is tractable. By way of contrast, the plastic zone approach possesses the drawback of strain-based procedures which rely on determining plastic zones within a cross-section and which require lengthwise integration. Following development of the theory, its application is illustrated with a number of varied examples.

Learning routines used by firms during construction of infrastructure projects using the alliance procurement method

Collaborative contracting has emerged over the past 15 years as an innovative project delivery framework that is particularly suited to infrastructure projects. Australia leads the world in the development of project and program alliance approaches to collaborative delivery. These approaches are considered to promise superior project results. However, very little is known about the learning routines that are most widely used in support of collaborative projects in general and alliance projects in particular. The literature on absorptive capacity and dynamic capabilities indicates that such learning enhances project performance. The learning routines employed at corporate level during the operation of collaborative infrastructure projects in Australia were examined through a large survey conducted in 2013. This paper presents a descriptive summary of the preliminary findings. The survey captured the experiences of 320 practitioners of collaborative construction projects, including public and private sector clients, contractors, consultants and suppliers (three per cent of projects were located in New Zealand, but for brevity’s sake the sample is referred to as Australian). The majority of projects identified used alliances (78.6%); whilst 9% used Early Contractor Involvement (ECI) contracts and 2.7% used Early Tender Involvement contracts, which are ‘slimmer’ types of collaborative contract. The remaining 9.7% of respondents used traditional contracts that employed some collaborative elements. The majority of projects were delivered for public sector clients (86.3%), and/or clients experienced with asset procurement (89.6%). All of the projects delivered infrastructure assets; one third in the road sector, one third in the water sector, one fifth in the rail sector, and the rest spread across energy, building and mining. Learning routines were explored within three interconnected phases: knowledge exploration, transformation and exploitation. The results show that explorative and exploitative learning routines were applied to a similar extent. Transformative routines were applied to a relatively low extent. It was also found that the most highly applied routine is ‘regularly applying new knowledge to collaborative projects’; and the least popular routine was ‘staff incentives to encourage information sharing about collaborative projects’. Future research planned by the authors will examine the impact of these routines on project performance.

Birth control : to what extent do women report being informed and involved in decisions about pregnancy and birth procedures?

Background: Health policy, guidelines, and standards advocate giving patients comprehensive information and facilitating their involvement in health-related decision-making. Routine assessment of patient reports of these processes is needed. Our objective was to examine decision-making processes, specifically information provision and consumer involvement in decision-making, for nine pregnancy, labour, and birth procedures, as reported by maternity care consumers in Queensland, Australia. Methods: Participants were women who had a live birth in Queensland in a specified time period and were not found to have had a baby that died since birth, who completed the extended Having a Baby in Queensland Survey, 2010 about their maternity care experiences, and who reported at least one of the nine procedures of interest. For each procedure, women answered two questions that measured perceived (i) receipt of information about the benefits and risks of the procedure and (ii) role in decision-making about the procedure. Results: In all, 3,542 eligible women (34.2%) completed the survey. Between 4% (for pre-labour caesarean section) and 60% (for vaginal examination) of women reported not being informed of the benefits and risks of the procedure they experienced. Between 2% (epidural) and 34% (episiotomy) of women reported being unconsulted in decision-making. Over one quarter (26%) of the women who experienced episiotomy reported being neither informed nor consulted. Conclusions: There is an urgent need for interventions that facilitate information provision and consumer involvement in decision-making about several perinatal procedures, especially those performed within the time-limited intrapartum care episode.

Inelastic finite element analysis of composite beams on the basis of the plastic hinge approach

This paper emphasizes material nonlinear effects on composite beams with recourse to the plastic hinge method. Numerous combinations of steel and concrete sections form arbitrary composite sections. Secondly, the material properties of composite beams vary remarkably across its section from ductile steel to brittle concrete. Thirdly, concrete is weak in tension, so composite section changes are dependent on load distribution. To this end, the plastic zone approach is convenient for inelastic analysis of composite sections that can evaluate member resistance, including material nonlinearities, by routine numerical integration with respect to every fiber across the composite section. As a result, many researchers usually adopt the plastic zone approach for numerical inelastic analyses of composite structures. On the other hand, the plastic hinge method describes nonlinear material behaviour of an overall composite section integrally. Consequently, proper section properties for use in plastic hinge spring stiffness are required to represent the material behaviour across the arbitrary whole composite section. In view of numerical efficiency and convergence, the plastic hinge method is superior to the plastic zone method. Therefore, based on the plastic hinge approach, how to incorporate the material nonlinearities of the arbitrary composite section into the plastic hinge stiffness formulation becomes a prime objective of the present paper. The partial shear connection in this paper is by virtue of the effective flexural rigidity as AISC 1993 [American Institute of Steel Construction (AISC). Load and resistance factor design specifications. 2nd ed., Chicago; 1993]. Nonlinear behaviour of different kinds of composite beam is investigated in this paper, including two simply supported composite beams, a cantilever and a two span continuous composite beam.

