Isotonic designs for phase I trials

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this payer, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs.

Predicting a new phase (T′′) of two-dimensional transition metal di-chalcogenides and strain-controlled topological phase transition

Single layered transition metal dichalcogenides have attracted tremendous research interest due to their structural phase diversities. By using a global optimization approach, we have discovered a new phase of transition metal dichalcogenides (labelled as T′′), which is confirmed to be energetically, dynamically and kinetically stable by our first-principles calculations. The new T′′ MoS2 phase exhibits an intrinsic quantum spin Hall (QSH) effect with a nontrivial gap as large as 0.42 eV, suggesting that a two-dimensional (2D) topological insulator can be achieved at room temperature. Most interestingly, there is a topological phase transition simply driven by a small tensile strain of up to 2%. Furthermore, all the known MX2 (M = Mo or W; X = S, Se or Te) monolayers in the new T′′ phase unambiguously display similar band topologies and strain controlled topological phase transitions. Our findings greatly enrich the 2D families of transition metal dichalcogenides and offer a feasible way to control the electronic states of 2D topological insulators for the fabrication of high-speed spintronics devices.

Queensland pharmacist immunisation pilot phase 1 pharmacist vaccination - Influenza final report

The results of the pilot demonstrated that a pharmacist delivered vaccinations services is feasible in community pharmacy and is safe and effective. The accessibility of the pharmacist across the influenza season provided the opportunity for more people to be vaccinated, particularly those who had never received an influenza vaccine before. Patient satisfaction was extremely high with nearly all patients happy to recommend the service and to return again next year. Factors critical to the success of the service were: 1. Appropriate facilities 2. Competent pharmacists 3. Practice and decision support tools 4. In-­‐store implementation support We demonstrated in the pilot that vaccination recipients preferred a private consultation area. As the level of privacy afforded to the patients increased (private room vs. booth), so did the numbers of patients vaccinated. We would therefore recommend that the minimum standard of a private consultation room or closed-­‐in booth, with adequate space for multiple chairs and a work / consultation table be considered for provision of any vaccination services. The booth or consultation room should be used exclusively for delivering patient services and should not contain other general office equipment, nor be used as storage for stock. The pilot also demonstrated that a pharmacist-­‐specific training program produced competent and confident vaccinators and that this program can be used to retrofit the profession with these skills. As vaccination is within the scope of pharmacist practice as defined by the Pharmacy Board of Australia, there is potential for the universities to train their undergraduates with this skill and provide a pharmacist vaccination workforce in the near future. It is therefore essential to explore appropriate changes to the legislation to facilitate pharmacists’ practice in this area. Given the level of pharmacology and medicines knowledge of pharmacists, combined with their new competency of providing vaccinations through administering injections, it is reasonable to explore additional vaccines that pharmacists could administer in the community setting. At the time of writing, QPIP has already expanded into Phase 2, to explore pharmacists vaccinating for whooping cough and measles. Looking at the international experience of pharmacist delivered vaccination, we would recommend considering expansion to other vaccinations in the future including travel vaccinations, HPV and selected vaccinations to those under the age of 18 years. Overall the results of the QPIP implementation have demonstrated that an appropriately trained pharmacist can deliver safely and effectively influenza vaccinations to adult patients in the community. The QPIP showed the value that the accessibility of pharmacists brings to public health outcomes through improved access to vaccinations and the ability to increase immunisation rates in the general population. Over time with the expansion of pharmacist vaccination services this will help to achieve more effective herd immunity for some of the many diseases which currently have suboptimal immunisation rates.

Phase accumulated carrier pulse width modulation

An alternative approach to digital PWM generation uses an accumulator rather than a counter to generate the carrier. This offers several advantages. The resolution and gain of the pulse width modulator remain constant regardless of the module clock frequency and PWM output frequency. The PWM resolution also becomes fixed at the register width. Even at high PWM frequencies, the resolution remains high when averaged over a number of PWM cycles. An inherent dithering of the PWM waveform introduced over successive cycles blurs the switching spectra without distorting the modulating waveform. The technique also lends itself to easily generating several phase shifted PWM waveforms suitable for multilevel converter modulation. Several example waveforms generated using both simulation and FPGA hardware are presented.

