Fasting increases serum bilirubin levels in clinically normal, healthy males but not females : a retrospective study from phase I clinical trial participants

Aim: To examine if fasting affects serum bilirubin levels in clinical healthy males and females. Methods: We utilised retrospective data from phase 1 clinical trials where blood was collected in either a fed or fasting state at screening and pre-dosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n = 105) or females (n = 30) aged 18 to 48 inclusive who participated in a phase 1 clinical trial in 2012 or 2013. Results: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared to non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.

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.

Symptom control and quality of life in lux-lung 3 : a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations

Purpose Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. Patients and Methods Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Results Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P lt; .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P lt; .001) and dyspnea (P = .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P = .001), role (P = .004), and cognitive (P lt; .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P = .01). Conclusion In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.

A methodological approach to reporting corrected small field relative outputs

Purpose The goal of this work was to set out a methodology for measuring and reporting small field relative output and to assess the application of published correction factors across a population of linear accelerators. Methods and materials Measurements were made at 6 MV on five Varian iX accelerators using two PTW T60017 unshielded diodes. Relative output readings and profile measurements were made for nominal square field sizes of side 0.5 to 1.0 cm. The actual in-plane (A) and cross-plane (B) field widths were taken to be the FWHM at the 50% isodose level. An effective field size, defined as FSeff=A·B, was calculated and is presented as a field size metric. FSeffFSeff was used to linearly interpolate between published Monte Carlo (MC) calculated kQclin,Qmsrfclin,fmsr values to correct for the diode over-response in small fields. Results The relative output data reported as a function of the nominal field size were different across the accelerator population by up to nearly 10%. However, using the effective field size for reporting showed that the actual output ratios were consistent across the accelerator population to within the experimental uncertainty of ±1.0%. Correcting the measured relative output using kQclin,Qmsrfclin,fmsr at both the nominal and effective field sizes produce output factors that were not identical but differ by much less than the reported experimental and/or MC statistical uncertainties. Conclusions In general, the proposed methodology removes much of the ambiguity in reporting and interpreting small field dosimetric quantities and facilitates a clear dosimetric comparison across a population of linacs

Looking back : students' perceptions of the relative enjoyment of primary and secondary school science

This paper reports and discusses a contentious result from an Australia-wide study of the influences on students' decisions about taking senior science subjects. As part of the Choosing Science study (Lyons and Quinn 2010) 3759 Year 10 students were asked to indicate which stage of their schooling (lower primary, upper primary, lower secondary, middle secondary) they had most enjoyed learning science. Crosstabulations of responses revealed that around 78% of students indicated that they had enjoyed learning science more in secondary than in primary school, and 55% enjoyed it the most during Years 9 and 10. The perception that school science was more enjoyable in high school was also found among students who did not intend taking science in Year 11, though to a lesser extent. These findings are unexpected and significant, challenging the prevailing view that enjoyment of school science steadily declines after primary school. The paper elaborates on the findings and suggests that the different conclusions arrived at by studies in this field may be due to the different methodologies employed.

The Implications of Activity Based Funding for Emergency Departments : A Comprehensive Literature Review