Factors associated with the isolation of Nontuberculous mycobacteria (NTM) from a large municipal water system in Brisbane, Australia

Background Nontuberculous mycobacteria (NTM) are normal inhabitants of a variety of environmental reservoirs including natural and municipal water. The aim of this study was to document the variety of species of NTM in potable water in Brisbane, QLD, with a specific interest in the main pathogens responsible for disease in this region and to explore factors associated with the isolation of NTM. One-litre water samples were collected from 189 routine collection sites in summer and 195 sites in winter. Samples were split, with half decontaminated with CPC 0.005%, then concentrated by filtration and cultured on 7H11 plates in MGIT tubes (winter only). Results Mycobacteria were grown from 40.21% sites in Summer (76/189) and 82.05% sites in winter (160/195). The winter samples yielded the greatest number and variety of mycobacteria as there was a high degree of subculture overgrowth and contamination in summer. Of those samples that did yield mycobacteria in summer, the variety of species differed from those isolated in winter. The inclusion of liquid media increased the yield for some species of NTM. Species that have been documented to cause disease in humans residing in Brisbane that were also found in water include M. gordonae, M. kansasii, M. abscessus, M. chelonae, M. fortuitum complex, M. intracellulare, M. avium complex, M. flavescens, M. interjectum, M. lentiflavum, M. mucogenicum, M. simiae, M. szulgai, M. terrae. M. kansasii was frequently isolated, but M. avium and M. intracellulare (the main pathogens responsible for disease is QLD) were isolated infrequently. Distance of sampling site from treatment plant in summer was associated with isolation of NTM. Pathogenic NTM (defined as those known to cause disease in QLD) were more likely to be identified from sites with narrower diameter pipes, predominantly distribution sample points, and from sites with asbestos cement or modified PVC pipes. Conclusions NTM responsible for human disease can be found in large urban water distribution systems in Australia. Based on our findings, additional point chlorination, maintenance of more constant pressure gradients in the system, and the utilisation of particular pipe materials should be considered.

Replacement of healthcare-associated MRSA by community-associated MRSA in Queensland : confirmation by genotyping

Objective To describe the changing prevalence of healthcare- and community-associated MRSA. Methods Susceptibility phenotypes of MRSA were observed from 2000 to 2012 using routine susceptibility data. Phenotypic definitions of major clones were validated by genotyping isolates from a nested period prevalence survey in 2011. Results The predominant healthcare-associated (AUS-2/3 like) MRSA phenotype decreased from 42 to 14 isolates per million occasions of service in outpatients (P < 0.0001) and from 650 to 75 isolates per million accrued patient days in inpatients (P 0.0005), while the respective rates of the healthcare-related EMRSA-15 like phenotype increased from 1 to 19 in outpatients (P < 0.0001) and from 11 to 83 in inpatients (P < 0.0001) and those of the community-associated MRSA phenotype increased from 17 to 296 in outpatients (P < 0.0001) and from 71 to 486 in inpatients (P < 0.0001). When compared with single nucleotide polymorphism genotyping the AUS-2/3 like phenotype had a sensitivity and positive predictive value (PPV) for CC239 of 1 and 0.791 respectively, while the EMRSA-15 like phenotype had a sensitivity and PPV for CC22 of 0.903 and 0.774. PVL-positive CA-MRSA, predominantly ST93 and CC30, accounted for 60.8% of MRSA, while PVL-negative CA-MRSA, mainly CC5 and CC1, accounted for 21.4%. Conclusions The initially dominant healthcare-associated MRSA clone has been progressively replaced, mainly by four community-associated lineages.

Implications of comorbidity for clinical practice

In the past, people with comorbidity have often received inadequate care. The ethical principle of equal access to quality services has important implications for agencies, when combined with knowledge about comorbidity and its management, and about diffusion of innovations across organizations. Comorbidity is common, and often has profound impacts on individuals and families. Tobacco smoking in particular is endemic and affects morbidity, mortality, and functioning. This implies that screening for co-occurring problems should be routine, and that a boutique comorbidity service is impractical. Large numbers mean that universal screening and intervention must be capable of large-scale implementation. Since multiple, closely linked problems are often present, treatments should address these multiple issues, and closely interrelated problems will require well-integrated treatment. Involvement of a single health agency is typically needed. Numbers and severity of problems can blind practitioners and patients to strengths and unaffected areas; these should be assessed and fostered. Better policies and practices for co-occurring disorders will require organizational change. Co-occurring disorders must become core business for organizations and practitioners, so that effective comorbidity practice is rewarded, required skills are present or taught, cues to use the practices are provided, and a culture supporting their application is established.