Electronic Building Passport - Final Report: Project 2 National Energy Efficient Building Project Phase 2

The National Energy Efficient Building Project (NEEBP) Phase One report, published in December 2014, investigated “process issues and systemic failures” in the administration of the energy performance requirements in the National Construction Code. It found that most stakeholders believed that under-compliance with these requirements is widespread across Australia, with similar issues being reported in all states and territories. The report found that many different factors were contributing to this outcome and, as a result, many recommendations were offered that together would be expected to remedy the systemic issues reported. To follow up on this Phase 1 report, three additional projects were commissioned as part of Phase 2 of the overall NEEBP project. This Report deals with the development and piloting of an Electronic Building Passport (EBP) tool – a project undertaken jointly by pitt&sherry and a team at the Queensland University of Technology (QUT) led by Dr Wendy Miller. The other Phase 2 projects cover audits of Class 1 buildings and issues relating to building alterations and additions. The passport concept aims to provide all stakeholders with (controlled) access to the key documentation and information that they need to verify the energy performance of buildings. This trial project deals with residential buildings but in principle could apply to any building type. Nine councils were recruited to help develop and test a pilot electronic building passport tool. The participation of these councils – across all states – enabled an assessment of the extent to which these councils are currently utilising documentation; to track the compliance of residential buildings with the energy performance requirements in the National Construction Code (NCC). Overall we found that none of the participating councils are currently compiling all of the energy performance-related documentation that would demonstrate code compliance. The key reasons for this include: a major lack of clarity on precisely what documentation should be collected; cost and budget pressures; low public/stakeholder demand for the documentation; and a pragmatic judgement that non-compliance with any regulated documentation requirements represents a relatively low risk for them. Some councils reported producing documentation, such as certificates of final completion, only on demand, for example. Only three of the nine council participants reported regularly conducting compliance assessments or audits utilising this documentation and/or inspections. Overall we formed the view that documentation and information tracking processes operating within the building standards and compliance system are not working to assure compliance with the Code’s energy performance requirements. In other words the Code, and its implementation under state and territory regulatory processes, is falling short as a ‘quality assurance’ system for consumers. As a result it is likely that the new housing stock is under-performing relative to policy expectations, consuming unnecessary amounts of energy, imposing unnecessarily high energy bills on occupants, and generating unnecessary greenhouse gas emissions. At the same time, Councils noted that the demand for documentation relating to building energy performance was low. All the participant councils in the EBP pilot agreed that documentation and information processes need to work more effectively if the potential regulatory and market drivers towards energy efficient homes are to be harnessed. These findings are fully consistent with the Phase 1 NEEBP report. It was also agreed that an EBP system could potentially play an important role in improving documentation and information processes. However, only one of the participant councils indicated that they might adopt such a system on a voluntary basis. The majority felt that such a system would only be taken up if it were: - A nationally agreed system, imposed as a mandatory requirement under state or national regulation; - Capable of being used by multiple parties including councils, private certifiers, building regulators, builders and energy assessors in particular; and - Fully integrated into their existing document management systems, or at least seamlessly compatible rather than a separate, unlinked tool. Further, we note that the value of an EBP in capturing statistical information relating to the energy performance of buildings would be much greater if an EBP were adopted on a nationally consistent basis. Councils were clear that a key impediment to the take up of an EBP system is that they are facing very considerable budget and staffing challenges. They report that they are often unable to meet all community demands from the resources available to them. Therefore they are unlikely to provide resources to support the roll out of an EBP system on a voluntary basis. Overall, we conclude from this pilot that the public good would be well served if the Australian, state and territory governments continued to develop and implement an Electronic Building Passport system in a cost-efficient and effective manner. This development should occur with detailed input from building regulators, the Australian Building Codes Board (ABCB), councils and private certifiers in the first instance. This report provides a suite of recommendations (Section 7.2) designed to advance the development and guide the implementation of a national EBP system.