Executive Summary Emergency Departments (EDs) locally, nationally and internationally are becoming increasingly busy. Within this context, it can be challenging to deliver a health service that is safe, of high quality and cost-effective. Whilst various models are described within the literature that aim to measure ED ‘work’ or ‘activity’, they are often not linked to a measure of costs to provide such activity. It is important for hospital and ED managers to understand and apply this link so that optimal staffing and financial resourcing can be justifiably sought. This research is timely given that Australia has moved towards a national Activity Based Funding (ABF) model for ED activity. ABF is believed to increase transparency of care and fairness (i.e. equal work receives equal pay). ABF involves a person-, performance- or activity-based payment system, and thus a move away from historical “block payment” models that do not incentivise efficiency and quality. The aim of the Statewide Workforce and Activity-Based Funding Modelling Project in Queensland Emergency Departments (SWAMPED) is to identify and describe best practice Emergency Department (ED) workforce models within the current context of ED funding that operates under an ABF model. The study is comprised of five distinct phases. This monograph (Phase 1) comprises a systematic review of the literature that was completed in June 2013. The remaining phases include a detailed survey of Queensland hospital EDs’ resource levels, activity and operational models of care, development of new resource models, development of a user-friendly modelling interface for ED mangers, and production of a final report that identifies policy implications. The anticipated deliverable outcome of this research is the development of an ABF based Emergency Workforce Modelling Tool that will enable ED managers to profile both their workforce and operational models of care. Additionally, the tool will assist with the ability to more accurately inform adequate staffing numbers required in the future, inform planning of expected expenditures and be used for standardisation and benchmarking across similar EDs. Summary of the Findings Within the remit of this review of the literature, the main findings include: 1. EDs are becoming busier and more congested Rising demand, barriers to ED throughput and transitions of care all contribute to ED congestion. In addition requests by organisational managers and the community require continued broadening of the scope of services required of the ED and further increases in demand. As the population live longer with more lifestyle diseases their propensity to require ED care continues to grow. 2. Various models of care within EDs exist Models often vary to account for site specific characteritics to suit staffing profile, ED geographical location (e.g. metropolitan or rural site), and patient demographic profile (e.g. paediatrics, older persons, ethnicity). Existing and new models implemented within EDs often depend on the target outcome requiring change. Generally this is focussed on addressing issues at the input, throughput or output areas of the ED. Even with models targeting similar demographic or illness, the structure and process elements underpinning the model can vary, which can impact on outcomes and variance to the patient and carer experience between and within EDs. Major models of care to manage throughput inefficiencies include: A. Workforce Models of Care focus on the appropriate level of staffing for a given workload to provide prompt, timely and clinically effective patient care within an emergency care setting. The studies reviewed suggest that the early involvement of senior medical decision maker and/or specialised nursing roles such as Emergency Nurse Practitioners and Clinical Initiatives Nurse, primary contact or extended scope Allied Health Practitioners can facilitate patient flow and improve key indicators such as length of stay and reducing the number of those who did not wait to be seen amongst others. B. Operational Models of Care within EDs focus on mechanisms for streaming (e.g. fast-tracking) or otherwise grouping patient care based on acuity and complexity to assist with minimising any throughput inefficiencies. While studies support the positive impact of these models in general, it appears that they are most effective when they are adequately resourced. 3. Various methods of measuring ED activity exist Measuring ED activity requires careful consideration of models of care and staffing profile. Measuring activity requires the ability to account for factors including: patient census, acuity, LOS, intensity of intervention, department skill-mix plus an adjustment for non-patient care time. 4. Gaps in the literature Continued ED growth calls for new and innovative care delivery models that are safe, clinically effective and cost effective. New roles and stand-alone service delivery models are often evaluated in isolation without considering the global and economic impact on staffing profiles. Whilst various models of accounting for and measuring health care activity exist, costing studies and cost effectiveness studies are lacking for EDs making accurate and reliable assessments of care models difficult. There is a necessity to further understand, refine and account for measures of ED complexity that define a workload upon which resources and appropriate staffing determinations can be made into the future. There is also a need for continued monitoring and comprehensive evaluation of newly implemented workforce modelling tools. This research acknowledges those gaps and aims to: • Undertake a comprehensive and integrated whole of department workforce profiling exercise relative to resources in the context of ABF. • Inform workforce requirements based on traditional quantitative markers (e.g. volume and acuity) combined with qualitative elements of ED models of care; • Develop a comprehensive and validated workforce calculation tool that can be used to better inform or at least guide workforce requirements in a more transparent manner.

Understanding the pre-internationalization phase decision heuristic of Australian SMEs

Since the 1970s, the Uppsala stages model has been one of the dominant explanations of firm internationalization. The model's focus on internationalization as a firm's gradual and incremental process of increasing international involvement has attracted much debate, with one criticism being that it is unclear in explaining how the internationalization process first originates within a firm. In this paper, the Uppsala model is extended through the incorporation of a pre-internationalization phase to explore the antecedents of firm internationalization. Adopting the Uppsala model's theoretical underpinnings, this paper develops and operationalizes a pre-internationalization phase decision heuristic in the form of an ‘export readiness index'. Four constructs are proposed that drive and inhibit export commencement decision-making during a firm's preinternationalization phase: export stimuli, attitudinal/psychological commitment, resources and lateral rigidity. Through a survey of Australian exporting and non-exporting small-medium sized enterprises (SMEs), the Export Readiness Index (ERI) is developed through factor analysis and tested using logistic regression. Results of the study and their potential implications are discussed.

A phase-locked-loop design for the smooth operation of a hybrid microgrid

A microgrid contains both distributed generators (DGs) and loads and can be viewed by a controllable load by utilities. The DGs can be either inertial synchronous generators or non-inertial converter interfaced. Moreover, some of them can come online or go offline in plug and play fashion. The combination of these various types of operation makes the microgrid control a challenging task, especially when the microgrid operates in an autonomous mode. In this paper, a new phase locked loop (PLL) algorithm is proposed for smooth synchronization of plug and play DGs. A frequency droop for power sharing is used and a pseudo inertia has been introduced to non-inertial DGs in order to match their response with inertial DGs. The proposed strategy is validated through PSCAD simulation studies.

Smart Inter-Phase Switching of Residential Loads in Low Voltage Distribution Feeders

In order to dynamically reduce voltage unbalance along a low voltage distribution feeder, a smart residential load transfer system is discussed. In this scheme, residential loads can be transferred from one phase to another to minimize the voltage unbalance along the feeder. Each house is supplied through a static transfer switch and a controller. The master controller, installed at the transformer, observes the power consumption in each house and will determine which house(s) should be transferred from an initially connected phase to another in order to keep the voltage unbalance minimum. The performance of the smart load transfer scheme is demonstrated by simulations.

UV Photodissociation Action Spectroscopy of Haloanilinium Ions in a Linear Quadrupole Ion Trap Mass Spectrometer

UV-vis photodissociation action spectroscopy is becoming increasingly prevalent because of advances in, and commercial availability of, ion trapping technologies and tunable laser sources. This study outlines in detail an instrumental arrangement, combining a commercial ion-trap mass spectrometer and tunable nanosecond pulsed laser source, for performing fully automated photodissociation action spectroscopy on gas-phase ions. The components of the instrumentation are outlined, including the optical and electronic interfacing, in addition to the control software for automating the experiment and performing online analysis of the spectra. To demonstrate the utility of this ensemble, the photodissociation action spectra of 4-chloroanilinium, 4-bromoanilinium, and 4-iodoanilinium cations are presented and discussed. Multiple photoproducts are detected in each case and the photoproduct yields are followed as a function of laser wavelength. It is shown that the wavelength-dependent partitioning of the halide loss, H loss, and NH3 loss channels can be broadly rationalized in terms of the relative carbon-halide bond dissociation energies and processes of energy redistribution. The photodissociation action spectrum of (phenyl)Ag-2 (+) is compared with a literature spectrum as a further benchmark.

Ultraviolet action spectroscopy of iodine labeled peptides and proteins in the gas phase

Structural investigations of large biomolecules in the gas phase are challenging. Herein, it is reported that action spectroscopy taking advantage of facile carbon-iodine bond dissociation can be used to examine the structures of large molecules, including whole proteins. Iodotyrosine serves as the active chromophore, which yields distinctive spectra depending on the solvation of the side chain by the remainder of the molecule. Isolation of the chromophore yields a double featured peak at ∼290 nm, which becomes a single peak with increasing solvation. Deprotonation of the side chain also leads to reduced apparent intensity and broadening of the action spectrum. The method can be successfully applied to both negatively and positively charged ions in various charge states, although electron detachment becomes a competitive channel for multiply charged anions. In all other cases, loss of iodine is by far the dominant channel which leads to high sensitivity and simple data analysis. The action spectra for iodotyrosine, the iodinated peptides KGYDAKA, DAYLDAG, and the small protein ubiquitin are reported in various charge states. © 2012 American Chemical Society.

Direct Observation of Photodissociation Products from Phenylperoxyl Radicals Isolated in the Gas Phase

Gas phase peroxyl radicals are central to our chemical understanding of combustion and atmospheric processes and are typically characterized by strong absorption in the UV (lambda(max) approximate to 240 nm). The analogous maximum absorption feature for arylperoxyl radicals is predicted to shift to the visible but has not previously been characterized nor have any photoproducts arising from this transition been identified. Here we describe the controlled synthesis and isolation in vacuo of an array of charge-substituted phenylperoxyl radicals at room temperature, including the 4-(N,N,N-trimethylammonium)methyl phenylperoxyl radical cation (4-Me3N[+]CH2-C6H4OO center dot), using linear ion-trap mass spectrometry. Photodissociation mass spectra obtained at wavelengths ranging from 310 to 500 nm reveal two major photoproduct channels corresponding to homolysis of aryl-OO and arylO-O bonds resulting in loss of O-2 and O, respectively. Combining the photodissociation yields across this spectral window produces a broad (FWHM approximate to 60 nm) but clearly resolved feature centered at lambda(max) = 403 nm (3.08 eV). The influence of the charge-tag identity and its proximity to the radical site are investigated and demonstrate no effect on the identity of the two dominant photoproduct channels. Electronic structure calculations have located the vertical (B) over tilde <- (X) over tilde transition of these substituted phenylperoxyl radicals within the experimental uncertainty and further predict the analogous transition for unsubstituted phenylperoxyl radical (C6H5OO center dot) to be 457 nm (2.71 eV), nearly 45 nm shorter than previous estimates and in good agreement with recent computational values.