Destinations, disasters and public relations: Stakeholder engagement in multi-phase disaster management

Research about disasters in tourism has emerged in earnest since the 1990s covering insights for preparedness and response. However, recently, authors have called for more systematic and holistic approaches to tourism disaster management research. To address this gap, this study adopted a public relations perspective to refocus attention to relationships and stakeholder expectations of destination communities across multiple phases of disaster management. The authors used a mixed method approach and developed a battery of disaster management attributes by conducting interviews and analyzing industry documents and the extant literature. These attributes formed part of a survey of tourism businesses. Exploratory factor analysis resulted in a two factor solution: - i) business disaster preparedness, and; - ii) destination disaster response and recovery. Findings also show that participants reported a gap between the importance and destination performance of these attributes. In particular, tourism businesses perceived destinations did not adequately engage in disaster preparedness activities, which had implications for disaster response and recovery.

Preparation of reticulated MAX-phase support with morphology-controllable nanostructured ceria coating for gas exhaust catalyst devices

Reticulated porous Ti3AlC2 ceramic, a member of the MAX-phase family (Mn+1AXn phases, where M is an early transition metal, A is an A-group element, and X is carbon and/or nitrogen), was prepared from the highly dispersed aqueous suspension by a replica template method. Through a cathodic electrogeneration method, nanocrystalline catalytic CeO2 coatings were deposited on the conductive porous Ti 3AlC2 supports. By adjusting the pH value and cathodic deposition current, coatings exhibiting nanocellar, nanosheets-like, or bubble-free morphologies can be obtained. This work expects to introduce a novel practically feasible material system and a catalytic coating preparation technique for gas exhaust catalyst devices.

Thermal properties of single-phase Y2SiO5

Y2SiO5 is a promising candidate for oxidation-resistant or environmental/thermal barrier coatings (ETBC) due to its excellent high-temperature stability, low elastic modulus and low oxygen permeability. In this paper, we investigated the thermal properties of Y2SiO5 comprehensively, including thermal expansion, thermal diffusivity, heat capacity and thermal conductivity. It is interesting that Y2SiO5 has a very low thermal conductivity (∼1.40 W/m K) but a relatively high linear thermal expansion coefficient ((8.36 ± 0.5) × 10-6 K-1), suggesting compatible thermal and mechanical properties to some non-oxide ceramics and nickel superalloys as ETBC layer. Y2SiO5 is also an ideal EBC on YSZ TBC layer due to their close thermal expansion coefficients. As a continuous source of Y3+, it is predicted that Y2SiO5 EBC may prolong the lifetime of zirconia-based TBC by stopping the degradation aroused by the loss of Y stabilizer.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Dancing into the second phase of creative industries

As we enter the second phase of creative industries there is a shift away from the early 1990s ideology of the arts as a creative content provider for the wealth generating ‘knowledge’ economy to an expanded rhetoric encompassing ‘cultural capital’ and its symbolic value. A renewed focus on culture is examined through a regional scan of creative industries in which social engineering of the arts occurs through policy imperatives driven by ‘profit oriented conceptualisations of culture’ (Hornidge 2011, p. 263) In the push for artists to become ‘culturpreneurs’ a trend has emerged where demand for ‘embedded creatives’ (Cunningham 2013) sees an exodus from arts-based employment through use of transferable skills into areas outside the arts. For those that stay, within the performing arts in particular, employment remains project-based, sporadic, underpaid, self-initiated and often self-financed, requiring adaptive career paths. Artist entrepreneurs must balance creation and performance of their art with increasing amounts of time spent on branding, compliance, fundraising and the logistical and commercial requirements of operating in a CI paradigm. The artists’ key challenge thus becomes one of aligning core creative and aesthetic values with market and business considerations. There is also the perceived threat posed by the ‘prosumer’ phenomenon (Bruns 2008), in which digital on-line products are created and produced by those formerly seen as consumers of art or audiences for art. Despite negative aspects to this scenario, a recent study (Steiner & Schneider 2013) reveals that artists are happier and more satisfied than other workers within and outside the creative industries. A lively hybridisation of creative practice is occurring through mobile and interactive technologies with dynamic connections to social media. Continued growth in arts festivals attracts participation in international and transdisciplinary collaborations, whilst cross-sectoral partnerships provide artists with opportunities beyond a socio-cultural setting into business, health, science and education. This is occurring alongside a renewed engagement with place through the rise of cultural precincts in ‘creative cities’ (Florida 2008, Landry 2000), providing revitalised spaces for artists to gather and work. Finally, a reconsideration of the specialist attributes and transferable skills that artists bring to the creative industries suggests ways to dance through both the challenges and opportunities occasioned by the current complexities of arts’ practices.