Ozone-induced dissociation of conjugated lipids reveals significant reaction rate enhancements and characteristic odd-electron product ions

Ozone-induced dissociation (OzID) is an alternative ion activation method that relies on the gas phase ion-molecule reaction between a mass-selected target ion and ozone in an ion trap mass spectrometer. Herein, we evaluated the performance of OzID for both the structural elucidation and selective detection of conjugated carbon-carbon double bond motifs within lipids. The relative reactivity trends for \[M + X](+) ions (where X = Li, Na, K) formed via electrospray ionization (ESI) of conjugated versus nonconjugated fatty acid methyl esters (FAMEs) were examined using two different OzID-enabled linear ion-trap mass spectrometers. Compared with nonconjugated analogues, FAMEs derived from conjugated linoleic acids were found to react up to 200 times faster and to yield characteristic radical cations. The significantly enhanced reactivity of conjugated isomers means that OzID product ions can be observed without invoking a reaction delay in the experimental sequence (i.e., trapping of ions in the presence of ozone is not required). This possibility has been exploited to undertake neutral-loss scans on a triple quadrupole mass spectrometer targeting characteristic OzID transitions. Such analyses reveal the presence of conjugated double bonds in lipids extracted from selected foodstuffs. Finally, by benchmarking of the absolute ozone concentration inside the ion trap, second order rate constants for the gas phase reactions between unsaturated organic ions and ozone were obtained. These results demonstrate a significant influence of the adducting metal on reaction rate constants in the fashion Li > Na > K.

Structural characterization of glycerophospholipids by combinations of ozone- and collision-induced dissociation mass spectrometry: The next step towards "top-down" lipidomics

The complete structural elucidation of complex lipids, including glycerophospholipids, using only mass spectrometry represents a major challenge to contemporary analytical technologies. Here, we demonstrate that product ions arising from the collision-induced dissociation (CID) of the [M + Na] + adduct ions of phospholipids can be isolated and subjected to subsequent gas-phase ozonolysis-known as ozone-induced dissociation (OzID)-in a linear ion-trap mass spectrometer. The resulting CID/OzID experiment yields abundant product ions that are characteristic of the acyl substitution on the glycerol backbone (i.e., sn-position). This approach is shown to differentiate sn-positional isomers, such as the regioisomeric phosphatidylcholine pair of PC 16:0/18:1 and PC 18:1/16:0. Importantly, CID/OzID provides a sensitive diagnostic for the existence of an isomeric mixture in a given sample. This is of very high value for the analysis of tissue extracts since CID/OzID analyses can reveal changes in the relative abundance of isomeric constituents even within different tissues from the same animal. Finally, we demonstrate the ability to assign carbon-carbon double bond positions to individual acyl chains at specific backbone positions by adding subsequent CID and/or OzID steps to the workflow and that this can be achieved in a single step using a hybrid triple quadrupole-linear ion trap mass spectrometer. This unique approach represents the most complete and specific structural analysis of lipids by mass spectrometry demonstrated to date and is a significant step towards comprehensive top-down lipidomics. This journal is © The Royal Society of Chemistry 2014. Grant Number ARC/DP0986628, ARC/FT110100249, ARC/LP110200648

Direct Detection of a Persistent Carbonyloxyl Radical in the Gas Phase

Long lived: Carbonyloxyl radicals (RCO2 .) are reactive intermediates that play key roles in initiating polymerization reactions. This reactivity also makes their direct observation difficult. For the first time a persistent organic RCO2 . radical is detected in the gas phase, its extraordinary longevity is attributed to the high barrier towards fragmentation owing to the endothermicity of the decarboxylation products. Grant Numbers ARC/DP0986738, ARC/DP120102922, ARC/DE120100467